Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods
Identifieur interne : 000A96 ( Pmc/Corpus ); précédent : 000A95; suivant : 000A97Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods
Auteurs : Nasir Javaid ; Farzana Yasmeen ; Sangdun ChoiSource :
- Pharmaceutics [ 1999-4923 ] ; 2019.
Abstract
The built-in innate immunity in the human body combats various diseases and their causative agents. One of the components of this system is Toll-like receptors (TLRs), which recognize structurally conserved molecules derived from microbes and/or endogenous molecules. Nonetheless, under certain conditions, these TLRs become hypofunctional or hyperfunctional, thus leading to a disease-like condition because their normal activity is compromised. In this regard, various small-molecule drugs and recombinant therapeutic proteins have been developed to treat the relevant diseases, such as rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, systemic lupus erythematosus, and allergy. Some drugs for these diseases have been clinically approved; however, their efficacy can be enhanced by conventional or targeted drug delivery systems. Certain delivery vehicles such as liposomes, hydrogels, nanoparticles, dendrimers, or cyclodextrins can be employed to enhance the targeted drug delivery. This review summarizes the TLR signaling pathway, associated diseases and their treatments, and the ways to efficiently deliver the drugs to a target site.
Url:
DOI: 10.3390/pharmaceutics11090441
PubMed: 31480568
PubMed Central: 6781272
Links to Exploration step
PMC:6781272Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods</title><author><name sortKey="Javaid, Nasir" sort="Javaid, Nasir" uniqKey="Javaid N" first="Nasir" last="Javaid">Nasir Javaid</name></author><author><name sortKey="Yasmeen, Farzana" sort="Yasmeen, Farzana" uniqKey="Yasmeen F" first="Farzana" last="Yasmeen">Farzana Yasmeen</name></author><author><name sortKey="Choi, Sangdun" sort="Choi, Sangdun" uniqKey="Choi S" first="Sangdun" last="Choi">Sangdun Choi</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31480568</idno><idno type="pmc">6781272</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781272</idno><idno type="RBID">PMC:6781272</idno><idno type="doi">10.3390/pharmaceutics11090441</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000A96</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A96</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods</title><author><name sortKey="Javaid, Nasir" sort="Javaid, Nasir" uniqKey="Javaid N" first="Nasir" last="Javaid">Nasir Javaid</name></author><author><name sortKey="Yasmeen, Farzana" sort="Yasmeen, Farzana" uniqKey="Yasmeen F" first="Farzana" last="Yasmeen">Farzana Yasmeen</name></author><author><name sortKey="Choi, Sangdun" sort="Choi, Sangdun" uniqKey="Choi S" first="Sangdun" last="Choi">Sangdun Choi</name></author></analytic><series><title level="j">Pharmaceutics</title><idno type="eISSN">1999-4923</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The built-in innate immunity in the human body combats various diseases and their causative agents. One of the components of this system is Toll-like receptors (TLRs), which recognize structurally conserved molecules derived from microbes and/or endogenous molecules. Nonetheless, under certain conditions, these TLRs become hypofunctional or hyperfunctional, thus leading to a disease-like condition because their normal activity is compromised. In this regard, various small-molecule drugs and recombinant therapeutic proteins have been developed to treat the relevant diseases, such as rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, systemic lupus erythematosus, and allergy. Some drugs for these diseases have been clinically approved; however, their efficacy can be enhanced by conventional or targeted drug delivery systems. Certain delivery vehicles such as liposomes, hydrogels, nanoparticles, dendrimers, or cyclodextrins can be employed to enhance the targeted drug delivery. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Pharmaceutics</journal-id><journal-id journal-id-type="iso-abbrev">Pharmaceutics</journal-id><journal-id journal-id-type="publisher-id">pharmaceutics</journal-id><journal-title-group><journal-title>Pharmaceutics</journal-title></journal-title-group><issn pub-type="epub">1999-4923</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31480568</article-id><article-id pub-id-type="pmc">6781272</article-id><article-id pub-id-type="doi">10.3390/pharmaceutics11090441</article-id><article-id pub-id-type="publisher-id">pharmaceutics-11-00441</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Javaid</surname><given-names>Nasir</given-names></name></contrib><contrib contrib-type="author"><name><surname>Yasmeen</surname><given-names>Farzana</given-names></name></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-5920-7848</contrib-id><name><surname>Choi</surname><given-names>Sangdun</given-names></name><xref rid="c1-pharmaceutics-11-00441" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-pharmaceutics-11-00441">Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea</aff><author-notes><corresp id="c1-pharmaceutics-11-00441"><label>*</label>Correspondence: <email>sangdunchoi@ajou.ac.kr</email>; Tel.: +82-31-219-2600</corresp></author-notes><pub-date pub-type="epub"><day>01</day><month>9</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>9</month><year>2019</year></pub-date><volume>11</volume><issue>9</issue><elocation-id>441</elocation-id><history><date date-type="received"><day>09</day><month>7</month><year>2019</year></date><date date-type="accepted"><day>28</day><month>8</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>The built-in innate immunity in the human body combats various diseases and their causative agents. One of the components of this system is Toll-like receptors (TLRs), which recognize structurally conserved molecules derived from microbes and/or endogenous molecules. Nonetheless, under certain conditions, these TLRs become hypofunctional or hyperfunctional, thus leading to a disease-like condition because their normal activity is compromised. In this regard, various small-molecule drugs and recombinant therapeutic proteins have been developed to treat the relevant diseases, such as rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, systemic lupus erythematosus, and allergy. Some drugs for these diseases have been clinically approved; however, their efficacy can be enhanced by conventional or targeted drug delivery systems. Certain delivery vehicles such as liposomes, hydrogels, nanoparticles, dendrimers, or cyclodextrins can be employed to enhance the targeted drug delivery. This review summarizes the TLR signaling pathway, associated diseases and their treatments, and the ways to efficiently deliver the drugs to a target site.</p></abstract><kwd-group><kwd>Toll-like receptor</kwd><kwd>immunological disease</kwd><kwd>therapeutic</kwd><kwd>drug delivery method</kwd></kwd-group></article-meta></front><body><sec sec-type="intro" id="sec1-pharmaceutics-11-00441"><title>1. Introduction</title><p>The immune system in an organism is the protective system combating pathogenic and/or abnormal conditions. Innate and adaptive immune systems are two basic components in vertebrates. Adaptive immunity is mediated by T and B lymphocytes with the help of their antigen-specific receptors that are encoded as a result of hypermutability and rearrangements in a genomic region of the organism. Nevertheless, evolutionarily conserved innate immunity is considered the first line of defense against invading pathogens [<xref rid="B1-pharmaceutics-11-00441" ref-type="bibr">1</xref>]. For a long time, innate immunity has been regarded as a nonspecific response accomplished by phagocytes such as neutrophils and macrophages. On the other hand, pioneering studies on the loss-of-function mutations in <italic>Drosophila melanogaster</italic> and mice highlighted the molecular mechanisms for recognition of the pathogens and activation of the immune response [<xref rid="B2-pharmaceutics-11-00441" ref-type="bibr">2</xref>,<xref rid="B3-pharmaceutics-11-00441" ref-type="bibr">3</xref>,<xref rid="B4-pharmaceutics-11-00441" ref-type="bibr">4</xref>]. Innate-immunity cells such as dendritic cells (DCs), macrophages, and neutrophils respond to invading pathogens by recognizing their associated markers, known as pathogen-associated molecular patterns (PAMPs). These PAMPs are specifically recognized by relevant cognate receptors known as pattern recognition receptors (PRRs). There are two main categories of theses PRRs: membrane-bound and cytoplasmic. The membrane-bound PRRs include Toll-like receptors (TLRs) and C-type lectin receptors. Cytoplasmic PRRs include NOD-like receptors and RIG-I-like receptors.</p><p>The very first human biological therapeutic obtained from gene manipulation was human insulin (Humulin<sup>®</sup>) generated by Eli Lilly at Genentech and approved in 1982 by the US Food and Drug Administration (FDA) [<xref rid="B5-pharmaceutics-11-00441" ref-type="bibr">5</xref>]. The application of peptides as therapeutic agents has gradually gained popularity and expanded with innovation in drug improvement and treatment archetypes [<xref rid="B6-pharmaceutics-11-00441" ref-type="bibr">6</xref>]. There has been growing interest in the development of targeted therapeutic drugs in the last three to four decades, which encouraged the progress in monoclonal antibodies, especially for the treatment of cancer and immunological diseases [<xref rid="B7-pharmaceutics-11-00441" ref-type="bibr">7</xref>]. Nowadays, fruitful results are obtained in clinical trials on different diseases including Parkinson’s disease [<xref rid="B8-pharmaceutics-11-00441" ref-type="bibr">8</xref>], Leber’s amaurosis [<xref rid="B9-pharmaceutics-11-00441" ref-type="bibr">9</xref>], hemophilia B [<xref rid="B10-pharmaceutics-11-00441" ref-type="bibr">10</xref>], thalassemia [<xref rid="B11-pharmaceutics-11-00441" ref-type="bibr">11</xref>], hereditary immunodeficiency diseases [<xref rid="B12-pharmaceutics-11-00441" ref-type="bibr">12</xref>,<xref rid="B13-pharmaceutics-11-00441" ref-type="bibr">13</xref>,<xref rid="B14-pharmaceutics-11-00441" ref-type="bibr">14</xref>], leukodystrophy [<xref rid="B15-pharmaceutics-11-00441" ref-type="bibr">15</xref>], B-cell cancers, and heart failure [<xref rid="B16-pharmaceutics-11-00441" ref-type="bibr">16</xref>]. For those drugs that require periodic or difficult delivery (such as ocular injectable drugs) and have poor pharmacodynamics, there is a precise solution: to construct molecules with high in vivo stability and potentially low immunogenicity. Some frequently used methods of molecular half-life expansion include the addition of stabilizing peptides, creation of Fc fusion proteins, and the inclusion of biomolecules into many discrete nanoparticle systems [<xref rid="B17-pharmaceutics-11-00441" ref-type="bibr">17</xref>]. In a few medical conditions, where drugs do not pass certain barriers (e.g., the blood–cerebrospinal fluid barrier or blood–brain barrier) or do not show binding or affinity to a definite target molecule, the ligand-modified type of nanocarriers has been used to allow a drug to cross the cell membrane and to enable organized drug delivery in a specific state. For instance, hyaluronic acid (a polysaccharide from the extracellular matrix) has been used as an appended ligand in various nanocarriers, thereby yielding good outcomes, e.g., enhancing antitumor activity against breast cancer cells [<xref rid="B18-pharmaceutics-11-00441" ref-type="bibr">18</xref>] and melanoma stem-like cells [<xref rid="B19-pharmaceutics-11-00441" ref-type="bibr">19</xref>], in addition to lowering the immunogenicity of the formed protein corona [<xref rid="B20-pharmaceutics-11-00441" ref-type="bibr">20</xref>], promotion of intravitreal drug distribution for retinal gene therapy [<xref rid="B21-pharmaceutics-11-00441" ref-type="bibr">21</xref>], and targeting of pulmonary adenocarcinoma cells [<xref rid="B22-pharmaceutics-11-00441" ref-type="bibr">22</xref>]. Biological therapeutics can be generally classified into three big groups based on their physical properties and mode of action. The first group includes peptides and small proteins such as cytokines, growth factors, and hormones. The second group includes therapeutic proteins which are nonimmunogenic such as blood factors, therapeutic replacement enzymes, and anticoagulants. The third group contains the most rapidly growing class of biotherapeutic drugs: therapeutic antibodies and Fc-like fusion proteins [<xref rid="B23-pharmaceutics-11-00441" ref-type="bibr">23</xref>]. Hundreds of monoclonal antibodies and fusion proteins are in the process of clinical evaluation [<xref rid="B24-pharmaceutics-11-00441" ref-type="bibr">24</xref>].</p><p>Biologics are currently the rapidly developing group of pharmaceuticals for the treatment of a number of chronic and deadly diseases. They consist of a varied group of biological substances that largely include proteins, nucleic acids, viral particles, whole cells, and vaccines [<xref rid="B25-pharmaceutics-11-00441" ref-type="bibr">25</xref>]. Many biologics have made their way to the market; they mainly include blood factors, antibody-based drugs, anticoagulants, engineered protein scaffolds, bone morphogenetic proteins (BMPs), enzymes, Fc (crystallizable fragment of an antibody), hormones, growth factors, fusion proteins, interferons, thrombolytics, and interleukins [<xref rid="B5-pharmaceutics-11-00441" ref-type="bibr">5</xref>]. The biological therapeutics’ production and development encounter various challenges that are quite different from those faced by classical small-molecule drugs [<xref rid="B26-pharmaceutics-11-00441" ref-type="bibr">26</xref>]. In general, biologics are designer drugs whose mode of action in an underlying disease pathophysiology is usually better understood than that of small-molecule drugs [<xref rid="B27-pharmaceutics-11-00441" ref-type="bibr">27</xref>]. The benefits of biologics are associated with the considerable technology and tool evolution for their development over the past three decades. Various protein engineering platforms, diverse selection technologies, new production systems, a profusion of biotherapeutics’ formats and scaffolds, and new methods for increasing aggregation resistance and stability have resulted in a new era of therapeutic candidates [<xref rid="B23-pharmaceutics-11-00441" ref-type="bibr">23</xref>]. The biological therapeutics have burst onto the scene undoubtedly because of a greater chance of being first-class therapeutics in comparison with small-molecule drugs, considering their quality and novelty [<xref rid="B27-pharmaceutics-11-00441" ref-type="bibr">27</xref>]. Despite their good properties, they are underestimated in the pharmaceutical market. The reason might mainly be their poor bioavailability, which necessitates the use of some special medical devices (e.g., inhalers) and nonoral administration. Another drawback is their lower metabolic stability because of proteolytic degradation. In addition, the cost to synthesize some biopharmaceutics is high. Their pharmacokinetics can be improved by conjugating them with other substances or by transforming them into small molecules [<xref rid="B28-pharmaceutics-11-00441" ref-type="bibr">28</xref>].</p><p>Here, we review TLRs and their signaling pathways, their involvement in various diseases, and relevant reported therapeutic drugs, including biologics, small-molecule inhibitors, and nucleic acids. Moreover, we explain various drug delivery approaches that could be used to enhance the efficacy of TLR-targeting drugs.</p></sec><sec id="sec2-pharmaceutics-11-00441"><title>2. Toll-Like Receptors and Their Signaling Pathways</title><p>To date, 10 members of the TLR family in humans and 13 in mice have been identified. They are present on different immune cells and recognize their respective ligands (<xref rid="pharmaceutics-11-00441-t001" ref-type="table">Table 1</xref>). TLRs trigger specific intracellular signaling pathways after recognition of microbial pathogens, resulting in the release of inflammatory cytokines, chemokines, and type I interferon (IFN). Moreover, TLRs link the innate immune response and adaptive immune response by upregulating the costimulatory molecules on antigen-presenting cells (DCs), a phenomenon known as DC maturation [<xref rid="B29-pharmaceutics-11-00441" ref-type="bibr">29</xref>]. Activation of common signaling pathways by TLRs results in the production of various cytokines including tumor necrosis factor alpha (TNF-α), IL-1β, IL-6, and IL-12 as well as response elements from alternate pathways that prevent a microbial attack (<xref ref-type="fig" rid="pharmaceutics-11-00441-f001">Figure 1</xref>) [<xref rid="B30-pharmaceutics-11-00441" ref-type="bibr">30</xref>]. Specifically, a type I IFN (IFNα and IFNβ)-based antiviral response is provoked by the activation of TLR3, TLR4, TLR7, TLR8, and TLR9 (<xref ref-type="fig" rid="pharmaceutics-11-00441-f001">Figure 1</xref>).</p><p>The extracellular leucine-rich repeats of TLRs recognize the pathogens while the transmembrane and cytoplasmic Toll/interleukin-1 receptor (TIR) domains initiate intracellular signaling [<xref rid="B30-pharmaceutics-11-00441" ref-type="bibr">30</xref>]. All the TLRs provoke an inflammatory and protective response by activating nuclear factor-κB (NF-κB), activating protein-1 (AP-1), interferon regulatory factor (IRF) 3, and IRF7. The dimeric transcription factor NF-κB belongs to the Rel domain-containing family, which includes RelB, c-Rel, p65/RelA, p50/NF-κB1, and p52/NF-κB2 [<xref rid="B31-pharmaceutics-11-00441" ref-type="bibr">31</xref>]. NF-κB is a heterodimer composed of subunits p50 and p65 and is sequestered in an inactive form by inhibitor of NF-κB (IκB) in unstimulated cells.</p><p>Upon TLR-mediated stimulation, phosphorylation of IκB is performed at serine residues by the IKK complex (IKKα, IKKβ, and IKKγ/NEMO) which targets IκB for ubiquitination-based degradation by 26S proteasome. This change frees NF-κB to relocate into the nucleus and bind to inflammation-responsive genes. On the other hand, dimeric basic leucine zipper (bZIP) protein AP-1 is composed of the members of Fos, Jun, Maf, and activating transcription factor (ATF) subfamilies, which bind to a cAMP response element and TPA-response element [<xref rid="B32-pharmaceutics-11-00441" ref-type="bibr">32</xref>]. Among them, c-Jun plays a central role in the initiation of an inflammatory response. TLR-associated AP-1 activation is mostly mediated by MAP kinases including p38, c-Jun N-terminal kinase (JNK), and extracellular signal–regulated kinase (ERK). The stimulation of cells with lipopolysaccharide (LPS) or poly-IC and/or a virus attack activates IRF3 and IRF7, which control the expression of type I interferon (IFN). The structurally related proteins IRF3 and IRF7 are present in the cytoplasm of unstimulated cells and relocate into the nucleus after stimulation-mediated phosphorylation by TANK-binding kinase (TBK)1, noncanonical IKKs, and IKKi and activate the expression of target genes [<xref rid="B33-pharmaceutics-11-00441" ref-type="bibr">33</xref>,<xref rid="B34-pharmaceutics-11-00441" ref-type="bibr">34</xref>]. The TLR-mediated activation of these transcription factors is divided into two main categories: MyD88 dependent and TRIF dependent.</p><sec id="sec2dot1-pharmaceutics-11-00441"><title>2.1. The MyD88-Dependent Pathway</title><p>The preliminary activation of intracellular TLR signaling is implemented by heterophilic interaction among TIR domains of TLRs and cytoplasmic adaptor proteins such as MyD88, TIR domain-containing adaptor protein (TIRAP/Mal), TIR domain-containing adaptor inducing IFNβ (TRIF/TICAM1), and TRIF-related adaptor molecule (TRAM/TICAM2; <xref ref-type="fig" rid="pharmaceutics-11-00441-f001">Figure 1</xref>) [<xref rid="B30-pharmaceutics-11-00441" ref-type="bibr">30</xref>]. MyD88 is considered a central adaptor shared by all TLRs except TLR3. The interaction of TLRs and MyD88 recruits interleukin 1 receptor-associated kinase (IRAK) family members: IRAK1, IRAK2, IRAK4, and/or IRAK-M. IRAK1 and IRAK4 positively regulate TLR signaling through their intrinsic serine/threonine kinase activities unlike IRAK2 and IRAK-M, which perform negative regulation because of a lack of this kinase activity [<xref rid="B35-pharmaceutics-11-00441" ref-type="bibr">35</xref>,<xref rid="B36-pharmaceutics-11-00441" ref-type="bibr">36</xref>]. TLR stimulation dissociates IRAK1 and IRAK4 from MyD88 after their phosphorylation, which in turn activates tumor necrosis factor receptor-associated factor 6 (TRAF6). TRAF6 contains a conserved E3 ubiquitin ligase N-terminal RING domain, which allows it to form a complex with Ubc13 and Uev1A with subsequent synthesis of lysine63-linked polyubiquitin chains [<xref rid="B37-pharmaceutics-11-00441" ref-type="bibr">37</xref>]. TRAF6 ubiquitination activates a MAP kinase kinase kinase (MAP3K) family member, transforming growth factor β–activated protein kinase (TAK) 1, which forms a complex with TAB-1, -2, and -3 [<xref rid="B37-pharmaceutics-11-00441" ref-type="bibr">37</xref>]. In particular, zinc-finger domains of TAB2 and TAB3 allow them to interact with lysine63-linked polyubiquitin chains; this event activates TAK1 [<xref rid="B37-pharmaceutics-11-00441" ref-type="bibr">37</xref>]. TAK1 activation causes the IKK complex to eventually activate NF-κB. Simultaneously, TAK1 phosphorylates MKK3 and MKK3, members of the MAP kinase kinase family, for subsequent activation of JNK and p38. ERK is stimulated through the TLR-mediated activation of MEK1 and MEK2. These mechanisms highlight the importance of TAK1 for the activation of NF-κB and MAP kinase family members [<xref rid="B38-pharmaceutics-11-00441" ref-type="bibr">38</xref>]. The TLR2- and TLR4-associated MyD88-dependent pathway needs an additional adaptor molecule (TIRAP, i.e., MAL) to provoke an inflammatory response [<xref rid="B39-pharmaceutics-11-00441" ref-type="bibr">39</xref>].</p></sec><sec id="sec2dot2-pharmaceutics-11-00441"><title>2.2. The TRIF-Dependent Pathway</title><p>MyD88-deficient macrophages and DCs fail to produce inflammatory cytokines after stimulation of TLR2, TLR5, TLR7, and TLR9 by their respective ligands; this observation points to the dependence of these TLRs upon MyD88 for their activation [<xref rid="B40-pharmaceutics-11-00441" ref-type="bibr">40</xref>,<xref rid="B41-pharmaceutics-11-00441" ref-type="bibr">41</xref>,<xref rid="B42-pharmaceutics-11-00441" ref-type="bibr">42</xref>]. Nonetheless, TLR4 yields a delayed response in MyD88-deficient cells upon LPS stimulation; this observation indicates the existence of an alternative pathway associated with TLR4 [<xref rid="B43-pharmaceutics-11-00441" ref-type="bibr">43</xref>]. This finding led to the discovery of another adaptor molecule, TRIF, which responds to the TLR activation independently of MyD88 and can activate all three transcription factors i.e., NF-κB, AP-1, and IRFs unlike MyD88 which cannot activate IRFs [<xref rid="B44-pharmaceutics-11-00441" ref-type="bibr">44</xref>]. TRIF-deficient mice show reduced production of inflammatory cytokines upon LPS stimulation, indicating the positive regulation of MyD88 by TRIF [<xref rid="B45-pharmaceutics-11-00441" ref-type="bibr">45</xref>]. The interaction between TLR4 and TRIF is mediated exclusively by TRIF-specific adaptor TRAM [<xref rid="B46-pharmaceutics-11-00441" ref-type="bibr">46</xref>]. TLR3 ligand poly-IC yields a normal response in MyD88-deficient cells but not in TRIF-deficient mice. Of note, TRAM-deficient cells also produce a normal response, which confirms that TRIF is the only adaptor for TLR3 [<xref rid="B46-pharmaceutics-11-00441" ref-type="bibr">46</xref>]. TRIF contains a Rip homotypic interaction motif (RHIM) at its C terminus to interact with receptor interacting protein (RIP) family members [<xref rid="B47-pharmaceutics-11-00441" ref-type="bibr">47</xref>]. TLR3-mediated activation of NF-κB and inflammation-responsive genes is abrogated in RIP1-deficient cells, highlighting its involvement in NF-κB activation [<xref rid="B47-pharmaceutics-11-00441" ref-type="bibr">47</xref>]. Nonetheless, RIP3 disrupts this interaction to inhibit the TLR3 signaling pathway [<xref rid="B47-pharmaceutics-11-00441" ref-type="bibr">47</xref>]. At its N terminus, TRIF contains three TRAF6-binding domains to interact with TRAF6 with subsequent activation of NF-κB. The mutational studies confirm the participation of both TRIF–RIP1 and TRIF–TRAF6 pathways in the activation of NF-κB via convergence at the IKK complex [<xref rid="B48-pharmaceutics-11-00441" ref-type="bibr">48</xref>].</p></sec></sec><sec id="sec3-pharmaceutics-11-00441"><title>3. Representative Diseases Associated with TLRs</title><p>A wide spectrum of diseases is associated with TLRs, which directly or indirectly aggravate these conditions. Recently, many accomplishments have been made regarding the TLR involvement in several diseases [<xref rid="B49-pharmaceutics-11-00441" ref-type="bibr">49</xref>,<xref rid="B50-pharmaceutics-11-00441" ref-type="bibr">50</xref>,<xref rid="B51-pharmaceutics-11-00441" ref-type="bibr">51</xref>,<xref rid="B52-pharmaceutics-11-00441" ref-type="bibr">52</xref>]. Here, we will provide a brief overview of the influence of TLRs on autoimmune, inflammatory, and malignant diseases [<xref rid="B53-pharmaceutics-11-00441" ref-type="bibr">53</xref>,<xref rid="B54-pharmaceutics-11-00441" ref-type="bibr">54</xref>,<xref rid="B55-pharmaceutics-11-00441" ref-type="bibr">55</xref>,<xref rid="B56-pharmaceutics-11-00441" ref-type="bibr">56</xref>].</p><p>Sepsis, being the leading cause of death in the United States, is the outcome of worst host–pathogen interactions [<xref rid="B57-pharmaceutics-11-00441" ref-type="bibr">57</xref>,<xref rid="B58-pharmaceutics-11-00441" ref-type="bibr">58</xref>]. The hyperactive immune response because of the infection by Gram-negative and Gram-positive bacteria leads to septic shock and multiorgan failure [<xref rid="B59-pharmaceutics-11-00441" ref-type="bibr">59</xref>]. The possession of TLR2 and TLR4 ligands, especially the TLR4 ligand (LPS), by these bacteria makes a significant contribution to the development of sepsis. On the other hand, the human body’s own immune response but not infection itself is mainly responsible for septic shock [<xref rid="B60-pharmaceutics-11-00441" ref-type="bibr">60</xref>]. Several TLR inhibitors and new modalities are being developed to control sepsis [<xref rid="B61-pharmaceutics-11-00441" ref-type="bibr">61</xref>].</p><p>Chronic obstructive pulmonary disease (COPD) is described as bronchial inflammation and poor reversible air-flow [<xref rid="B56-pharmaceutics-11-00441" ref-type="bibr">56</xref>,<xref rid="B62-pharmaceutics-11-00441" ref-type="bibr">62</xref>]. The interaction of TLRs with attacking viruses can worsen this condition, and patients with higher levels of inflammatory cytokines such as CCL5 and TNF-α have been described in the literature [<xref rid="B63-pharmaceutics-11-00441" ref-type="bibr">63</xref>]. The inhibition of TLRs is one of the treatments of COPD [<xref rid="B50-pharmaceutics-11-00441" ref-type="bibr">50</xref>].</p><p>Rheumatoid arthritis (RA) is a well-known inflammatory disease associated with TLRs. With yet unclear pathogenesis, this disease is believed to be related to PAMPs of the commensal microflora, which lead to the hyperupregulation of inflammatory cytokines [<xref rid="B64-pharmaceutics-11-00441" ref-type="bibr">64</xref>]. After an initial encounter with a PAMP, the condition worsens via the autocrine exacerbation by metalloproteinases (MMPs). Moreover, peptidoglycan and DNA from intestinal bacteria also contribute to RA [<xref rid="B65-pharmaceutics-11-00441" ref-type="bibr">65</xref>]. This action damages the affected cells thereby releasing proteins featuring damage-associated molecular patterns, e.g., HMGB1, S100-A8, and RNAs, which aggravate the condition by further activating TLRs.</p><p>Systemic lupus erythematosus (SLE), simply known as lupus, is an autoimmune disease characterized by the presence of autoantibodies against the nucleic-acid-bound proteins and double-stranded DNA; however, the initial mechanism is still unclear [<xref rid="B66-pharmaceutics-11-00441" ref-type="bibr">66</xref>]. SLE patients cannot get rid of apoptotic cells and the build-up of immune complexes inside their body; these problems cause lupus by activating endosomal TLRs. Nevertheless, TLR9 has been reported to have a regulatory role in TLR7-mediated inflammation in a subgroup of SLE patients [<xref rid="B67-pharmaceutics-11-00441" ref-type="bibr">67</xref>,<xref rid="B68-pharmaceutics-11-00441" ref-type="bibr">68</xref>,<xref rid="B69-pharmaceutics-11-00441" ref-type="bibr">69</xref>].</p><p>Sjogren’s syndrome is an autoimmune disease where the fluid-secreting glands, e.g., salivary glands, are destroyed by the body’s own immune system, and this process potentially involves the TLRs. Patients with Sjogren’s syndrome have higher expression of TLRs, which lead to the hyperactivation of inflammatory genes especially by the activation of TLR7 and TLR9 [<xref rid="B70-pharmaceutics-11-00441" ref-type="bibr">70</xref>,<xref rid="B71-pharmaceutics-11-00441" ref-type="bibr">71</xref>].</p><p>Cancers are complex diseases, and TLRs’ involvement acts as a double-edge sword in these diseases. The activation of TLR(s) can either exaggerate or suppress cancer depending upon the extent of activation, type of cancer, and a cancer microenvironment [<xref rid="B49-pharmaceutics-11-00441" ref-type="bibr">49</xref>]. Moreover, TLR-mediated inflammation and cancer have a strong correlation during initiation or exacerbation of various diseases [<xref rid="B72-pharmaceutics-11-00441" ref-type="bibr">72</xref>]. This observation might be the reason why organs such as the gastrointestinal tract and skin, which contain more PAMPs, are at a higher risk to TLR-mediated oncogenesis. In this regard, TLR4 has been demonstrated to enhance colon cancer, whereas TLR4 deficiency lessens the signs of inflammation and tumor load [<xref rid="B73-pharmaceutics-11-00441" ref-type="bibr">73</xref>,<xref rid="B74-pharmaceutics-11-00441" ref-type="bibr">74</xref>]. TLR4 activation is also positively linked with liver cancer progression [<xref rid="B75-pharmaceutics-11-00441" ref-type="bibr">75</xref>]; however, its role is dependent upon the environment in case of skin cancer [<xref rid="B76-pharmaceutics-11-00441" ref-type="bibr">76</xref>,<xref rid="B77-pharmaceutics-11-00441" ref-type="bibr">77</xref>]. TLR4 activation by the LPS from <italic>Helicobacter pylori</italic> increased the proliferation rate of human gastric cancer cell lines [<xref rid="B78-pharmaceutics-11-00441" ref-type="bibr">78</xref>]. In addition to increased cell survival and proliferation, TLR4 activation on breast and cancer cells can release factors (such as MMPs, NO, VEGF, IL-6, and IL-12) and ligands (such as B7-H1 and B7-H2) which are responsible for immune evasion of cancerous cells [<xref rid="B79-pharmaceutics-11-00441" ref-type="bibr">79</xref>,<xref rid="B80-pharmaceutics-11-00441" ref-type="bibr">80</xref>,<xref rid="B81-pharmaceutics-11-00441" ref-type="bibr">81</xref>,<xref rid="B82-pharmaceutics-11-00441" ref-type="bibr">82</xref>]. Activation of other TLRs, such as TLR2, TLR5, TLR7, TLR8 and TLR9, has been reported to enhance proliferation in various cancers including liver, gastric, lung, and breast cancer [<xref rid="B83-pharmaceutics-11-00441" ref-type="bibr">83</xref>,<xref rid="B84-pharmaceutics-11-00441" ref-type="bibr">84</xref>,<xref rid="B85-pharmaceutics-11-00441" ref-type="bibr">85</xref>,<xref rid="B86-pharmaceutics-11-00441" ref-type="bibr">86</xref>,<xref rid="B87-pharmaceutics-11-00441" ref-type="bibr">87</xref>]. Similarly, cellular transformation in the case of breast cancers is also attributed to the involvement of TLRs [<xref rid="B88-pharmaceutics-11-00441" ref-type="bibr">88</xref>] because they modify the metabolism of a tumor microenvironment [<xref rid="B89-pharmaceutics-11-00441" ref-type="bibr">89</xref>], which can favor pro- or antitumor signaling networks [<xref rid="B90-pharmaceutics-11-00441" ref-type="bibr">90</xref>,<xref rid="B91-pharmaceutics-11-00441" ref-type="bibr">91</xref>,<xref rid="B92-pharmaceutics-11-00441" ref-type="bibr">92</xref>].</p></sec><sec id="sec4-pharmaceutics-11-00441"><title>4. TLR-Targeting Therapeutics</title><p>TLRs are promising targets for drug development because of their involvement in inflammation, pathogen clearance, cancer, and many other related diseases. Therefore, many pharmaceutical companies are developing peptide- (protein-), chemical-, or aptamer-based modulators specific to TLRs. The natural drugs like peptides have more specificity, higher molecular weight (>1 kDa), and longer half-life than small molecule-based drugs. Moreover, they can be modified for better activity by using some non-natural amino acids. Nevertheless, as compared to many small-molecule drugs, biologics are generally less stable and are likely to undergo aggregation [<xref rid="B93-pharmaceutics-11-00441" ref-type="bibr">93</xref>], oxidation, or deamidation [<xref rid="B94-pharmaceutics-11-00441" ref-type="bibr">94</xref>]. Small molecules have more stability, lower molecular weight (<700 Da), oral administration, lower price, nonimmunogenicity, and accessibility to intracellular targets [<xref rid="B95-pharmaceutics-11-00441" ref-type="bibr">95</xref>]. Aptamers are nucleic acid-based structures which have advantages over peptides and small molecules in certain applications like to detect toxin, non-immunogenic targets [<xref rid="B96-pharmaceutics-11-00441" ref-type="bibr">96</xref>]. The ideal candidates to target TLRs are scaffolds of naturally occurring modulators: this is a productive approach to the clinical development of TLR modulators.</p><sec id="sec4dot1-pharmaceutics-11-00441"><title>4.1. TLR1/2 and TLR2/6</title><p>The heterodimeric coexistence of TLR2 with TLR1 and TLR6 enables it to interact with diverse ligands including lipoproteins, glycoproteins, peptidoglycan, and zymosan [<xref rid="B97-pharmaceutics-11-00441" ref-type="bibr">97</xref>]. Moreover, TLR2 is thought to be functionally ubiquitous because of its expression in immune, epithelial, and endothelial cells [<xref rid="B98-pharmaceutics-11-00441" ref-type="bibr">98</xref>]. This observation makes TLR2 an attractive therapeutic target in multiple diseases. The compounds being evaluated in clinical trials include antibodies, lipoproteins, and lipopeptides (<xref rid="pharmaceutics-11-00441-t002" ref-type="table">Table 2</xref>). The most recent ligands, such as OPN-305 (antagonistic antibody), ISA-201 (agonistic peptide), and CBLB612 (agonistic lipopeptide), are in phase 2 clinical trials for cancer therapy and are being used as a drug and adjuvant [<xref rid="B99-pharmaceutics-11-00441" ref-type="bibr">99</xref>,<xref rid="B100-pharmaceutics-11-00441" ref-type="bibr">100</xref>]. Potential adverse effects of small-molecule drugs can be overcome by replacement with biologics such as TLR2-targeting monoclonal antibodies (OPN-305) [<xref rid="B99-pharmaceutics-11-00441" ref-type="bibr">99</xref>].</p><p>There is cavity formation on the convex side of the binding site of TLR2 for TLR1 or TLR6; this cavity allows for the docking of TLR2 modulators including Pam3CSK4 [<xref rid="B101-pharmaceutics-11-00441" ref-type="bibr">101</xref>,<xref rid="B102-pharmaceutics-11-00441" ref-type="bibr">102</xref>]. There are two lipid and ester chains in the structure of Pam3CSK4. The lipid chains are lodged into the hydrophobic cavity generated by TLR1, while ester chains communicate with TLR2 [<xref rid="B101-pharmaceutics-11-00441" ref-type="bibr">101</xref>,<xref rid="B103-pharmaceutics-11-00441" ref-type="bibr">103</xref>]. The interplay of hydrophobic interactions and hydrogen bonding also makes the TLR1–TLR2 complex stable [<xref rid="B101-pharmaceutics-11-00441" ref-type="bibr">101</xref>]. A mutational study (Met338 and Leu360 to Phe in TLR1) explains the necessity of diacyls for the formation of the TLR2–TLR6 complex.</p></sec><sec id="sec4dot2-pharmaceutics-11-00441"><title>4.2. TLR3</title><p>The homodimeric TLR3 generates signals for the production of IFNs in a TRIF-dependent manner after TLR3 is activated by viral infections (double-stranded RNA). Poly-ICLC and derivatives are the only known TLR3-specific agonists currently being evaluated in clinical trials [<xref rid="B104-pharmaceutics-11-00441" ref-type="bibr">104</xref>,<xref rid="B105-pharmaceutics-11-00441" ref-type="bibr">105</xref>]. Recently, some other small-molecule drugs were reported to be inhibitors or activators of TLR3 [<xref rid="B106-pharmaceutics-11-00441" ref-type="bibr">106</xref>,<xref rid="B107-pharmaceutics-11-00441" ref-type="bibr">107</xref>]. Few clinical trials for antibodies targeting TLR3 have been conducted with asthmatic patients [<xref rid="B108-pharmaceutics-11-00441" ref-type="bibr">108</xref>]. The success of antibody-based prevention of diseases will lay the foundation for the treatment of endosomal-TLR-related diseases. Nonetheless, an antibody cannot treat the asthmatic condition in patients infected by rhinovirus [<xref rid="B109-pharmaceutics-11-00441" ref-type="bibr">109</xref>]. Various types of cancers can be treated with TLR3 agonists as an adjuvant therapy with other vaccines or drugs (<xref rid="pharmaceutics-11-00441-t002" ref-type="table">Table 2</xref>).</p><p>A synthetic TLR3 agonist, poly-ICLC, is a complex of polyinosinic/polycytidylic acid, carboxymethylcellulose, and poly-<sc>l</sc>-lysine. The mimetics of a natural ligand of TLR3, dsRNA, are promising candidates for activation of associated TLRs. TLR3 activation is initiated by the interaction of its ectodomains with dsRNA, which relocates the C terminus of an ectodomain for further interactions and stability [<xref rid="B110-pharmaceutics-11-00441" ref-type="bibr">110</xref>,<xref rid="B111-pharmaceutics-11-00441" ref-type="bibr">111</xref>]. Moreover, TLR3 activation is caused by its interaction with a ligand backbone rather than sidechains (bases); this mechanism allows TLR3 to be activated by multiple combinations of nucleotides [<xref rid="B110-pharmaceutics-11-00441" ref-type="bibr">110</xref>].</p></sec><sec id="sec4dot3-pharmaceutics-11-00441"><title>4.3. TLR4</title><p>The only TLR functioning on the plasma membrane and in endosomes in both a MyD88- and TRIF-dependent manner is TLR4. This observation enables various options for the design of modulators such as those targeting CD14, LBP, MD2, MAL, and/or TRAM. Of all TLRs, only TLR4 contains an MD2-provided ligand-binding pocket rather than a pocked formed by its own ectodomain; this finding highlights the importance of TLR4 as a therapeutic target [<xref rid="B112-pharmaceutics-11-00441" ref-type="bibr">112</xref>]. Because of the large hydrophobic cavity of MD2 and suitability for the binding of lipid-A derivatives, disruption of an MD2 interaction with a ligand or TLR4 is regarded as one of the therapeutic options [<xref rid="B113-pharmaceutics-11-00441" ref-type="bibr">113</xref>]. If we consider the interaction of MD2 and lipid-A, a six-acyl-chain-carrying lipid molecule can completely occupy the pocket; this event reorients a sidechain into the binding pocket to dock TLR4 with MD2 properly for the activation of signaling [<xref rid="B114-pharmaceutics-11-00441" ref-type="bibr">114</xref>]. Nevertheless, a smaller number of acyl chains inhibits the TLR4 activation because of the failure to reorient the side chains properly [<xref rid="B112-pharmaceutics-11-00441" ref-type="bibr">112</xref>,<xref rid="B115-pharmaceutics-11-00441" ref-type="bibr">115</xref>].</p><p>Well-known TLR4 modulators include lipid VI-A and its derivatives (glucopyranosyl lipid adjuvant (agonist) [<xref rid="B116-pharmaceutics-11-00441" ref-type="bibr">116</xref>], lipid 4A (antagonist), and monophosphoryl lipid A (weak agonist)) [<xref rid="B117-pharmaceutics-11-00441" ref-type="bibr">117</xref>] and peptide- or antibody-based therapeutics [<xref rid="B113-pharmaceutics-11-00441" ref-type="bibr">113</xref>,<xref rid="B118-pharmaceutics-11-00441" ref-type="bibr">118</xref>]. The TLR4 modulation holds promise for the treatment of various pathologies including immunological diseases, viral infections, cancers, and inflammation (<xref rid="pharmaceutics-11-00441-t002" ref-type="table">Table 2</xref>).</p></sec><sec id="sec4dot4-pharmaceutics-11-00441"><title>4.4. TLR5</title><p>Bacterial monomeric flagella are recognized by the ectodomain of TLR5, thereby eliciting an immune response [<xref rid="B119-pharmaceutics-11-00441" ref-type="bibr">119</xref>]. After enterobacterial invasion, TLR5 activates the MyD88-dependent pathway thus maintaining the intestinal homeostasis. Most of immune cells there, predominantly mucosal DCs, express TLR5 [<xref rid="B120-pharmaceutics-11-00441" ref-type="bibr">120</xref>,<xref rid="B121-pharmaceutics-11-00441" ref-type="bibr">121</xref>]. A recombinant flagellin protein is being used for targeting TLR5 in many clinical trials [<xref rid="B122-pharmaceutics-11-00441" ref-type="bibr">122</xref>,<xref rid="B123-pharmaceutics-11-00441" ref-type="bibr">123</xref>,<xref rid="B124-pharmaceutics-11-00441" ref-type="bibr">124</xref>,<xref rid="B125-pharmaceutics-11-00441" ref-type="bibr">125</xref>]. Moreover, preclinical studies on a small-molecule inhibitor of the TLR5–flagellin interaction are under way [<xref rid="B126-pharmaceutics-11-00441" ref-type="bibr">126</xref>]. From the therapeutic point of view, most of TLR5 ligands are being used as adjuvants to enhance the efficacy of vaccine candidates rather than being used as drugs (<xref rid="pharmaceutics-11-00441-t002" ref-type="table">Table 2</xref>). TLR5 detects only protein-based ligands; this property allows researchers to design peptide-based activators and/or inhibitors [<xref rid="B124-pharmaceutics-11-00441" ref-type="bibr">124</xref>,<xref rid="B127-pharmaceutics-11-00441" ref-type="bibr">127</xref>].</p><p>Recently reported crystal structure of flagellin complexed with zebrafish TLR5 provides insights into the mechanism of TLR5 activation [<xref rid="B128-pharmaceutics-11-00441" ref-type="bibr">128</xref>]. The residues Arg89, Glu114, and Leu93 in flagellin and leucine-rich repeat 9 (LRR9) of TLR5 are critical regions in the structure of the complex for the interaction; these data could be further explored for designing therapeutics [<xref rid="B128-pharmaceutics-11-00441" ref-type="bibr">128</xref>].</p></sec><sec id="sec4dot5-pharmaceutics-11-00441"><title>4.5. TLR7 and TLR8</title><p>TLR7 and TLR8 are located in the endosomal compartment and activate signaling in a MyD88-dependent manner after being stimulated by single-stranded RNA (ssRNA) [<xref rid="B129-pharmaceutics-11-00441" ref-type="bibr">129</xref>,<xref rid="B130-pharmaceutics-11-00441" ref-type="bibr">130</xref>]. Most of the TLR7/8 modulators in clinical studies are small-molecule compounds such as resiquimod, imiquimod, or GSK2245035 (<xref rid="pharmaceutics-11-00441-t002" ref-type="table">Table 2</xref>) [<xref rid="B131-pharmaceutics-11-00441" ref-type="bibr">131</xref>,<xref rid="B132-pharmaceutics-11-00441" ref-type="bibr">132</xref>,<xref rid="B133-pharmaceutics-11-00441" ref-type="bibr">133</xref>]. Because of some structural differences, monocytes and plasmacytoid DCs can be directly activated by TLR7; however, monocyte-derived DCs can be directly activated by TLR8. IFN and the associated cytokine-based antiviral response in human peripheral mononuclear cells (PBMCs) is more potently regulated by a TLR7 agonist rather than by a TLR8 agonist [<xref rid="B134-pharmaceutics-11-00441" ref-type="bibr">134</xref>]. Nevertheless, proinflammatory cytokines such as TNF-α, IL-12, and MIP-1α are more strongly upregulated by a TLR8 agonist rather than by a TLR7 agonist. TLR7 agonists are being evaluated in phase I/II trials to limit the viral load in HBV- and HIV-infected patients [<xref rid="B135-pharmaceutics-11-00441" ref-type="bibr">135</xref>]. TLR8 can be activated by a synthetic small-molecule ligand (motolimod (VTX-2337)) and a natural ligand (ssRNA), and they are currently assessed in clinical trials [<xref rid="B130-pharmaceutics-11-00441" ref-type="bibr">130</xref>,<xref rid="B136-pharmaceutics-11-00441" ref-type="bibr">136</xref>]. VTX-2337 has been tested for the treatment of various cancers such as colorectal cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma, breast cancer, and non-small cell lung carcinoma. This compound has been tested alone and in combination therapy for lymphoma [<xref rid="B136-pharmaceutics-11-00441" ref-type="bibr">136</xref>].</p><p>Both TLR7 and TLR8 contain Z-loops to recognize ssRNA and two binding sites: the first one to bind guanosine (G) and uridine (U) in TLR7 and TLR8, respectively, and the second site to bind ssRNA in both [<xref rid="B137-pharmaceutics-11-00441" ref-type="bibr">137</xref>]. This observation reveals the similarity in their mechanism of action on signaling. The binding of ssRNA in TLR7 primes it to bind guanosine for subsequent dimerization, whereas synthetic molecules, such as R848, do not require ssRNA for the TLR7 activation [<xref rid="B138-pharmaceutics-11-00441" ref-type="bibr">138</xref>,<xref rid="B139-pharmaceutics-11-00441" ref-type="bibr">139</xref>]. Moreover, TLR7 exists in a monomeric form in the absence of a ligand and dimerizes after recognizing the respective ligand, whereas TLR8 is a weak dimer without a ligand and undergoes conformational changes after recognizing the ligand to activate downstream signaling. The reason might be the regulatory role of Z-loops in TLR8 because their cleavage from TLR8 can activate signaling in the absence of a ligand via the formation of a tight functional dimer [<xref rid="B140-pharmaceutics-11-00441" ref-type="bibr">140</xref>].</p></sec><sec id="sec4dot6-pharmaceutics-11-00441"><title>4.6. TLR9</title><p>CpG DNA is recognized by endosomal TLR9 to activate the IFN response [<xref rid="B141-pharmaceutics-11-00441" ref-type="bibr">141</xref>,<xref rid="B142-pharmaceutics-11-00441" ref-type="bibr">142</xref>]. Because of its involvement in multiple diseases, many approaches have been employed to design relevant therapeutics. All the TLR9-specific ligands in clinical studies are nucleotides and their derivatives. AZD1419, a CpG-based TLR9 agonist, stimulates IFN production for the treatment of asthma and is considered safe for treating various diseases in humans [<xref rid="B143-pharmaceutics-11-00441" ref-type="bibr">143</xref>]. Similarly, some other TLR9 agonists such as CYT003, EMD 1201081, and GNKG168 have been tested clinically against various cancers (<xref rid="pharmaceutics-11-00441-t002" ref-type="table">Table 2</xref>) [<xref rid="B144-pharmaceutics-11-00441" ref-type="bibr">144</xref>,<xref rid="B145-pharmaceutics-11-00441" ref-type="bibr">145</xref>,<xref rid="B146-pharmaceutics-11-00441" ref-type="bibr">146</xref>].</p><p>TLR9 also forms a symmetrical complex with its ligand like other TLRs do; however, it maintains its monomeric form during an inhibitory interaction with an antagonistic ligand. There is a symmetric interaction in the 2:2 stoichiometric ratio between CpG-DNA and TLR9, specifically via the carboxy terminus (LRR20–22) with one protomer and the amino terminus (LRRNT–LRR10) with the other [<xref rid="B147-pharmaceutics-11-00441" ref-type="bibr">147</xref>]. On the other hand, TLR9 inhibition is mediated by the binding of CpG-DNA to the concave surface (LRR2–10) of TLR9.</p></sec><sec id="sec4dot7-pharmaceutics-11-00441"><title>4.7. TLR10–TLR13</title><p>Along with above-mentioned TLRs, humans also possess TLR10 and TLR11; however, they do not have TLR12 and TLR13 [<xref rid="B148-pharmaceutics-11-00441" ref-type="bibr">148</xref>]. TLR10 expression has been observed in various human cells and organs such as monocytes, neutrophils, B cells, lymph nodes, and the spleen; however, its specific ligand and function are not known yet [<xref rid="B149-pharmaceutics-11-00441" ref-type="bibr">149</xref>]. Recently, the anti-inflammatory rather than proinflammatory nature of TLR10 was revealed because of modulation of the TLR2 response via heterodimer formation with TLR1 and TLR6 [<xref rid="B150-pharmaceutics-11-00441" ref-type="bibr">150</xref>]. A pseudogene of TLR11 with a premature stop codon has been found in humans; it is unable to express a functional protein [<xref rid="B151-pharmaceutics-11-00441" ref-type="bibr">151</xref>]. Murine TLR11 and TLR12 are reported to recognize profilin from <italic>Toxoplasma gondii</italic> by forming a heterodimeric structure [<xref rid="B148-pharmaceutics-11-00441" ref-type="bibr">148</xref>].</p></sec></sec><sec id="sec5-pharmaceutics-11-00441"><title>5. Controlled Drug Delivery Systems</title><p>Drug delivery is the procedure of administering a medicinal product to attain a therapeutic outcome in humans or animals. Controlled-drug release systems got their start in the 1950s with the advancement of transdermal and oral constant-release systems. To achieve this objective, different drug delivery systems have been devised and are being investigated [<xref rid="B152-pharmaceutics-11-00441" ref-type="bibr">152</xref>]. Polymeric materials are utilized for this purpose and allow for increased circulation time, solubility of otherwise insoluble drug molecules, increased in vivo stability, site-specific targeting, a confined release, easier clearance from kidneys, and reduced adverse effects [<xref rid="B153-pharmaceutics-11-00441" ref-type="bibr">153</xref>,<xref rid="B154-pharmaceutics-11-00441" ref-type="bibr">154</xref>,<xref rid="B155-pharmaceutics-11-00441" ref-type="bibr">155</xref>]. A drug can be delivered via polymers by conjugation, encapsulation, or an embedding method [<xref rid="B156-pharmaceutics-11-00441" ref-type="bibr">156</xref>,<xref rid="B157-pharmaceutics-11-00441" ref-type="bibr">157</xref>]. For these systems, the drug delivery rate is controlled by the degradation rate of the polymer or the diffusion rate of the drug through a polymer matrix. Presently applicable polymer-based drug delivery systems can be grouped into five types based on their mechanism: diffusion-controlled systems, solvent-activated systems, chemically controlled systems, magnetically controlled systems, and targeted drug delivery system.</p><sec id="sec5dot1-pharmaceutics-11-00441"><title>5.1. The Diffusion-Controlled System</title><p>One of the vital processes in the body and nature is the exchange of materials via diffusional mass transport. This phenomenon was first illustrated by Adolf Eugen Fick (1829–1901) in a quantitative way [<xref rid="B12-pharmaceutics-11-00441" ref-type="bibr">12</xref>]. Based on the internal network of a drug delivery system and loading of a drug into it, diffusion-controlled systems are classified into two major categories [<xref rid="B158-pharmaceutics-11-00441" ref-type="bibr">158</xref>]. If the drug is in the center and the drug-releasing material (usually a polymer) is partitioned in consonance with the core shell framework, then this is called a “reservoir system.” In contrast, if the drug is uniformly dispersed in a continuous polymeric matrix, held together by a drug release-regulating material, then this is called a “monolithic system” [<xref rid="B158-pharmaceutics-11-00441" ref-type="bibr">158</xref>]. Both systems contain noncovalently bonded drugs that are embedded or incorporated inside their polymeric matrices [<xref rid="B159-pharmaceutics-11-00441" ref-type="bibr">159</xref>] and are further subdivided into two main subtypes. Reservoir devices can be porous or nonporous: In porous devices, the drug has to diffuse through the pores filled with oil or water; however, in nonporous devices, the drug has to pass via diffusion through the membrane of the polymer. Monolithic devices are further classified based on the concentration of the loaded drug: In monolithic solution devices, drug concentration in the matrix is equal to the solubility of the drug if the partition coefficient of the drug is 1.0; in contrast, in monolithic dispersion devices, drug concentration in the matrix is higher than its solubility. In a reservoir system, the integrity of the polymeric membrane is highly important because its accidental rupture may cause a sudden discharge of the drug, a phenomenon known as drug dumping [<xref rid="B160-pharmaceutics-11-00441" ref-type="bibr">160</xref>]. Moreover, it is necessary to remove the intact polymer of the reservoir from the body after the drug has been depleted. In contrast, the monolithic system ensures a uniform release of the drug without the risk of drug dumping.</p></sec><sec id="sec5dot2-pharmaceutics-11-00441"><title>5.2. The Solvent-Activated System</title><p>This system is associated with one of two phenomena: osmosis or swelling. The osmotically driven system depends upon the manufacturing material of the semipermeable membrane through which the solvent flows into the drug-carrying chamber, and the difference in osmotic pressure between the two sides of the membrane. An external fluid has a lower drug concentration and moves inside the device (having a higher drug concentration) through a membrane. The drug inside the system diffuses outside through an orifice with velocity that depends on the amount of water being absorbed by the polymeric matrix [<xref rid="B161-pharmaceutics-11-00441" ref-type="bibr">161</xref>]. The swelling system involves a hydrophilic polymer that forms a three-dimensionally organized structure after absorbing water without dissolving in it. There are three driving forces in this process: a polymer stress gradient, a water concentration gradient, and osmotic forces. These systems allow for a zero order and environment-independent release of the drug without reformulation of the material for different drugs. Nevertheless, these can be more expensive and require more quality control.</p></sec><sec id="sec5dot3-pharmaceutics-11-00441"><title>5.3. The Chemically Controlled System</title><p>This system involves a polymer–drug conjugate in which drug molecules are attached through spacer molecules to the polymer backbone. Inside the body, the bond between drug and polymer carrier is broken by either enzymatic cleavage or other hydrolysis. Diverse types of hydrolysable and biodegradable chemical linkages are used to affix the desired drug to the polymer backbone [<xref rid="B162-pharmaceutics-11-00441" ref-type="bibr">162</xref>]. Usually these polymer–drug conjugates have a transport system to direct the polymer to target tissues or organs. Aside from cleavable and hydrolysable polymers, chemically controlled systems also use biodegradable or bioerodible polymers. The difference between the two systems depends upon the mechanism of polymer degradation. The biodegradation involves the cleavage of polymer chains with a subsequent decrease in size; however, bioerosion is mediated by the bulk or surface erosion of the polymer with a subsequent decrease in size. In all these cases, the drug release depends on the composition of the polymer, so the polymer can control the kinetics of the drug release into a target area [<xref rid="B163-pharmaceutics-11-00441" ref-type="bibr">163</xref>].</p></sec><sec id="sec5dot4-pharmaceutics-11-00441"><title>5.4. The Magnetically Controlled System</title><p>This system involves fabrication of the drug-carrying polymeric matrix with a tiny magnetic ring. The outer surface is covered with a drug-impermeable polymer except for one central cavity. After application of an external magnetic field, the magnet starts vibrating and releasing the drug molecules at the desired rate. On the other hand, to gain efficient control over the particle motion, it is necessary to overcome the hemodynamic force by the external magnetic force. Thus, weak magnetic fields should be applied in case of an in vivo application. Metals such as iron, nickel, and cobalt are commonly used for this purpose [<xref rid="B164-pharmaceutics-11-00441" ref-type="bibr">164</xref>].</p></sec><sec id="sec5dot5-pharmaceutics-11-00441"><title>5.5. A Targeted Drug Delivery System</title><p>Despite the effectiveness of the above-mentioned methods, they are not applicable to all kinds of drugs and associated diseases. There is a need to optimize other delivery systems including self-regulated insulin delivery vehicles, protein delivery systems, poorly soluble formulations, and targeted delivery systems. Among these, targeted drug delivery systems have received a lot of attention because they involve nanotechnology-based delivery systems. Two types of approaches are mostly used for targeted drug delivery: active targeted drug delivery and passive targeted drug delivery.</p><sec id="sec5dot5dot1-pharmaceutics-11-00441"><title>5.5.1. Active Targeted Drug Delivery</title><p>In this system, delivery vehicles (such as nanoparticles) are more specific to the target area. This is achieved by getting the information about the receptors of the target cells and by attaching the receptor-specific ligand to the vehicle. For example, tumor cells are targeted by conjugating transferrin to the nanoparticles that mediate transferrin–receptor endocytosis after interaction. This conjugation process increases drug delivery efficiency as compared to the nonconjugation method. Magneto liposomes are another method of targeted drug delivery and act as a contrast agent in magnetic resonance imaging. Liposomes conjugated to a desired drug can be delivered to the target area through the mechanism of magnetic positioning [<xref rid="B165-pharmaceutics-11-00441" ref-type="bibr">165</xref>]. Moreover, activation of targeted nanoparticles can be implemented by target-specific triggers such as pH and redox potential. Some special areas or cellular compartments in the body have pH different from that of most of the other body parts. This difference can be exploited by trigger-based nanoparticles to release a loaded drug in only specific areas. Tumor cells create hypoxic conditions by altering the redox potential in the surrounding area. Redox-sensitive nanoparticles are utilized to selectively release the drug in the tumor area [<xref rid="B166-pharmaceutics-11-00441" ref-type="bibr">166</xref>].</p></sec><sec id="sec5dot5dot2-pharmaceutics-11-00441"><title>5.5.2. Passive Targeted Drug Delivery</title><p>In this process, the efficacy of a drug is directly linked to circulation time [<xref rid="B167-pharmaceutics-11-00441" ref-type="bibr">167</xref>]. To reach this goal, nanoparticles are covered by a distinct type of covering such as polyethylene glycol (PEG). This approach allows for the linkage of water molecules to the oxygen atom on the PEG surface through hydrogen bonding, which imparts hydrophilic properties to the surface. Because of the establishment of a thin water film on the surface of nanoparticles, they are protected from phagocytosis. Moreover, drug-carrying molecules remain longer in the circulation because of hydrophobic interactions common in the reticuloendothelial system [<xref rid="B165-pharmaceutics-11-00441" ref-type="bibr">165</xref>]. Nanoparticles having a size of 10 and 100 nanometers are recommended for the longer persistence in the systemic circulation [<xref rid="B166-pharmaceutics-11-00441" ref-type="bibr">166</xref>].</p><p>Via application of both active and passive targeting, drug-carrying nanoparticles can have major advantages over a conventional drug. The circulation time of nanoparticles inside the body is prolonged substantially unless they are strongly drawn to their target via magnetic positioning, cell-specific ligands, or pH-responsive materials. Because of specific targeting by nanoparticles, there are fewer adverse effects [<xref rid="B163-pharmaceutics-11-00441" ref-type="bibr">163</xref>].</p></sec></sec><sec id="sec5dot6-pharmaceutics-11-00441"><title>5.6. Examples of Targeted Drug Delivery</title><p>The efficacy of a designed drug mainly depends upon its half-life, specificity, and delivery to a target site. Half-life and specificity are the characteristics of the drug itself; however, targeted delivery depends on the target location. It is relatively easy to target the cell surface rather than intracellular compartments. Many approaches have been developed for efficient drug delivery with minimal off-target effects; some of which are discussed above in detail.</p><p>TLRs are mainly expressed on immune cells such as monocytes, macrophages, and DCs. The overactivation of TLRs in these cells can cause inflammation, which is a cause of various diseases such as asthma, COPD, cancer, tuberculosis, and HIV infection. The on-target delivery of drugs to activate or inhibit the key factors is the ultimate goal in these cases and may result in a cure. It is more challenging to target intracellular compartments because of the outer barrier in the form of the plasma membrane, especially in the case of gene therapy.</p><p>Liposomes are considered one of the delivery systems for phagocyte-associated therapies to deliver drugs into target cells. Liposomes have the advantage of biocompatibility, low immunogenicity, good drug protection, and cell specificity. Nonetheless, they also possess some limitations such as short shelf life, high cost, poor scale-up, and in some cases off-target effects and toxicity. They should be protected from macrophages by shielding with PEG if the target is other than macrophages [<xref rid="B168-pharmaceutics-11-00441" ref-type="bibr">168</xref>]. The following physicochemical properties of liposomes contribute to the successful delivery of drug molecules into cells. (1) Size: some studies show greater uptake of small liposomes (<100 nm) [<xref rid="B169-pharmaceutics-11-00441" ref-type="bibr">169</xref>] while others illustrate a direct relation of size with the ease of uptake [<xref rid="B170-pharmaceutics-11-00441" ref-type="bibr">170</xref>,<xref rid="B171-pharmaceutics-11-00441" ref-type="bibr">171</xref>]. (2) Charge: cationic liposomes containing stearylamine induce apoptosis in RAW 264.7 macrophages via the mitochondrial pathway by stimulating the production of reactive oxygen species, cytochrome C release, expression of caspases, and activation of protein kinase C (PKC) [<xref rid="B172-pharmaceutics-11-00441" ref-type="bibr">172</xref>,<xref rid="B173-pharmaceutics-11-00441" ref-type="bibr">173</xref>,<xref rid="B174-pharmaceutics-11-00441" ref-type="bibr">174</xref>,<xref rid="B175-pharmaceutics-11-00441" ref-type="bibr">175</xref>]. These findings have shifted the trend toward anionic and neutral liposomes. Macrophages preferentially recognize negatively charged liposomes such as phosphatidylglycerol and phosphatidylserine [<xref rid="B169-pharmaceutics-11-00441" ref-type="bibr">169</xref>]. A comparison of liposomes containing phosphatidylserine (anionic) and phosphatidylcholine (neutral) has revealed enhanced internalization of negatively charged liposomes by macrophages [<xref rid="B176-pharmaceutics-11-00441" ref-type="bibr">176</xref>]. (3) pH: Liposomes with pH-sensitive properties are used to carry plasmid DNA to RAW 264.7 cells [<xref rid="B177-pharmaceutics-11-00441" ref-type="bibr">177</xref>]. Recently developed amphoteric liposomes, Nov038, are employed to deliver antisense oligonucleotides to an inflammatory site in experimental arthritis. They are anionic at neutral pH and cationic at low pH thereby avoiding nonspecific interactions in blood and facilitating complexation with nucleic acids, respectively [<xref rid="B178-pharmaceutics-11-00441" ref-type="bibr">178</xref>]. (4) Ligands: The specificity and uptake of liposomes can be improved by the addition of some ligands such as peptides, antibodies, proteins, polysaccharides, or glycoproteins. Cell-penetrating peptides and cell-targeting peptides have been linked to liposomes to enhance cellular uptake and specificity, respectively, for various cell types [<xref rid="B179-pharmaceutics-11-00441" ref-type="bibr">179</xref>]. Conjugation of GGP-peptide (GGPNLTGRW) to liposomes enhances its specificity to monocytes and neutrophils [<xref rid="B180-pharmaceutics-11-00441" ref-type="bibr">180</xref>,<xref rid="B181-pharmaceutics-11-00441" ref-type="bibr">181</xref>]. Similarly, integrin receptors on monocytes can be targeted more specifically by the addition of RGD-peptide (Arg–Gly–Asp) to liposomes [<xref rid="B182-pharmaceutics-11-00441" ref-type="bibr">182</xref>,<xref rid="B183-pharmaceutics-11-00441" ref-type="bibr">183</xref>]. Conjugation of nonspecific or monoclonal antibodies to liposomes (immunoliposomes) opsonizes the liposome, and this event may activate the complement system with subsequent enhanced uptake by phagocytes [<xref rid="B184-pharmaceutics-11-00441" ref-type="bibr">184</xref>,<xref rid="B185-pharmaceutics-11-00441" ref-type="bibr">185</xref>]. The conjugation of IgG and IgM to liposomes (nonimmunoliposomes) can cause their opsonization in vivo for enhanced uptake by macrophages [<xref rid="B185-pharmaceutics-11-00441" ref-type="bibr">185</xref>]. Mannosylated liposomes can target immune cells by interacting with the C-type lectins expressed by them; this approach enhances the in vitro and in vivo uptake of liposomes [<xref rid="B186-pharmaceutics-11-00441" ref-type="bibr">186</xref>]. Mannosylated liposomes have been used to deliver anticancer agents, a nuclear factor-B (NFB) decoy, and an anti-inflammatory drug, dexamethasone palmitate [<xref rid="B186-pharmaceutics-11-00441" ref-type="bibr">186</xref>,<xref rid="B187-pharmaceutics-11-00441" ref-type="bibr">187</xref>].</p><p>Nanoparticles have been employed to deliver immunotherapeutic drugs to target cells. An immune-cell response can strongly inhibit the progression of cancer; therefore, targeting these cells holds great promise for cancer treatment. In this regard, TLR agonists are used as adjuvants to treat various cancers [<xref rid="B188-pharmaceutics-11-00441" ref-type="bibr">188</xref>]. Aside from their role in an innate immune response, TLRs can trigger adaptive immunity by activating CD8<sup>+</sup> T cells and CD4<sup>+</sup> T helper (T<sub>H</sub>) cells by priming antigen-presenting cells [<xref rid="B189-pharmaceutics-11-00441" ref-type="bibr">189</xref>]. Because of the TLR3-, TLR7-, and TLR9-mediated CD8<sup>+</sup> T-cell response in T<sub>H</sub>1 mode, agonists specific to these TLRs are used for cancer nonvaccines [<xref rid="B190-pharmaceutics-11-00441" ref-type="bibr">190</xref>,<xref rid="B191-pharmaceutics-11-00441" ref-type="bibr">191</xref>]. A TLR9 agonist, CpG, has been tested for enhanced immune activation via conjugation with a nanocarrier or cationic polymer [<xref rid="B192-pharmaceutics-11-00441" ref-type="bibr">192</xref>,<xref rid="B193-pharmaceutics-11-00441" ref-type="bibr">193</xref>]. The cationic antigen peptide and anionic TLR3 agonist poly-I:C have been coloaded onto gold nanoparticles for a robust antigen-specific response of CD8<sup>+</sup> T cells in vivo [<xref rid="B194-pharmaceutics-11-00441" ref-type="bibr">194</xref>]. The synergy among various TLR agonists has been achieved via multifaceted drug loading by means of relevant nanoparticles [<xref rid="B195-pharmaceutics-11-00441" ref-type="bibr">195</xref>]. Moreover, TLR agonists and small interfering RNAs have been codelivered using nanoparticles against cancer [<xref rid="B196-pharmaceutics-11-00441" ref-type="bibr">196</xref>,<xref rid="B197-pharmaceutics-11-00441" ref-type="bibr">197</xref>].</p><p>Hydrogels are three-dimensional hydrophilic polymers capable of absorbing a large amount of physiological fluid while maintaining their networking structure [<xref rid="B198-pharmaceutics-11-00441" ref-type="bibr">198</xref>,<xref rid="B199-pharmaceutics-11-00441" ref-type="bibr">199</xref>]. Instead of macroscopic hydrogels, there is a huge interest in microscopic and nanoscopic hydrogels which are known as microgels and nanogels, respectively [<xref rid="B200-pharmaceutics-11-00441" ref-type="bibr">200</xref>,<xref rid="B201-pharmaceutics-11-00441" ref-type="bibr">201</xref>]. Phase I clinical trials of amphiphilic cholesterol-modified pullulan nanogels carrying a truncated HER2 protein have been conducted as cancer vaccination via a T-cell immune response and antibody response against HER2 [<xref rid="B202-pharmaceutics-11-00441" ref-type="bibr">202</xref>,<xref rid="B203-pharmaceutics-11-00441" ref-type="bibr">203</xref>]. The toxicity of the intracellularly targeted drugs can be minimized by means of the degradable nanogels, which are affected by various stimuli such as pH, enzymatic activity, or reducing agents [<xref rid="B204-pharmaceutics-11-00441" ref-type="bibr">204</xref>]. The acrylamide nanogels copolymerized with an acid cleavable bisacrylamide acetal crosslinker can be used to deliver TLR9-targeting CpG DNA into antigen-presenting cells [<xref rid="B205-pharmaceutics-11-00441" ref-type="bibr">205</xref>,<xref rid="B206-pharmaceutics-11-00441" ref-type="bibr">206</xref>].</p></sec></sec><sec id="sec6-pharmaceutics-11-00441"><title>6. Drug Delivery Vehicles</title><p>Vehicles are primarily used for the targeted delivery of drugs. The targeted approaches have three main advantages over conventional ones: (1) more stability and solubility; (2) better pharmacokinetic properties due to longer half-life, better absorption, and low volume for distribution; (3) better pharmacodynamic properties due to more specificity and high therapeutic index. An ideal drug delivery vehicle should possess qualities such as biocompatibility, nontoxicity, biodegradability, nonimmunogenicity [<xref rid="B207-pharmaceutics-11-00441" ref-type="bibr">207</xref>], and resistance to phagocytosis by the host’s defense system [<xref rid="B208-pharmaceutics-11-00441" ref-type="bibr">208</xref>]. It must cross blood–brain barrier and tumor vasculature (for tumor chemotherapy). It must be selectively and specifically recognized by the target cells while maintaining the specificity of other surface ligands. The ligand–drug complex must keep stability in interstitial fluid, plasma, and other body fluids. The vehicle must release the drug inside target cells, tissues, or organs [<xref rid="B209-pharmaceutics-11-00441" ref-type="bibr">209</xref>,<xref rid="B210-pharmaceutics-11-00441" ref-type="bibr">210</xref>]. There are different types of drug delivery vehicles that carry the drug to a diseased tissue. A few of them are discussed below (<xref ref-type="fig" rid="pharmaceutics-11-00441-f002">Figure 2</xref>).</p><sec id="sec6dot1-pharmaceutics-11-00441"><title>6.1. Liposomes</title><p>Liposomes are composed of either natural or synthetic phospholipids. The prevailing chemical and physical attributes of a liposome are confined to the characteristics of the constituent phospholipids including charge density, permeability, and steric hindrance [<xref rid="B211-pharmaceutics-11-00441" ref-type="bibr">211</xref>]. Drug loading within liposomes can be accomplished by (i) the use of organic solvents and solvent exchange mechanisms; (ii) liposome formation in an aqueous solution saturated with a soluble drug; (iii) pH gradient methods; and (iv) the use of lipophilic drugs [<xref rid="B212-pharmaceutics-11-00441" ref-type="bibr">212</xref>].</p><p>Generally, liposomes reach their site of action from the bloodstream by exiting into the interstitial space. They achieve specific targeting by both active and passive targeting approaches. This is due to their smaller size (~400 nm) and additional outer covering with other molecules such as PEG. PEGylation increases the circulation half-life of liposomes by lowering clearance by the mononuclear phagocyte system. The delivery mechanism by liposomes involves their fusion to the plasma membrane with a subsequent release of a drug inside the cell [<xref rid="B213-pharmaceutics-11-00441" ref-type="bibr">213</xref>]. Nevertheless, liposomes face the problems of instability, poor skin permeation, sterilization, and difficulties with large-scale production [<xref rid="B214-pharmaceutics-11-00441" ref-type="bibr">214</xref>,<xref rid="B215-pharmaceutics-11-00441" ref-type="bibr">215</xref>,<xref rid="B216-pharmaceutics-11-00441" ref-type="bibr">216</xref>,<xref rid="B217-pharmaceutics-11-00441" ref-type="bibr">217</xref>].</p><p>Proliposomes were introduced in 1986 to improve the stability of conventional liposomes [<xref rid="B218-pharmaceutics-11-00441" ref-type="bibr">218</xref>]. They are a smart substitute of conventional liposomes and consist of dry and free-floating particles that form a liposomal suspension on contact with water molecules. The solid nature solves the stability problem of conventional liposomes without affecting their intrinsic characteristics. They consist of three main components: a phospholipid, drug, and porous powder whose size controls the size of reconstituted liposomes [<xref rid="B219-pharmaceutics-11-00441" ref-type="bibr">219</xref>,<xref rid="B220-pharmaceutics-11-00441" ref-type="bibr">220</xref>,<xref rid="B221-pharmaceutics-11-00441" ref-type="bibr">221</xref>]. They can be synthesized by many methods such as film deposition on carriers [<xref rid="B222-pharmaceutics-11-00441" ref-type="bibr">222</xref>], crystal–film [<xref rid="B223-pharmaceutics-11-00441" ref-type="bibr">223</xref>], powder bed grinding [<xref rid="B224-pharmaceutics-11-00441" ref-type="bibr">224</xref>], fluidized-bed [<xref rid="B225-pharmaceutics-11-00441" ref-type="bibr">225</xref>], spray drying [<xref rid="B226-pharmaceutics-11-00441" ref-type="bibr">226</xref>], and freezing and drying [<xref rid="B227-pharmaceutics-11-00441" ref-type="bibr">227</xref>].</p><p>Niosomes (another version of liposomes) are spherical vesicles primarily consisting of nonionic hydrated surfactants, most commonly cholesterol (CHOL) and its derivatives. The exclusive architecture of niosomes makes them well suited for encapsulating both lipophilic and hydrophilic drugs. This can be done via absorption of the hydrophilic part in an aqueous core; meanwhile, the lipophilic material is sheathed by subdivision into a lipophilic sphere of the niosome bilayer [<xref rid="B228-pharmaceutics-11-00441" ref-type="bibr">228</xref>]. Generally, niosomes are synthesized by means of convenient and accessible surfactant materials [<xref rid="B229-pharmaceutics-11-00441" ref-type="bibr">229</xref>]. Hydrophilic–lipophilic balance is a dimensionless parameter that describes drug-entrapping capability and helps to regulate this property [<xref rid="B230-pharmaceutics-11-00441" ref-type="bibr">230</xref>]. Besides the surfactant composition, the methods of niosome preparation and drug encapsulation are additional criteria for the self-assembly of surfactants into niosomes [<xref rid="B231-pharmaceutics-11-00441" ref-type="bibr">231</xref>]. Depending upon the size of niosomes, they can be classified into three basic types. Unilamellar small vesicles range in size from 10 to 100 nm; unilamellar large vesicles range in size from 100 to 3000 nm; and multilamellar vesicles are composed of more than one bilayer [<xref rid="B232-pharmaceutics-11-00441" ref-type="bibr">232</xref>]. A variety of methods are being used to form niosomes: the thin-film hydration method [<xref rid="B233-pharmaceutics-11-00441" ref-type="bibr">233</xref>], hand-shaking method [<xref rid="B234-pharmaceutics-11-00441" ref-type="bibr">234</xref>], the “bubble” method [<xref rid="B234-pharmaceutics-11-00441" ref-type="bibr">234</xref>], ether injection method [<xref rid="B234-pharmaceutics-11-00441" ref-type="bibr">234</xref>], reverse phase evaporation method [<xref rid="B235-pharmaceutics-11-00441" ref-type="bibr">235</xref>], sonication method [<xref rid="B236-pharmaceutics-11-00441" ref-type="bibr">236</xref>], microfluidization method [<xref rid="B234-pharmaceutics-11-00441" ref-type="bibr">234</xref>], heating method [<xref rid="B237-pharmaceutics-11-00441" ref-type="bibr">237</xref>], freeze and thaw method [<xref rid="B235-pharmaceutics-11-00441" ref-type="bibr">235</xref>], dehydration rehydration method [<xref rid="B231-pharmaceutics-11-00441" ref-type="bibr">231</xref>], and proniosome technology [<xref rid="B238-pharmaceutics-11-00441" ref-type="bibr">238</xref>]. The drug-loading mechanism for niosomes includes a direct entrapment (passive loading) method and a remote loading (active loading) method; the former is the simpler one, whereas the latter boosts the efficiency of drug loading with the help of ions and pH [<xref rid="B239-pharmaceutics-11-00441" ref-type="bibr">239</xref>]. The drug release mechanism of niosomes depends on the concentration, course of administration, presence time, and effects of the drug in organs such as the liver, spleen, lungs, and bone marrow. Niosomal modification with polyethylene glycol (PEG) causes them to last for a longer period in circulation [<xref rid="B239-pharmaceutics-11-00441" ref-type="bibr">239</xref>]. Niosomes were first used in the cosmetics industry but now have caught the attention of pharmaceutical companies because of their many benefits for controlled drug delivery systems (nonimmunogenicity, biodegradability, and bioavailability), thus being a powerful candidate with excellent properties of the drug release mechanism [<xref rid="B240-pharmaceutics-11-00441" ref-type="bibr">240</xref>] and encapsulating a variety of drugs, e.g., insulin, DNA vaccine, doxorubicin, hemagglutinin, EGFP, ovalbumin, α-interferon, etc. [<xref rid="B233-pharmaceutics-11-00441" ref-type="bibr">233</xref>].</p></sec><sec id="sec6dot2-pharmaceutics-11-00441"><title>6.2. Hydrogels</title><p>A hydrogel is a cross-linked polymeric network material produced by a reaction of one or more monomers and can swell and preserve a large quantity of water without being dissolved. Hydrogels have gained huge recognition in the last 50 years owing to their extraordinary role in drug delivery and a wide range of other applications [<xref rid="B241-pharmaceutics-11-00441" ref-type="bibr">241</xref>]. Hydrogels can be produced from synthetic as well as natural polymers. Synthetic polymers have hydrophobic properties and are much stronger than natural polymers. Their stability and deliberate degeneration are implemented by the mechanical durability of the material which in turn depends on its optical design [<xref rid="B242-pharmaceutics-11-00441" ref-type="bibr">242</xref>]. The water-absorbing property of hydrogels is due to the hydrophilic functional groups attached to the polymeric backbone, whereas their insolubility is a consequence of cross-links among network chains [<xref rid="B243-pharmaceutics-11-00441" ref-type="bibr">243</xref>]. Almost all hydrogels are glassy when dehydrated, and drug discharge mostly occurs after simultaneous water and drug retention through a swelling-based controlled-release system [<xref rid="B244-pharmaceutics-11-00441" ref-type="bibr">244</xref>]. Different authors have recommended a novel class of hydrogels that feature both a temperature- and pH-sensitive swelling mechanism. These materials can yield tremendous results in protein drug delivery and enzymatic processes [<xref rid="B245-pharmaceutics-11-00441" ref-type="bibr">245</xref>]. N-alkyl acrylamide is a very common class of monomers that is being used in the production of temperature-sensitive hydrogels. This monomer has various side chains which have a useful link with water via hydrogen bonding [<xref rid="B246-pharmaceutics-11-00441" ref-type="bibr">246</xref>].</p></sec><sec id="sec6dot3-pharmaceutics-11-00441"><title>6.3. Prodrugs</title><p>Prodrugs are chemical byproducts that require one or two enzymatic or chemical conversional steps to form an active drug. In some situations, a prodrug is composed of a single compound in which two pharmacologically active drugs are joined together and this single molecule serves as a promoiety for other derivatives such as codrugs [<xref rid="B247-pharmaceutics-11-00441" ref-type="bibr">247</xref>]. Prodrugs give various opportunities to scientists to overcome numerous hurdles on the path of drug production and release, e.g., chemical instability, low aqueous solubility, insufficient oral absorption, poor brain penetration, local irritation and toxicity, and fast presystemic metabolism. The prodrug format can also enhance drug targeting and life cycle management after improvement of the drug release properties of existing prodrugs [<xref rid="B248-pharmaceutics-11-00441" ref-type="bibr">248</xref>]. The most inspiring feature of a prodrug is that it is site selective. This site selectivity can be accomplished in four ways: (i) selective metabolic activation through enzymes, (ii) transporter-mediated delivery, (iii) antigen targeting, and (iv) passive drug enrichment in an organ [<xref rid="B249-pharmaceutics-11-00441" ref-type="bibr">249</xref>].</p></sec><sec id="sec6dot4-pharmaceutics-11-00441"><title>6.4. The Nanoparticle System</title><p>Nanocapsules are vesicles in which a drug is uniformly and physically diffused inside a cavity ringed by a polymeric membrane. Nanoparticles range in size from 10 to 1000 nm. To produce nanospheres or nanocapsules, the drug is either entrapped, dissolved, encapsulated, or affixed to a nanoparticle matrix [<xref rid="B250-pharmaceutics-11-00441" ref-type="bibr">250</xref>]. Nanoparticles can be prepared by various methods including polymerization of poly(alkyl cyanoacrylate) (despite being biodegradable, it is well tolerated in vivo) [<xref rid="B251-pharmaceutics-11-00441" ref-type="bibr">251</xref>], the solvent extraction method (good for a laboratory scale operation) [<xref rid="B252-pharmaceutics-11-00441" ref-type="bibr">252</xref>], salting out emulsification method, and supercritical fluid technology (this method is advantageous because the solvent-free solute is precipitated) [<xref rid="B253-pharmaceutics-11-00441" ref-type="bibr">253</xref>]. The main purpose of an active nanoparticle delivery system is to lower the drug dose required to accomplish a distinct therapeutic outcome and thereby to reduce the cost and reduce the adverse effects. The two complementary and synergistic attributes of organic and inorganic nanostructured materials are extensively used in a drug delivery system. On one hand, hard nanoparticles constructed of an inorganic material (such as mesoporous and gold particles and quantum dots) can be used for the detection and diagnosis of a pathology inside diseased tissues. On the other hand, soft nanoparticles constructed of an organic material (such as liposomes and amphiphilic polymers) offer improved characteristics to deal with physicochemical conditions in pathological and healthy tissues [<xref rid="B254-pharmaceutics-11-00441" ref-type="bibr">254</xref>]. Appreciable developments in biodegradable nanoparticles have transpired in the past few decades. To enhance the therapeutic efficacy, numerous polymers have been tested in drug delivery research to effectively carry a drug to a target site with fewer adverse effects [<xref rid="B255-pharmaceutics-11-00441" ref-type="bibr">255</xref>].</p></sec><sec id="sec6dot5-pharmaceutics-11-00441"><title>6.5. Dendrimers</title><p>These are hyperbranched three-dimensional nanosized molecules composed of branching groups covalently attached to a pivotal core, arranged in monocentric layers that end with various externally activated functional groups [<xref rid="B256-pharmaceutics-11-00441" ref-type="bibr">256</xref>]. In solution, the structure of dendrimers can be determined by various factors such as the spacer length, generation, surface modification, ionic strength, temperature, and pH [<xref rid="B257-pharmaceutics-11-00441" ref-type="bibr">257</xref>]. They can boost the bioavailability and solubility of hydrophobic drugs that are conjugated to their surface functional groups or entrapped in their intramolecular cavity. Their surface modification with peptides, sugar groups, monoclonal antibodies, or folic acid can be employed for site-specific delivery of a drug [<xref rid="B258-pharmaceutics-11-00441" ref-type="bibr">258</xref>]. Analysis of the association between inclusion components and dendrimers is an essential step for the advancement of this novel technology [<xref rid="B259-pharmaceutics-11-00441" ref-type="bibr">259</xref>]. Dendrimers are useful as a carrier for gene therapy and move into the cell through endocytosis with subsequent degradation by lysosomes [<xref rid="B260-pharmaceutics-11-00441" ref-type="bibr">260</xref>]. The targeted cargo genes are then discharged and penetrate the nucleus to perform their work in gene therapy [<xref rid="B258-pharmaceutics-11-00441" ref-type="bibr">258</xref>].</p></sec><sec id="sec6dot6-pharmaceutics-11-00441"><title>6.6. Cyclodextrins</title><p>Cyclodextrins are a group of cyclic oligosaccharides and have tremendous applications in the pharmaceutical industry. They are synthesized from glucose-containing compounds, e.g., <sc>d</sc>-glucopyranoside building blocks that have both α-1,6-glycosidic and α-1,4-linkages. Cyclodextrins have three-dimensional structure, which makes them suitable for pharmaceutical applications. The enormous number of hydroxyl groups makes cyclodextrins water soluble, while their hydrophobic cavity allows for encapsulation of various lipophilic molecules ranging from ions to small-molecule drugs, oligonucleotides, and proteins [<xref rid="B261-pharmaceutics-11-00441" ref-type="bibr">261</xref>]. At a laboratory scale, cyclodextrins enhance drug delivery through membranes if specific parameters are considered, e.g., unstirred water layer [<xref rid="B262-pharmaceutics-11-00441" ref-type="bibr">262</xref>].</p></sec></sec><sec id="sec7-pharmaceutics-11-00441"><title>7. Concluding Remarks</title><p>TLRs are involved in various autoimmune, inflammatory, and malignant diseases. It is worthwhile to design drugs targeting TLRs and their associated members participating in TLR signaling pathways. The designed drugs must be safe, highly specific, and effective to treat the patient. Few such drugs are mentioned above; however, there is always room for improvement of the existing ones via deep analysis of the structure of a target molecule and via improvement of drug discovery approaches. Even after successful in vitro evaluation, sometimes the drugs do not work as expected in vivo. They might also show adverse effects because of their nonspecific unloading inside the human body. Therefore, selection of an appropriate delivery method is very important for maximal and safe therapeutic benefits. Liposomes, hydrogels, nanoparticles, and other drug delivery modalities must be kept in mind during in vivo evaluation.</p></sec></body><back><notes><title>Author Contributions</title><p>Writing—original draft preparation and visualization, N.J., F.Y., and N.J.; conceptualization and writing—review and editing, S.C.</p></notes><notes><title>Funding</title><p>This study was supported by the National Research Foundation of Korea (NRF-2019M3A9A8065098; NRF-2019R1H1A2039674; 2019M3D1A1078938) and the Commercialization Promotion Agency for R&D Outcomes funded by the Ministry of Science and ICT (2018K000369).</p></notes><notes notes-type="COI-statement"><title>Conflicts of Interest</title><p>The authors declare no conflict of interest.</p></notes><ref-list><title>References</title><ref id="B1-pharmaceutics-11-00441"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Akira</surname><given-names>S.</given-names></name><name><surname>Takeda</surname><given-names>K.</given-names></name><name><surname>Kaisho</surname><given-names>T.</given-names></name></person-group><article-title>Toll-like receptors: Critical proteins linking innate and acquired immunity</article-title><source>Nat. 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Most of TLRs activate downstream signaling in a MyD88-dependent manner with or without recruiting MAL; however, TLR3 (only) and TLR4 (alternatively) use TRIF/TRAM adaptors to activate IRFs. The activation of a TLR signaling pathway leads to the translocation of transcription factors (NF-κB (p50 or p65), AP-1, IRF3, and IRF7) into the nucleus and allows them to bind the target sequence(s) of inflammatory and interferon-responsive genes. Abbreviations: TLR, Toll-like receptor; TIR, Toll/interleukin-1 receptor domain; MAL, MyD88 adaptor like; MyD88, myeloid differentiation primary response 88; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain-containing adaptor inducing interferon β; IRAK, interleukin receptor-associated kinase; RIP, receptor-interacting protein; TRAF, tumor necrosis factor receptor (TNFR)-associated factor; TAB, TAK-1–binding protein; TAK1, transforming growth factor β-activated kinase 1; TBK1, TANK-binding kinase 1; NEMO, NF-κB essential modulator; IκB, inhibitor of κB; IKK, inhibitor of κB kinase; MAP, mitogen-activated protein; ERK, extracellular signal–regulated kinase; JNK, c-Jun N-terminal kinase; p38, protein 38; AP-1, activated protein 1; IFN, interferon; IL, interleukin; IRF, interferon response factor; NF-κB, nuclear factor κB; TNF-α, tumor necrosis factor α.</p></caption><graphic xlink:href="pharmaceutics-11-00441-g001"></graphic></fig><fig id="pharmaceutics-11-00441-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Drug delivery vehicles. (<bold>a</bold>) Liposomes are composed of phospholipids or other small-molecule compounds with various sizes, composition, and drug-loading capability. A lipid-soluble drug is attached to the lipid bilayer for safe and reliable transport to a target tissue. (<bold>b</bold>) Dendrimers are abundantly branched macromolecular structures having three major components: the core, branches, and a reactive surface, which has drug-entrapping properties. (<bold>c</bold>) A hydrogel is a three-dimensional structure consisting of a hydrophilic network of polymer chains, where drug molecules are attached to the polymeric chains. After exposure to the specific stimuli in an aqueous environment, the hydrogel swells and releases drug molecules into the surrounding environment. (<bold>d</bold>) Nanoparticles are small particles ranging in size from 1 to 100 nm where drugs are attached to the surface. (<bold>e</bold>) A prodrug is an inactive form of a drug and is activated after enzymatic or chemical metabolism inside the human body by releasing a promoiety. This property makes the drug a suitable candidate for specific targeting and controlled release. (<bold>f</bold>) Cyclodextrin represents a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity.</p></caption><graphic xlink:href="pharmaceutics-11-00441-g002"></graphic></fig><table-wrap id="pharmaceutics-11-00441-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceutics-11-00441-t001_Table 1</object-id><label>Table 1</label><caption><p>Expression, localization, and ligands of Toll-like receptors (TLRs).</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Receptor</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Microbial Ligand(s)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Microbial Ligand Source</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Endogenous Ligand(s)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Adaptor</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">TLR Localization</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Expression</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR1/2/6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Triacyl and diacyl lipopeptides, glycolipids, zymosan, lipoteichoic acid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bacterial lipoprotein and peptidoglycan, fungi, mycoplasma, gram-positive bacteria</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HMGB1, HSPs, HDLs, hyaluronan,</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell surface</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, Mon, Mac, B</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Double-stranded RNA (dsRNA)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Viruses</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Self dsRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TRIF-TRAM</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, L, Plt, B</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lipopolysaccharide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Gram-negative bacteria</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HSPs, fibrinogen, HA, heparin sulfate, HMGB1, LDLs</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL/TRIF-TRAM</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell surface</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mon, Mac, N, DCs, M, B, C</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR5</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Flagellin, profilin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bacteria, <italic>Toxoplasma gondii</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HMGB1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell surface</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, Mon, Mac, C, IE</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Single-stranded RNA (ssRNA)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Viruses</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Self ssRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, Mon, Mc, Plt, B</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ssRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Viruses</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Self ssRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, Mon, Mac, M, IECs</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bacteria, viruses</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Self DNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, Mon, Mac, Plt, B</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR10</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Triacylated lipopeptides</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell surface</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mon, N, B, LN, S</td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations: HMGB1, high mobility group box 1; HSPs, heat shock proteins; HDLs, high-density lipoproteins; LDLs, low density lipoproteins; MyD88, myeloid differentiation primary response protein 88; MAL, MyD88-adaptor-like; DCs, dendritic cells; Mon, monocytes; Mac, macrophages; B, B-cell; Plt, platelets; N, neutrophils; M, mast cells; C, cancer cells; IE, intestinal epithelium; IECs, intestinal epithelial cells; LN, lymph node; S, spleen; HA, hyaluronic acid; NA, not available.</p></fn></table-wrap-foot></table-wrap><table-wrap id="pharmaceutics-11-00441-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceutics-11-00441-t002_Table 2</object-id><label>Table 2</label><caption><p>TLR-targeting drugs in clinical trials.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">TLR</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ligand</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Type</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Disease</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mechanism</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Phase</th></tr></thead><tbody><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR2 (with TLR1 or -6)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">OPN-305 and derivatives</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Monoclonal antibody</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inflammatory disease, myelodysplastic syndrome, kidney transplant rejection, pancreatic tumor</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CBLB6I2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Synthetic lipopeptide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancers (breast)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Blood cell recovery</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ISA-20I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Peptide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Head and neck tumor</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Maturation of DCs</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Poly-ICLC</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Synthetic dsRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Various cancers (e.g., colon, ovarian, breast, prostate)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulation and modulation of tumor microenvironment</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PRV-300</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Antibody</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td rowspan="10" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NI-0I0I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Antibody</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Rheumatoid arthritis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GLA and derivatives</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glycolipid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma, sarcoma, viral infection</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LPS</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glycolipid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inflammation</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GSKI79509I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glycolipid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancer</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Eritoran</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glycolipid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Insulin sensitivity</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CX-0I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Polysaccharide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Leukemia</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Microenvironment modulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEPA-I0</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancer</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PET-lipid A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glycolipid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancers</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">JKB and derivatives</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hepatitis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MN-I66</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Brain injury, glioblastoma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR5</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Entolimod</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recombinant protein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancers</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mobilan</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recombinant protein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancers (prostate)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">VAX and derivatives</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recombinant protein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Influenza</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td rowspan="5" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Imiquimod</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Various cancers, actinic keratosis, and viral infections</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I to Phase IV, approved</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GSK2245035</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma and rhinitis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IFN production</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GS-9620</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hepatitis B</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">pDC activator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">RO702053I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hepatitis B</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GSK2245035</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IFN-α production and immune stimulation</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">VTX-2337</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Various cancers</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td rowspan="8" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SD-I0I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CpG-C class oligonucleotide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lymphoma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Antitumor immune response</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CYT003</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oligonucleotide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TH-I–mediated immune response</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MGNI703</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DNA-based molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HIV and melanoma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Antiviral and antitumor response</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CpG-7909</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oligonucleotide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lymphoma, malaria, HIV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CpG-I0I04</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oligonucleotide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hookworm infection</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CpG-ODN</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nucleotide-based</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung tumor</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hydroxychloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sjogren’s syndrome</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune suppressor</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase III</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AZDI4I9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CpG oligonucleotide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IFN production</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations: TLR, Toll-like receptor; DCs, dendritic cells; dsRNA, double-stranded RNA; GLA, glucopyranosyl lipid A; IFN, interferon; HIV, human immunodeficiency virus; ODN, oligodeoxynucleotide.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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