Polyphenol nanoformulations for cancer therapy: experimental evidence and clinical perspective
Identifieur interne : 004A76 ( Pmc/Corpus ); précédent : 004A75; suivant : 004A77Polyphenol nanoformulations for cancer therapy: experimental evidence and clinical perspective
Auteurs : Yasamin Davatgaran-Taghipour ; Salar Masoomzadeh ; Mohammad Hosein Farzaei ; Roodabeh Bahramsoltani ; Zahra Karimi-Soureh ; Roja Rahimi ; Mohammad AbdollahiSource :
- International Journal of Nanomedicine [ 1176-9114 ] ; 2017.
Abstract
Cancer is defined as the abnormal cell growth that can cause life-threatening malignancies with high financial costs for patients as well as the health care system. Natural polyphenols have long been used for the prevention and treatment of several disorders due to their antioxidant, anti-inflammatory, cytotoxic, antineoplastic, and immunomodulatory effects discussed in the literature; thus, these phytochemicals are potentially able to act as chemopreventive and chemotherapeutic agents in different types of cancer. One of the problems regarding the use of polyphenolic compounds is their low bioavailability. Different types of formulations have been designed for the improvement of bioavailability of these compounds, nanonization being one of the most notable approaches among them. This study aimed to review current data on the nanoformulations of natural polyphenols as chemopreventive and chemotherapeutic agents and to discuss their molecular anticancer mechanisms of action. Nanoformulations of natural polyphenols as bioactive agents, including resveratrol, curcumin, quercetin, epigallocatechin-3-gallate, chrysin, baicalein, luteolin, honokiol, silibinin, and coumarin derivatives, in a dose-dependent manner, result in better efficacy for the prevention and treatment of cancer. The impact of nanoformulation methods for these natural agents on tumor cells has gained wider attention due to improvement in targeted therapy and bioavailability, as well as enhancement of stability. Today, several nanoformulations are designed for delivery of polyphenolic compounds, including nanosuspensions, solid lipid nanoparticles, liposomes, gold nanoparticles, and polymeric nanoparticles, which have resulted in better antineoplastic activity, higher intracellular concentration of polyphenols, slow and sustained release of the drugs, and improvement of proapoptotic activity against tumor cells. To conclude, natural polyphenols demonstrate remarkable anticancer potential in pharmacotherapy; however, the obstacles in terms of their bioavailability in and toxicity to normal cells, as well as targeted drug delivery to malignant cells, can be overcome using nanoformulation-based technologies, which optimize the bioefficacy of these natural drugs.
Url:
DOI: 10.2147/IJN.S131973
PubMed: 28435252
PubMed Central: 5388197
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PMC:5388197Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Polyphenol nanoformulations for cancer therapy: experimental evidence and clinical perspective</title><author><name sortKey="Davatgaran Taghipour, Yasamin" sort="Davatgaran Taghipour, Yasamin" uniqKey="Davatgaran Taghipour Y" first="Yasamin" last="Davatgaran-Taghipour">Yasamin Davatgaran-Taghipour</name><affiliation><nlm:aff id="af1-ijn-12-2689">Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation><affiliation><nlm:aff id="af2-ijn-12-2689">PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran</nlm:aff></affiliation></author><author><name sortKey="Masoomzadeh, Salar" sort="Masoomzadeh, Salar" uniqKey="Masoomzadeh S" first="Salar" last="Masoomzadeh">Salar Masoomzadeh</name><affiliation><nlm:aff id="af3-ijn-12-2689">Zanjan Pharmaceutical Nanotechnology Research Center, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran</nlm:aff></affiliation></author><author><name sortKey="Farzaei, Mohammad Hosein" sort="Farzaei, Mohammad Hosein" uniqKey="Farzaei M" first="Mohammad Hosein" last="Farzaei">Mohammad Hosein Farzaei</name><affiliation><nlm:aff id="af4-ijn-12-2689">Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran</nlm:aff></affiliation><affiliation><nlm:aff id="af5-ijn-12-2689">Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran</nlm:aff></affiliation></author><author><name sortKey="Bahramsoltani, Roodabeh" sort="Bahramsoltani, Roodabeh" uniqKey="Bahramsoltani R" first="Roodabeh" last="Bahramsoltani">Roodabeh Bahramsoltani</name><affiliation><nlm:aff id="af6-ijn-12-2689">Department of Traditional Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation></author><author><name sortKey="Karimi Soureh, Zahra" sort="Karimi Soureh, Zahra" uniqKey="Karimi Soureh Z" first="Zahra" last="Karimi-Soureh">Zahra Karimi-Soureh</name><affiliation><nlm:aff id="af7-ijn-12-2689">School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation></author><author><name sortKey="Rahimi, Roja" sort="Rahimi, Roja" uniqKey="Rahimi R" first="Roja" last="Rahimi">Roja Rahimi</name><affiliation><nlm:aff id="af6-ijn-12-2689">Department of Traditional Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation><affiliation><nlm:aff id="af8-ijn-12-2689">Evidence-Based Medicine Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation></author><author><name sortKey="Abdollahi, Mohammad" sort="Abdollahi, Mohammad" uniqKey="Abdollahi M" first="Mohammad" last="Abdollahi">Mohammad Abdollahi</name><affiliation><nlm:aff id="af9-ijn-12-2689">Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation><affiliation><nlm:aff id="af10-ijn-12-2689">Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28435252</idno><idno type="pmc">5388197</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388197</idno><idno type="RBID">PMC:5388197</idno><idno type="doi">10.2147/IJN.S131973</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">004A76</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004A76</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Polyphenol nanoformulations for cancer therapy: experimental evidence and clinical perspective</title><author><name sortKey="Davatgaran Taghipour, Yasamin" sort="Davatgaran Taghipour, Yasamin" uniqKey="Davatgaran Taghipour Y" first="Yasamin" last="Davatgaran-Taghipour">Yasamin Davatgaran-Taghipour</name><affiliation><nlm:aff id="af1-ijn-12-2689">Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation><affiliation><nlm:aff id="af2-ijn-12-2689">PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran</nlm:aff></affiliation></author><author><name sortKey="Masoomzadeh, Salar" sort="Masoomzadeh, Salar" uniqKey="Masoomzadeh S" first="Salar" last="Masoomzadeh">Salar Masoomzadeh</name><affiliation><nlm:aff id="af3-ijn-12-2689">Zanjan Pharmaceutical Nanotechnology Research Center, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran</nlm:aff></affiliation></author><author><name sortKey="Farzaei, Mohammad Hosein" sort="Farzaei, Mohammad Hosein" uniqKey="Farzaei M" first="Mohammad Hosein" last="Farzaei">Mohammad Hosein Farzaei</name><affiliation><nlm:aff id="af4-ijn-12-2689">Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran</nlm:aff></affiliation><affiliation><nlm:aff id="af5-ijn-12-2689">Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran</nlm:aff></affiliation></author><author><name sortKey="Bahramsoltani, Roodabeh" sort="Bahramsoltani, Roodabeh" uniqKey="Bahramsoltani R" first="Roodabeh" last="Bahramsoltani">Roodabeh Bahramsoltani</name><affiliation><nlm:aff id="af6-ijn-12-2689">Department of Traditional Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation></author><author><name sortKey="Karimi Soureh, Zahra" sort="Karimi Soureh, Zahra" uniqKey="Karimi Soureh Z" first="Zahra" last="Karimi-Soureh">Zahra Karimi-Soureh</name><affiliation><nlm:aff id="af7-ijn-12-2689">School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation></author><author><name sortKey="Rahimi, Roja" sort="Rahimi, Roja" uniqKey="Rahimi R" first="Roja" last="Rahimi">Roja Rahimi</name><affiliation><nlm:aff id="af6-ijn-12-2689">Department of Traditional Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation><affiliation><nlm:aff id="af8-ijn-12-2689">Evidence-Based Medicine Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation></author><author><name sortKey="Abdollahi, Mohammad" sort="Abdollahi, Mohammad" uniqKey="Abdollahi M" first="Mohammad" last="Abdollahi">Mohammad Abdollahi</name><affiliation><nlm:aff id="af9-ijn-12-2689">Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation><affiliation><nlm:aff id="af10-ijn-12-2689">Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran</nlm:aff></affiliation></author></analytic><series><title level="j">International Journal of Nanomedicine</title><idno type="ISSN">1176-9114</idno><idno type="eISSN">1178-2013</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Cancer is defined as the abnormal cell growth that can cause life-threatening malignancies with high financial costs for patients as well as the health care system. Natural polyphenols have long been used for the prevention and treatment of several disorders due to their antioxidant, anti-inflammatory, cytotoxic, antineoplastic, and immunomodulatory effects discussed in the literature; thus, these phytochemicals are potentially able to act as chemopreventive and chemotherapeutic agents in different types of cancer. One of the problems regarding the use of polyphenolic compounds is their low bioavailability. Different types of formulations have been designed for the improvement of bioavailability of these compounds, nanonization being one of the most notable approaches among them. This study aimed to review current data on the nanoformulations of natural polyphenols as chemopreventive and chemotherapeutic agents and to discuss their molecular anticancer mechanisms of action. Nanoformulations of natural polyphenols as bioactive agents, including resveratrol, curcumin, quercetin, epigallocatechin-3-gallate, chrysin, baicalein, luteolin, honokiol, silibinin, and coumarin derivatives, in a dose-dependent manner, result in better efficacy for the prevention and treatment of cancer. The impact of nanoformulation methods for these natural agents on tumor cells has gained wider attention due to improvement in targeted therapy and bioavailability, as well as enhancement of stability. Today, several nanoformulations are designed for delivery of polyphenolic compounds, including nanosuspensions, solid lipid nanoparticles, liposomes, gold nanoparticles, and polymeric nanoparticles, which have resulted in better antineoplastic activity, higher intracellular concentration of polyphenols, slow and sustained release of the drugs, and improvement of proapoptotic activity against tumor cells. To conclude, natural polyphenols demonstrate remarkable anticancer potential in pharmacotherapy; however, the obstacles in terms of their bioavailability in and toxicity to normal cells, as well as targeted drug delivery to malignant cells, can be overcome using nanoformulation-based technologies, which optimize the bioefficacy of these natural drugs.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ochwang, Do" uniqKey="Ochwang D">DO Ochwang’i</name></author><author><name sortKey="Kimwele, Cn" uniqKey="Kimwele C">CN Kimwele</name></author><author><name sortKey="Oduma, Ja" uniqKey="Oduma J">JA Oduma</name></author><author><name sortKey="Gathumbi, Pk" uniqKey="Gathumbi P">PK Gathumbi</name></author><author><name sortKey="Mbaria, Jm" uniqKey="Mbaria J">JM Mbaria</name></author><author><name sortKey="Kiama, Sg" uniqKey="Kiama S">SG Kiama</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jemal, A" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Nanomedicine</journal-id><journal-id journal-id-type="iso-abbrev">Int J Nanomedicine</journal-id><journal-id journal-id-type="publisher-id">International Journal of Nanomedicine</journal-id><journal-title-group><journal-title>International Journal of Nanomedicine</journal-title></journal-title-group><issn pub-type="ppub">1176-9114</issn><issn pub-type="epub">1178-2013</issn><publisher><publisher-name>Dove Medical Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28435252</article-id><article-id pub-id-type="pmc">5388197</article-id><article-id pub-id-type="doi">10.2147/IJN.S131973</article-id><article-id pub-id-type="publisher-id">ijn-12-2689</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Polyphenol nanoformulations for cancer therapy: experimental evidence and clinical perspective</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Davatgaran-Taghipour</surname><given-names>Yasamin</given-names></name><xref ref-type="aff" rid="af1-ijn-12-2689">1</xref><xref ref-type="aff" rid="af2-ijn-12-2689">2</xref></contrib><contrib contrib-type="author"><name><surname>Masoomzadeh</surname><given-names>Salar</given-names></name><xref ref-type="aff" rid="af3-ijn-12-2689">3</xref></contrib><contrib contrib-type="author"><name><surname>Farzaei</surname><given-names>Mohammad Hosein</given-names></name><xref ref-type="aff" rid="af4-ijn-12-2689">4</xref><xref ref-type="aff" rid="af5-ijn-12-2689">5</xref></contrib><contrib contrib-type="author"><name><surname>Bahramsoltani</surname><given-names>Roodabeh</given-names></name><xref ref-type="aff" rid="af6-ijn-12-2689">6</xref></contrib><contrib contrib-type="author"><name><surname>Karimi-Soureh</surname><given-names>Zahra</given-names></name><xref ref-type="aff" rid="af7-ijn-12-2689">7</xref></contrib><contrib contrib-type="author"><name><surname>Rahimi</surname><given-names>Roja</given-names></name><xref ref-type="aff" rid="af6-ijn-12-2689">6</xref><xref ref-type="aff" rid="af8-ijn-12-2689">8</xref></contrib><contrib contrib-type="author"><name><surname>Abdollahi</surname><given-names>Mohammad</given-names></name><xref ref-type="aff" rid="af9-ijn-12-2689">9</xref><xref ref-type="aff" rid="af10-ijn-12-2689">10</xref><xref ref-type="corresp" rid="c1-ijn-12-2689"></xref></contrib></contrib-group><aff id="af1-ijn-12-2689"><label>1</label>Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran</aff><aff id="af2-ijn-12-2689"><label>2</label>PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran</aff><aff id="af3-ijn-12-2689"><label>3</label>Zanjan Pharmaceutical Nanotechnology Research Center, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran</aff><aff id="af4-ijn-12-2689"><label>4</label>Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran</aff><aff id="af5-ijn-12-2689"><label>5</label>Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran</aff><aff id="af6-ijn-12-2689"><label>6</label>Department of Traditional Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran</aff><aff id="af7-ijn-12-2689"><label>7</label>School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran</aff><aff id="af8-ijn-12-2689"><label>8</label>Evidence-Based Medicine Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran</aff><aff id="af9-ijn-12-2689"><label>9</label>Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran</aff><aff id="af10-ijn-12-2689"><label>10</label>Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran</aff><author-notes><corresp id="c1-ijn-12-2689">Correspondence: Mohammad Abdollahi, Division of Toxicology, Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Keshavarz Bulvard, Ebn-E-Sina Street, Tehran 1417614411, Iran, Email <email>mohammad@tums.ac.ir</email></corresp></author-notes><pub-date pub-type="collection"><year>2017</year></pub-date><pub-date pub-type="epub"><day>04</day><month>4</month><year>2017</year></pub-date><volume>12</volume><fpage>2689</fpage><lpage>2702</lpage><permissions><copyright-statement>© 2017 Davatgaran-Taghipour et al. This work is published and licensed by Dove Medical Press Limited</copyright-statement><copyright-year>2017</copyright-year><license><license-p>The full terms of this license are available at <ext-link ext-link-type="uri" xlink:href="https://www.dovepress.com/terms.php">https://www.dovepress.com/terms.php</ext-link> and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link>). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.</license-p></license></permissions><abstract><p>Cancer is defined as the abnormal cell growth that can cause life-threatening malignancies with high financial costs for patients as well as the health care system. Natural polyphenols have long been used for the prevention and treatment of several disorders due to their antioxidant, anti-inflammatory, cytotoxic, antineoplastic, and immunomodulatory effects discussed in the literature; thus, these phytochemicals are potentially able to act as chemopreventive and chemotherapeutic agents in different types of cancer. One of the problems regarding the use of polyphenolic compounds is their low bioavailability. Different types of formulations have been designed for the improvement of bioavailability of these compounds, nanonization being one of the most notable approaches among them. This study aimed to review current data on the nanoformulations of natural polyphenols as chemopreventive and chemotherapeutic agents and to discuss their molecular anticancer mechanisms of action. Nanoformulations of natural polyphenols as bioactive agents, including resveratrol, curcumin, quercetin, epigallocatechin-3-gallate, chrysin, baicalein, luteolin, honokiol, silibinin, and coumarin derivatives, in a dose-dependent manner, result in better efficacy for the prevention and treatment of cancer. The impact of nanoformulation methods for these natural agents on tumor cells has gained wider attention due to improvement in targeted therapy and bioavailability, as well as enhancement of stability. Today, several nanoformulations are designed for delivery of polyphenolic compounds, including nanosuspensions, solid lipid nanoparticles, liposomes, gold nanoparticles, and polymeric nanoparticles, which have resulted in better antineoplastic activity, higher intracellular concentration of polyphenols, slow and sustained release of the drugs, and improvement of proapoptotic activity against tumor cells. To conclude, natural polyphenols demonstrate remarkable anticancer potential in pharmacotherapy; however, the obstacles in terms of their bioavailability in and toxicity to normal cells, as well as targeted drug delivery to malignant cells, can be overcome using nanoformulation-based technologies, which optimize the bioefficacy of these natural drugs.</p></abstract><kwd-group><title>Keywords</title><kwd>natural products</kwd><kwd>flavonoid</kwd><kwd>anthocyanin</kwd><kwd>tumor</kwd><kwd>malignancy</kwd></kwd-group></article-meta></front><body><sec sec-type="intro"><title>Introduction</title><p>Cancer has always been a great health problem all over the world despite growing advances in its prevention and treatment strategies. This disease is characterized by abnormal proliferation of cells that cannot be controlled or stopped. In addition, cells of malignant tumors have a tendency to become metastatic and attack tissues other than the place in which the primary tumor was formed.<xref rid="b1-ijn-12-2689" ref-type="bibr">1</xref> Common modalities in the treatment of cancer consist of nonpharmacological treatments, such as radiation therapy, surgical operation, stem cell therapy and hyperthermia, as well as pharmacological intervention, including immunotherapy, chemotherapy, and hormone therapy, as well as a combination of these methods.<xref rid="b1-ijn-12-2689" ref-type="bibr">1</xref> Nevertheless, all of these methods, including chemotherapy, have significant limitations such as dissatisfying specificity, which can cause low concentrations of drugs at the tumor site, causing multiple side effects and off-target toxic effects.<xref rid="b2-ijn-12-2689" ref-type="bibr">2</xref></p><p>Nanotechnology is the study of particles within the range of ≤ 100 nm, and a nanometer is defined as one-billionth of a meter.<xref rid="b3-ijn-12-2689" ref-type="bibr">3</xref> High surface area-to-volume ratio of atoms or molecules is one of the significant advantages of nanoparticles. This property leads to boosting of the surface activity and changes the physical and biological properties of the nanomaterials.</p><p>Rapid diagnosis of cancer and exact targeted drug delivery to the site of the neoplasms with the least possible adverse effects on other normal tissues are the desired goals of anticancer therapies. Nanotechnology has shown promising effects in the treatment of cancer.<xref rid="b4-ijn-12-2689" ref-type="bibr">4</xref> Through targeted drug delivery via nanoformulations, improvement in drug delivery to the tumor site can be achieved, and better therapeutic responses are expected. Another parameter is the increased selectivity that reduces the adverse effects of chemotherapy drugs.<xref rid="b5-ijn-12-2689" ref-type="bibr">5</xref> Nanoformulations such as liposomes,<xref rid="b6-ijn-12-2689" ref-type="bibr">6</xref> micelles,<xref rid="b7-ijn-12-2689" ref-type="bibr">7</xref> natural and synthetic nanoparticles, metal nanoparticles, and microspheres are among the important nanoformulations. Selection of these methods for nanoformulation provides improvements in bioavailability, biodistribution, specificity, and pharmacokinetics of drugs delivered to the site of tumor. Recently, several liposomal formulations have become available in the market for treatment of cancer, such as doxorubicin (Doxil<sup>®</sup>), cytarabine (Depocyt<sup>®</sup>), daunorubicin (DaunoXome<sup>®</sup>), and vincristine (Onco-TCS<sup>®</sup>). Doxil has been examined for head and neck cancer, brain tumors, ovarian cancer, breast neoplasms, and acquired immunodeficiency syndrome (AIDS)-related Kaposi’s sarcoma. Liposomal drug delivery has shown great promise, but it still has obstacles to overcome, including its short shelf life, limited loading potential, insufficient bioavailability on oral administration, decomposition of the drug inside the liposome, lack of enough control of drug release, and the unpredictable clearance by the reticuloendothelial system (RES). Polymeric, metal-, or lipid-based nanoparticles have a fundamental advantage for systemic drug delivery due to their smaller size, which permits lower RES uptake, extended circulation time, and better ability of penetration into capillaries.<xref rid="b8-ijn-12-2689" ref-type="bibr">8</xref>,<xref rid="b9-ijn-12-2689" ref-type="bibr">9</xref></p><p>Polyphenolic compounds comprise one of the most diverse groups of plant secondary metabolites, with several health-promoting properties, including antioxidant, anti-inflammatory, and antineoplastic activities.<xref rid="b10-ijn-12-2689" ref-type="bibr">10</xref> Previous studies have discussed the anticancer effects of numerous natural polyphenols such as curcumin, resveratrol, and several flavonoids;<xref rid="b11-ijn-12-2689" ref-type="bibr">11</xref> thus, these compounds have attracted the attention of scientists for more extensive research.</p><p>The aim of the current study is to review current available data on the nanoformulations of natural polyphenols as chemopreventive and chemotherapeutic agents and to discuss the molecular mechanisms of their anticancer action.</p></sec><sec><title>Description of study selection</title><p>Electronic databases including “Scopus”, “PubMed”, and “ScienceDirect” were searched with the keywords “cancer” in title/abstract, along with “plant”, “phytochemical”, “extract”, and “herb” in the whole text. Data were collected from the inception date until August 2016. Only English language papers were included. Primarily obtained articles were screened by two independent investigators. Articles that had assessed nanoformulations of polyphenolic compounds in an in vitro or in vivo model of cancer were selected for this study, and conventional formulations (without using a nanonization technique), preparations of phytochemicals other than polyphenols, eg, terpenoids or alkaloids, and animal or cellular models of disease other than cancer were excluded. References of the retrieved studies were also screened for relevant articles. Included articles were screened for the name of phytochemical, nanonization technique, and the type of cancer in animal or cellular models. From a total of 1,939 results, 1,033 were excluded because of duplication, 138 for being reviews, and 713 being irrelevant judged on the title and/or abstract From the 55 primarily selected papers, 15 were excluded based on the full texts (four were excluded because they were not on polyphenols, four because no anti-cancer effects were assessed,. From the 55 primarily selected papers, 15 were excluded based on the full texts (four were excluded because they were not on polyphenols, four because no anti-cancer effects were assessed, three because the cell cultures were not cancerous cell lines, three because the polyphenol was not prepared in the form of a nanoformulation, and 1 because the full-text was in Chinese). Finally, 40 articles were included in this review. <xref ref-type="table" rid="t1-ijn-12-2689">Table 1</xref> shows the summary of the obtained results.</p></sec><sec><title>Nanostructures and polymers</title><p>Several polymers and nanostructures have been used for the preparation of polyphenolic compounds as anticancer agents. Poly(lactic-<italic>co</italic>-glycolic acid) (PLGA) nanoparticles are a group of hydrophobic, biocompatible, and biodegradable polymers that have attracted immense interest since being approved by the US Food and Drug Administration as a safe drug delivery system. This polymer consists of lactic acid and glycolic acid, which can be metabolized by the body, and the degradation rate depends on their ratio.<xref rid="b12-ijn-12-2689" ref-type="bibr">12</xref> Polylactic acid (PLA) is another biodegradable and biocompatible polymer that is metabolized into monomeric units of lactic acid in the body. The preparation method for PLA nanoparticles is mostly via solvent evaporation, solvent displacement,<xref rid="b13-ijn-12-2689" ref-type="bibr">13</xref> salting out,<xref rid="b14-ijn-12-2689" ref-type="bibr">14</xref> and solvent diffusion.<xref rid="b15-ijn-12-2689" ref-type="bibr">15</xref> Recently, researchers have focused on polymeric systems activated by a water-soluble stimulus, which represents a phase transition in response to external stimuli such as pH, specific ions, temperature, and electrical field.</p><p>Dendrosome is an amphipathic, neutral, and biodegradable nanostructure that has been used for delivering genes into diverse cell lines.<xref rid="b16-ijn-12-2689" ref-type="bibr">16</xref> Dendrosomes are liposomes encapsulating dendrimers in their aqueous core and can be functionalized using different functional groups.<xref rid="b17-ijn-12-2689" ref-type="bibr">17</xref></p><p>Poly(β-amino ester) (PAE) is a biodegradable and pH-responsive polymer that is not soluble at pH of 7.4, but it turns into a soluble form at a lower pH (<6.8) through the protonation process of tertiary amino groups.<xref rid="b18-ijn-12-2689" ref-type="bibr">18</xref> Another popular polymer is poly(<italic>N</italic>-isopropylacrylamide) (PNIPAAm) that is used for the preparation of temperature- and pH-sensitive structures for biomedical applications.<xref rid="b19-ijn-12-2689" ref-type="bibr">19</xref> Cyclodextrins (CDs) consist of cyclic oligosaccharide molecular structures including six (a-), seven (b-), or eight (c-) <sc>d</sc>-glucopyranose units linked together by α-(1,4) glycosidic linkages. These structures are popular to form molecular complexes loaded with other molecules, eg, drugs.<xref rid="b20-ijn-12-2689" ref-type="bibr">20</xref> β-CD is the most commonly used type because of the easier synthesis, low price, and large loading capacity for polar molecules that can be loaded into the internal cavity.</p><p>A new drug delivery system for anticancer drugs is based on cellulose nanocrystals (CNCs) consisting of uniform nanorods with liquid crystalline features, high mechanical resistance, high surface area-to-volume ratio, ability for sustained drug release, biodegradability, and biocompatibility.<xref rid="b21-ijn-12-2689" ref-type="bibr">21</xref> This structure is obtained by the acid hydrolysis of cotton fibers, and the surface can be easily modified.<xref rid="b22-ijn-12-2689" ref-type="bibr">22</xref></p><p>Micelles are lipid structures that are converted into a spherical form in water. This reaction is the result of the amphipathic properties of fatty acid molecules, which contain both hydrophilic polar heads and long hydrophobic regions. The hydrophilic head groups of micelles usually form the outside surface of micelles, and the hydrophobic tails are retained inside because they are nonpolar. The core–shell structure of the polymeric micelles is the result of the amphiphilic block, which is useful for solubilizing water-insoluble or poorly soluble drugs. Some advantages of the use of micelles as a drug delivery system include conjugation with the targeted molecules via surface modification, trapping of hydrophobic drugs into a hydrophobic core that protects drugs from fast degradation, and reduction of nonspecific uptake by RES.<xref rid="b23-ijn-12-2689" ref-type="bibr">23</xref></p><p>Poly(ε-caprolactone) (PCL) is a biodegradable and biocompatible polymer that is extensively studied for controlled drug delivery systems.<xref rid="b24-ijn-12-2689" ref-type="bibr">24</xref> A wide range of drugs are compatible with this polymer, which provides homogeneous drug dispersal in the formulation and lower degradation rate.<xref rid="b24-ijn-12-2689" ref-type="bibr">24</xref> Poly(2-hydroxyethyl methacrylate) (PHEMA) is an artificially synthesized polymer with numerous applications in medical instruments and devices, such as soft contact lenses and artificial cornea, as well as in drug delivery systems.<xref rid="b25-ijn-12-2689" ref-type="bibr">25</xref> The polar hydroxyl groups and carbonyl functional groups on the repeating units of PHEMA make it a water-compatible polymer. Hydrophobic α-methyl groups in the PHEMA backbone result in better hydrolytic stability of the polymer.<xref rid="b26-ijn-12-2689" ref-type="bibr">26</xref> Among the different drug delivery systems, lipid nanoparticles, such as nanostructured lipid carriers, can be applied for the delivery of many types of drugs.<xref rid="b27-ijn-12-2689" ref-type="bibr">27</xref> Large-scale production in high quality and lack of need for organic solvent during the production are advantages of lipid-based nanocarriers. They have good stability during long storage and can be either lyophilized or steam sterilized.<xref rid="b28-ijn-12-2689" ref-type="bibr">28</xref> Nanostructured lipid carriers consist of standard ingredients for pharmaceutical use in humans and are recognized as safe structures.<xref rid="b29-ijn-12-2689" ref-type="bibr">29</xref></p></sec><sec><title>Polyphenol nanoformulations for cancer therapy</title><sec><title>Coumarins</title><p>Coumarins are polyphenols with appetite-suppressing properties that discourage animals from eating plants containing them. They can also be used in the treatment of lymphedema.<xref rid="b30-ijn-12-2689" ref-type="bibr">30</xref> They can also cause bleeding, which is their most well-known feature.<xref rid="b31-ijn-12-2689" ref-type="bibr">31</xref> Fabaceae, Lamiaceae,<xref rid="b32-ijn-12-2689" ref-type="bibr">32</xref> and Rosaceae<xref rid="b33-ijn-12-2689" ref-type="bibr">33</xref> are among the natural sources of coumarins. These phytochemicals have shown anticancer properties via several mechanisms of action.</p><p>4-Methyl-7-hydroxycoumarin is a synthetic coumarin that is made by methylation of umbelliferone (7-hydroxycoumarin). PLGA nanoparticles of 4-methyl-7-hydroxy coumarin have demonstrated anticancer effects in melanoma A375 cell cultures by increasing cell apoptosis, DNA fragmentation, caspase-3, and p53 (tumor suppressor factors) and by decreasing cell viability.<xref rid="b34-ijn-12-2689" ref-type="bibr">34</xref> Farnesiferol C is another coumarin extracted from plant species such as <italic>Ferula asafoetida</italic>. Dendrosomal nanoformulation of farnesiferol C exhibited antineoplastic activity by decreasing cell proliferation in AGS gastric cancer cell line. The expression of Bax (an antiapoptotic marker) and Bcl-2 (a proapoptotic factor) was modified so that the Bax/Bcl-2 ratio increased as a result of treatment with dendrosomal farnesiferol C.<xref rid="b35-ijn-12-2689" ref-type="bibr">35</xref></p></sec><sec><title>Diarylheptanoid (curcumin)</title><p>Curcumin is the principal diarylheptanoid polyphenolic structure extracted from turmeric (<italic>Curcuma longa</italic>) rhizome, and it has numerous biological and pharmacological properties such as antioxidant, anti-inflammatory, and anticarcinogenic activities. It has been thoroughly studied in the field of cancer therapeutics.<xref rid="b36-ijn-12-2689" ref-type="bibr">36</xref></p><p>Several studies have assessed the antineoplastic properties of curcumin-loaded PLGA nanoparticles on different cancerous cell lines. The anticancer activity of nanocurcumin in cervical cancer has been investigated, wherein CaSki and SiHa cells were treated with nanocurcumin, which resulted in reduction of cell growth and cellular proliferation. The formulation also induced apoptosis via G1/S cell cycle arrest.<xref rid="b37-ijn-12-2689" ref-type="bibr">37</xref> Beta-catenin is a protein involved in transcription and cell proliferation, whose phosphorylation is controlled by glycogen synthase kinase 3 (GSK3); thus, any malfunction in β-catenin signaling can result in abnormal cell proliferation.<xref rid="b38-ijn-12-2689" ref-type="bibr">38</xref> Small noncoding sequences of RNA, known as microRNAs (miRNAs), are found to have regulatory effects on oncogenic or tumor suppressor genes and to be involved in tumorigenesis. Investigations have suggested miRNAs as novel therapeutic targets for cancer. The potential therapies of miRNAs with oncogenic activities include miRNA masking, microRNA sponges, and anti-miRNA oligonucleotides. Natural agents that block or enhance the expression of specific miRNAs can lead to the suppression of oncogenic effects.<xref rid="b39-ijn-12-2689" ref-type="bibr">39</xref>,<xref rid="b40-ijn-12-2689" ref-type="bibr">40</xref> Nanocurcumin has been shown to diminish the levels of miRNA-2, nuclear β-catenin, and E6/E7 human papillomavirus (HPV) oncoproteins in an orthotopic mouse model of cervical cancer.<xref rid="b37-ijn-12-2689" ref-type="bibr">37</xref> Using the same formulation, Xie et al<xref rid="b41-ijn-12-2689" ref-type="bibr">41</xref> showed the anticancer effects in human colorectal cancer HCT116 cells via decrease in cell viability, increase in apoptosis by G2/M phase cell cycle arrest, and decrease in the toxicity for normal cells. In another study, PLGA nanocurcumin showed antineoplastic properties for cisplatin-resistant A2780CP ovarian cancer cells, as well as metastatic MDA-MB-231 breast cancer cell cultures by increasing apoptosis and decreasing tumor cell proliferation and colony formation.<xref rid="b42-ijn-12-2689" ref-type="bibr">42</xref> The same formulation could elevate mitochondrial cytochrome (cyt) C release and reduce both mitochondrial reactive oxygen species (ROS) generation as well as levels of inducible nitric oxide synthase (iNOS), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), in diethylnitrosamine-induced hepatocellular carcinoma in Swiss albino rat.<xref rid="b43-ijn-12-2689" ref-type="bibr">43</xref></p><p>PLGA nanoparticles loaded with curcumin and conjugated with anti-P-glycoprotein could exhibit cytotoxic effects in human cervical carcinoma KB-V1 and KB-3-1 cells, which resulted in increased curcumin solubility and cellular uptake as well as decreased cell viability.<xref rid="b44-ijn-12-2689" ref-type="bibr">44</xref> A micellar system based on methoxy polyethylene glycol (MPEG)-poly(lactide)-poly(b-amino ester) (MPEG-PLA-PAE) copolymers loaded with curcumin was assessed for its anticancer activity in MCF-7 human breast cancer cell cultures and MCF-7 tumor-bearing mice. The study showed better cellular internalization than free curcumin and significantly diminished tumor cell growth both in vitro and in vivo.<xref rid="b45-ijn-12-2689" ref-type="bibr">45</xref> A nanoformulation of thermoresponsive chitosan-g-poly(<italic>N</italic>-isopropylacrylamide) co-polymeric nanoparticles (TRC-NPs) loaded with curcumin was tested for anticancer effects in human prostate cancer PC3, breast cancer MCF-7 cells, and human nasopharyngeal cancer KB cells.<xref rid="b46-ijn-12-2689" ref-type="bibr">46</xref> The formulation yielded a better uptake of curcumin by cancerous cells, decreased the cell viability, and augmented apoptosis in PC3 cells, as well as diminished the mitochondrial membrane potential in PC3 cells.<xref rid="b46-ijn-12-2689" ref-type="bibr">46</xref> In a recent study,<xref rid="b47-ijn-12-2689" ref-type="bibr">47</xref> CD/CNCs loaded with curcumin were examined. The formulation improved the cellular uptake of curcumin and could inhibit cell proliferation in human prostate cancer PC-3 and DU145 cells and in human colorectal carcinoma HT-29 cells.<xref rid="b47-ijn-12-2689" ref-type="bibr">47</xref> In another study, folate-modified PLA-PEG micelles loaded with curcumin were examined in human hepatocellular carcinoma HepG2 cells, which resulted in decreased cell growth.<xref rid="b23-ijn-12-2689" ref-type="bibr">23</xref> Dextran micelles loaded with curcumin were studied as a pH-sensitive drug delivery system in C6 glioma cells, which demonstrated improved cellular uptake and reduction of cell proliferation.<xref rid="b23-ijn-12-2689" ref-type="bibr">23</xref> Dendrosomal nanoparticles loaded with curcumin exhibited antineoplastic activity in metastatic breast cancer cells in BALB/c mice by reducing the tumor size and expression of the <italic>STAT3</italic>, interleukin-10 (<italic>IL-10</italic>), and arginase-1 genes, as well as by augmentation of <italic>STAT4</italic> and <italic>IL-12</italic> gene expression.<xref rid="b48-ijn-12-2689" ref-type="bibr">48</xref> Curcumin-loaded caprolactone was also found to decrease tumor growth in S180 cancer-bearing mice.<xref rid="b49-ijn-12-2689" ref-type="bibr">49</xref> Curcumin-loaded PHEMA nanoparticles could increase apoptosis and inhibit tumor cell growth in ovarian cancer SKOV-3 cells.<xref rid="b49-ijn-12-2689" ref-type="bibr">49</xref> The colloidal system of curcumin nanoparticles in esophageal Barrett cancer OE19 and OE33 cells was tested.<xref rid="b50-ijn-12-2689" ref-type="bibr">50</xref> The results showed a decrease in proliferation rate of cancer cells, but not in normal cells. The formulation also activated apoptosis of T cells and reduced the production of IL-1β, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α.<xref rid="b50-ijn-12-2689" ref-type="bibr">50</xref> Nanoparticles of curcumin prepared by ultrasonic spray also showed anti-cancer properties in human PC3 prostate cancer and human embyronic kidney HEK cell lines.<xref rid="b51-ijn-12-2689" ref-type="bibr">51</xref> Nanostructured lipid carriers loaded with curcumin were examined in human neuroblastoma LAN5 cells, which showed diminishing cell viability and increasing Hsp70 activity.<xref rid="b52-ijn-12-2689" ref-type="bibr">52</xref> Polymer-coated magnetic nanoparticles of curcumin could decrease cell viability in human ovarian carcinoma SKOV-3 cells.<xref rid="b53-ijn-12-2689" ref-type="bibr">53</xref> Lipid–polymer hybrid nanoparticles loaded with a combination of docetaxel and curcumin were studied in human PC3 prostate adenocarcinoma cells, which resulted in better adherence of the nanoparticles to the cell membrane and antitumor effects in PC3 cells.<xref rid="b54-ijn-12-2689" ref-type="bibr">54</xref> In vivo tumor growth was also inhibited by a docetaxel–curcumin nanoformulation in a BALB/c nude mouse model of the disease.<xref rid="b54-ijn-12-2689" ref-type="bibr">54</xref></p></sec><sec><title>Flavonolignans</title><p>Flavonolignans are natural compounds of flavonoids and lignans with antioxidant and hepatoprotective properties. Silibinin, silychristin, silydianin, dehydrosilybin, and deoxysilycistin are the examples of flavonolignans that can be found in sylimarin, the extract of milk thistle (<italic>Sylibum marianum</italic>), and in other plants of the Asteraceae family.<xref rid="b55-ijn-12-2689" ref-type="bibr">55</xref></p><p>Silibinin in combination with glycyrrhizic acid (a triterpene from licorice), formulated as nanoliposomes containing its PEG conjugate (pegylated nanoliposomes), demonstrated its anticancer effect by decreasing the cell viability in human hepatocellular carcinoma HepG2 cells. The nanoformulation was about 10-fold more potent than the free molecules.<xref rid="b55-ijn-12-2689" ref-type="bibr">55</xref></p></sec><sec><title>Lignans</title><p>Lignans are plant chemical compounds that are found in dietary fiber; thus, fiber-rich food items can be a good source for lignans. Plants of Pedaliaceae<xref rid="b56-ijn-12-2689" ref-type="bibr">56</xref> and Linaceae<xref rid="b57-ijn-12-2689" ref-type="bibr">57</xref> families are among the well-known sources of lignans. Lignans have several therapeutic activities such as anti-inflammatory and antioxidant properties, which are beneficial for the management of pathologic conditions in humans.<xref rid="b58-ijn-12-2689" ref-type="bibr">58</xref></p><p>Honokiol is a lignan extracted from the seed cones, bark, and leaves of trees of the Magnoliaceae family.<xref rid="b59-ijn-12-2689" ref-type="bibr">59</xref> A nanoformulation of honokiol caused an anticancer effect in the mouse Lewis lung cancer LL/2 cell lines by induction of cell cycle arrest at the G0/G1 phase.<xref rid="b60-ijn-12-2689" ref-type="bibr">60</xref></p></sec><sec><title>Naphthoquinones</title><p>Naphthoquinones are a subcategory of phenolic compounds derived from naphthalene. Alkanin from <italic>Alkanna tinctoria</italic><xref rid="b61-ijn-12-2689" ref-type="bibr">61</xref> and juglone from <italic>Juglans regia</italic><xref rid="b62-ijn-12-2689" ref-type="bibr">62</xref> are well-known examples of naphthoquinones. Naphthoquinones have an important role in blood coagulation and ossification. Overuse of naphthoquinones can cause internal bleeding and peptic ulcers.<xref rid="b63-ijn-12-2689" ref-type="bibr">63</xref> Naphthoquinones have also demonstrated acceptable anticancer properties and have attracted the attention of scientists to be formulated as a novel drug delivery system such as nanoparticles.</p><p>Plumbagin is a naphthoquinone that is extracted from <italic>Plumbago</italic> spp, family Plumbaginaceae, and it has demonstrated anticancer activity in human cancerous cell lines.<xref rid="b64-ijn-12-2689" ref-type="bibr">64</xref> Silver nanoparticles of plumbagin induced apoptosis in cancerous human skin HaCaT and A431 cells by producing free radicals. The compound also showed anticancer effect by increasing pyruvate kinase activity (an enzyme that catalyzes pyruvate and ATP synthesis in glycolysis and has a crucial role in the metabolism of normal as well as cancerous cells).<xref rid="b65-ijn-12-2689" ref-type="bibr">65</xref>,<xref rid="b66-ijn-12-2689" ref-type="bibr">66</xref></p></sec><sec><title>Stilbenes</title><p>Stilbenes are E- or Z-isomers of 1,2-diphenylethene derivatives. These compounds are distributed in a few number of plant families, especially Vitaceae (grapes family), which is the source of the most well-known stilbene, resveratrol.<xref rid="b67-ijn-12-2689" ref-type="bibr">67</xref> There are numerous studies on the anticancer properties of resveratrol. Nanoformulated resveratrol using PLGA-PEG demonstrated anticancer effects by decreasing cell growth and proliferation in human prostate cancer DU-145, PC-3, and LNCaP cell lines.<xref rid="b68-ijn-12-2689" ref-type="bibr">68</xref> Another study also reported the antineoplastic activity of resveratrol PCL nanocapsule formulation on cultures of mouse B16F10 skin melanoma cells.<xref rid="b69-ijn-12-2689" ref-type="bibr">69</xref> In rat C6 glioma cells, resveratrol nanoformulated with MPEG–PCL polymer exhibited cytotoxic effects.<xref rid="b70-ijn-12-2689" ref-type="bibr">70</xref> Bovine serum albumin nanoparticles of resveratrol also inhibited tumor growth in a nude mouse model of human ovarian cancer SKOV3 cells.<xref rid="b71-ijn-12-2689" ref-type="bibr">71</xref> Resveratrol coencapsulated with 5-fluorouracil (5-FU) using PEG polymer showed mixed cytotoxicity in human NT8e head and neck cancer, because the effect was synergistic at high concentrations of resveratrol, whereas an antagonistic effect was observed with low resveratrol concentrations.<xref rid="b72-ijn-12-2689" ref-type="bibr">72</xref> This shows that the use of resveratrol in cancer should be closely monitored; otherwise, it may cause undesirable results.</p></sec><sec><title>Flavonoids</title><p>Flavonoids are a group of polyphenols that have several subclasses, such as chalcones, flavones, isoflavones, flavanones, flavonols, and anthocyanins.<xref rid="b73-ijn-12-2689" ref-type="bibr">73</xref> Many pharmacological effects of flavonoids have been reported, such as antioxidant,<xref rid="b74-ijn-12-2689" ref-type="bibr">74</xref> anti-inflammatory,<xref rid="b75-ijn-12-2689" ref-type="bibr">75</xref> immunomodulatory,<xref rid="b76-ijn-12-2689" ref-type="bibr">76</xref> and antineoplastic activities.<xref rid="b77-ijn-12-2689" ref-type="bibr">77</xref> Flavonoids can be extracted from higher plants. They can be found in yellow, orange, or red colors and are widely available as colorful fruits and vegetables in the human diet: Apiaceae (parsley), Ericaceae (blueberries),<xref rid="b78-ijn-12-2689" ref-type="bibr">78</xref> Rutaceae (citrus fruits), Rosaceae (apple), as well as the popular delicious product of <italic>Theobroma cacao</italic>, namely, dark chocolate.<xref rid="b79-ijn-12-2689" ref-type="bibr">79</xref> Flavonoids have demonstrated antineoplastic activity in several studies.<xref rid="b80-ijn-12-2689" ref-type="bibr">80</xref></p><p>Baicalein is a flavonoid that can be found in the roots of <italic>Scutellaria baicalensis</italic> and <italic>S. lateriflora</italic>.<xref rid="b81-ijn-12-2689" ref-type="bibr">81</xref> Baicalein nanoparticles with dual-targeted ligands of folate and hyaluronic acid demonstrated anticancer effect on human lung cancer A549 as well as paclitaxel-resistant lung cancer A549/PTX cells by decreasing cell viability and inhibiting tumor growth in xenograft mouse model of A549/PTX.<xref rid="b82-ijn-12-2689" ref-type="bibr">82</xref> Chrysin is another flavonoid that can be extracted from many plants such as <italic>Passiflora</italic> spp., as well as from some mushrooms such as <italic>Pleurotus ostreatus</italic>.<xref rid="b83-ijn-12-2689" ref-type="bibr">83</xref> Chrysin has many pharmacological effects such as anti-inflammatory, antioxidant, and anticancer properties.<xref rid="b84-ijn-12-2689" ref-type="bibr">84</xref> A nanosuspension of chrysin showed anticancer effects on human hepatocellular carcinoma HepG2 cells by inhibiting cell growth.<xref rid="b85-ijn-12-2689" ref-type="bibr">85</xref> EGCG can be found in several plants, especially in green tea.<xref rid="b86-ijn-12-2689" ref-type="bibr">86</xref> The flavonoid demonstrated anticancer effects on human and animal cells by several different mechanisms. EGCG formulated as Ca/Al-NO<sub>3</sub> layered double-hydroxide nanoparticles induced apoptosis, decreased cell viability, and inhibited colony formation in human prostate cancer PC-3 cells.<xref rid="b87-ijn-12-2689" ref-type="bibr">87</xref> Another study reported that chitosan nanoparticles of EGCG exhibited anticancer effects on human melanoma Mel 928 cells by apoptosis via increase in Bax levels, increased poly (ADP-ribose) polymerase (PARP) cleavage, G2/M phase cell cycle arrest, inhibition of cyclin D1 and D3, induction of p21 and p27, decrease in Bcl-2, caspase-3 and caspase-9 protein expression, which resulted in the reduction of cancer cell viability.<xref rid="b88-ijn-12-2689" ref-type="bibr">88</xref> The anticancer effect of EGCG chitosan nanoparticles on xenograft athymic mouse model of melanoma was shown by suppression of tumor growth and proliferation, inhibition of CDK4 and 6, and an increase in apoptosis.<xref rid="b88-ijn-12-2689" ref-type="bibr">88</xref> EGCG core–shell PLGA–casein nanoparticles in combination with paclitaxel also showed anticancer activity on MCF-7 cells and human MDA-MB-231 breast cancer cells by increasing apoptosis and decreasing NF-κB activation.<xref rid="b89-ijn-12-2689" ref-type="bibr">89</xref> Green tea polyphenols containing EGCG as one of the major components were nanoformulated by graphene nanosheets and showed anticancer effects on colon cancer HT29 and SW48 cells, via photothermal destruction of cells, assessed by high-efficiency near-infrared photothermal therapy.<xref rid="b90-ijn-12-2689" ref-type="bibr">90</xref> Luteolin is a flavonoid with yellow crystalline appearance and is widely found in plants and vegetables of human diet.<xref rid="b91-ijn-12-2689" ref-type="bibr">91</xref> Phytosomes containing luteolin demonstrated anticancer effects on human MDA-MB-231 breast cancer cells by reducing cell viability and decreasing the expression of <italic>Nrf2</italic> and its related downstream gene <italic>Ho1</italic>.<xref rid="b92-ijn-12-2689" ref-type="bibr">92</xref> The formulation also reduced sensitivity of cells to the chemotherapeutic agent doxorubicin.<xref rid="b92-ijn-12-2689" ref-type="bibr">92</xref> Another study<xref rid="b93-ijn-12-2689" ref-type="bibr">93</xref> reported that nanoformulated luteolin with PLA-PEG polymer possesses anticancer effects against lung cancer H292 cells and TU212 head and neck squamous cell carcinoma, demonstrated by inhibition of tumor growth and colony formation. In addition, these effects were observable in xenograft mouse model of head and neck cancer, which resulted in reduced tumor growth and tumor size.<xref rid="b93-ijn-12-2689" ref-type="bibr">93</xref> Quercetin is another widely distributed flavonoid that can be found in several fruits such as the apple. Quercetin supplements are used for their cancer-preventive effects.<xref rid="b94-ijn-12-2689" ref-type="bibr">94</xref> Quercetin nanoformulated as phytosomes had anticancer effects on human breast cancer MCF-7 cells by increasing apoptosis and decreasing mRNA expression of <italic>Nrf2</italic> downstream genes <italic>NQO1</italic> and <italic>MRP1</italic>; however, quercetin did not make a significant change in <italic>Nrf2</italic>.<xref rid="b95-ijn-12-2689" ref-type="bibr">95</xref> In another study, quercetin nanoformulated in liposomes showed anticancer effects on human breast cancer MCF-7 cells by reducing cancer cell proliferation and induction of antitoxic effects.<xref rid="b96-ijn-12-2689" ref-type="bibr">96</xref></p></sec></sec><sec><title>Concerns regarding the safety of nanopolyphenols</title><p>Although most of the current evidence supports the idea of anticancer activity of natural polyphenols,<xref rid="b97-ijn-12-2689" ref-type="bibr">97</xref> there are some concerns regarding their antioxidant properties, which may not only help normal cells but also increase the surveillance of cancerous cells against oxidative stress caused by conventional anticancer agents. In other words, polyphenols should act in an intelligent manner in order to support the viability of only normal cells, not the cancerous ones, which is not currently guaranteed with respect to available evidence.<xref rid="b98-ijn-12-2689" ref-type="bibr">98</xref></p><p>Another concern is with reference to the safety of the nanostructures used for formulation of polyphenols. As nanotechnology is rather a new field of science and research, many questions are still left unanswered. Some types of nanostructures can accumulate at the site of injection and may not be completely cleared from the blood circulation.<xref rid="b99-ijn-12-2689" ref-type="bibr">99</xref> It should be mentioned that nanoformulations of a drug have different physicochemical properties in comparison to their simple preparations; thus, different pharmacokinetics and pharmacodynamics are expected. Hence, studies performed on the simple form of the drugs cannot totally reflect the toxicity of the nanoformulated products, and toxicological studies should be conducted for nanoformulations.<xref rid="b100-ijn-12-2689" ref-type="bibr">100</xref>,<xref rid="b101-ijn-12-2689" ref-type="bibr">101</xref></p></sec><sec sec-type="discussion"><title>Discussion</title><p>Cancer has always been a major calamity for health care providers all over the world due to difficulties in the selection of a suitable treatment approach. Chemotherapy, radiotherapy, immunotherapy, and surgery are currently used in cancerous patients; nevertheless, fast cellular and molecular changes in the cells, which result in drug-resistant types of the disease, can prevent achieving the ideal results.<xref rid="b102-ijn-12-2689" ref-type="bibr">102</xref></p><p>Severe adverse effects of chemotherapy such as gastrointestinal complications, alopecia, bone marrow suppression, and secondary malignancies have limited its use. Lower cellular permeability, unusual vascularization, and abnormal expression of surface molecules (such as drug-resistant pumps) have caused chemotherapeutic drugs to have a low concentration in these cells.<xref rid="b11-ijn-12-2689" ref-type="bibr">11</xref> Nanonization, as a recently developed technique in drug delivery systems, can improve the bioavailability of antineoplastic agents via passive or active targeting.<xref rid="b103-ijn-12-2689" ref-type="bibr">103</xref><xref ref-type="table" rid="t2-ijn-12-2689">Table 2</xref> shows a summary of the advantages and disadvantages of nanoformulations in comparison to conventional drugs. In the current paper, we have discussed the nanoformulation of polyphenols and their application as anticancer agents. <xref ref-type="fig" rid="f1-ijn-12-2689">Figure 1</xref> summarizes the main anticancer properties of nanoformulated polyphenols.</p><p>Polyphenols, as a group of phytochemicals with a wide range of pharmacological and therapeutic activities, have been extensively studied in the area of oncology. Nanoformulations of polyphenols have been prepared using a wide variety of techniques that use carriers such as liposomes, dendrosomes, nanocapsules, and nanosheets. In addition, micelles of polymers such as PLA, PLGA, PEG, PHEMA, CD, dextran, and chitosan, as well as bovine serum albumin and silver nanoparticles, have been used. These polymers were activated by using different functional groups such as carboxyl (COOH) or methoxy (OMe) groups. Most of these nanostructures were successful in demonstrating anticancer activity. Curcumin, resveratrol, EGCG, chrysin, baicalein, luteolin, quercetin, honokiol, silibinin, and coumarin derivatives are among the polyphenols assessed for their anticancer properties in nanoformulated forms (<xref ref-type="table" rid="t1-ijn-12-2689">Table 1</xref>).</p><p>Polyphenol nanoformulations perform their anticancer activity via several cellular mechanisms, including induction of cell cycle arrest at different phases of cancer cell cycle, activation of caspase enzymes, reduction of tumor vascularization, reducing tumor cell invasion and metastasis, induction of mitochondrial damage, as well as apoptosis in the neoplasm. Apoptosis, an important indicator for anticancer therapy, is one of the main functions of nanoformulated polyphenols in cancer cells. Many natural products exert their anticancer effect through apoptosis, which is the programmed cell death responsible for removal of unwanted cells. Among the Bcl-2 family proteins that regulate apoptosis, Bcl-2 and Bax possess opposite actions in the apoptosis process. Bcl-2 blocks apoptosis, while Bax promotes apoptosis.<xref rid="b104-ijn-12-2689" ref-type="bibr">104</xref>,<xref rid="b105-ijn-12-2689" ref-type="bibr">105</xref> The elevation of the ratio of Bax/Bcl-2 has a pivotal contribution to apoptosis, which is considered as one of the main mechanisms of these drugs in the induction of apoptosis in cancer cells.</p><p>Natural remedies have been broadly administered as complementary and alternative medicines for thousands of years for the management of different types of malignancies to achieve optimal body performance. The conventional medicines delivered via currently available dosage forms provide anticancer potential only up to a suboptimal degree. Hence, the existence of limitations in the management of malignancies is predictable. This requires exploring novel drug delivery strategies for the development of targeted and safe drug delivery medicines with enhanced therapeutic activity. The most important improvement in nanoformulated polyphenols, in comparison to their free molecules, is their higher antineoplastic activity and better bioavailability, which can improve passive targeting of cancerous cells. In the meantime, this scenario requires lower doses of drugs to obtain optimum response while bypassing the pharmacokinetic problems of conventional formulations. Several studies have suggested that phytochemicals, including polyphenols, have anticancer properties exploitable in an intelligent manner, ie, showing cytotoxicity only against neoplasms, not against normal cells, whereas no such intelligence has been detected for conventional anticancer agents.<xref rid="b43-ijn-12-2689" ref-type="bibr">43</xref>,<xref rid="b52-ijn-12-2689" ref-type="bibr">52</xref>,<xref rid="b106-ijn-12-2689" ref-type="bibr">106</xref></p></sec><sec><title>Conclusion</title><p>Thus, polyphenols are suitable candidates to be studied as future anticancer agents. Nanoformulation techniques are suggested to be promising alternatives relative to the conventional drug delivery systems as they encompass exclusive drug delivery properties. It is concluded that nanonization can potentiate the beneficial effects of natural polyphenols against cancer by different mechanisms, hence opening a new field of research in oncology. However, it should be mentioned that all of the abovementioned formulations were evaluated in cellular and/or animal models of malignancies; thus, a long path lies ahead of commercializing these agents, including assessment of their safety and efficacy in healthy as well as cancerous subjects in preclinical and clinical settings.</p></sec></body><back><fn-group><fn><p><bold>Author contributions</bold></p><p>All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.</p></fn><fn fn-type="COI-statement"><p><bold>Disclosure</bold></p><p>The authors report no conflicts of interest in this work.</p></fn></fn-group><ref-list><title>References</title><ref id="b1-ijn-12-2689"><label>1</label><element-citation publication-type="journal"><person-group 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valign="top" align="left" rowspan="1" colspan="1">Anticancer activity</th><th valign="top" align="left" rowspan="1" colspan="1">Reference</th></tr></thead><tbody><tr><td rowspan="2" valign="top" align="left" colspan="1">Coumarin</td><td valign="top" align="left" rowspan="1" colspan="1">4-Methyl-7-hydroxy coumarin<break></break><graphic xlink:href="ijn-12-2689Fig2"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">PLGA nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Melanoma A375 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Cell viability<break></break>↑ Apoptosis<break></break>↑DNA fragmentation<break></break>↑Caspase-3 and p53</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b34-ijn-12-2689" ref-type="bibr">34</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Farnesiferol C<break></break><graphic xlink:href="ijn-12-2689Fig3"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">Dendrosomal nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">AGS gastric cancer cell line</td><td valign="top" align="left" rowspan="1" colspan="1">↓Proliferation<break></break>↑Expression ratio of Bax/Bcl-2</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b35-ijn-12-2689" ref-type="bibr">35</xref></td></tr><tr><td rowspan="13" valign="top" align="left" colspan="1">Diarylheptanoid</td><td rowspan="13" valign="top" align="left" colspan="1">Curcumin
<graphic xlink:href="ijn-12-2689Fig4"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">PLGA nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">CaSki and SiHa cervical cancer cells<break></break>Orthotopic mouse model of cervical cancer</td><td valign="top" align="left" rowspan="1" colspan="1">↓Cell growth<break></break>↑Apoptosis and Gl/S cell cycle arrest<break></break>↓miRNA-2, nuclear β-catenin and E6/E7 HPV oncoproteins</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b37-ijn-12-2689" ref-type="bibr">37</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">MPEG-PLA-PAE nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Human breast cancer MCF-7 cells<break></break>MCF-7 tumor-bearing mice</td><td valign="top" align="left" rowspan="1" colspan="1">↑Curcumin uptake<break></break>↓Cell growth<break></break>↓Tumor growth in vivo</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b45-ijn-12-2689" ref-type="bibr">45</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">PLGA nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Cisplatin-resistant A2780CP ovarian cancer cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Bcl-XL and Mcl-l<break></break>↓Cell growth<break></break>↑Apoptosis</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b43-ijn-12-2689" ref-type="bibr">43</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">PLGA nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Human colorectal cancer HCT116 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Apoptosis by G2/M phase cell cycle arrest<break></break>↓Cell viability<break></break>↓Toxicity for normal cells</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b41-ijn-12-2689" ref-type="bibr">41</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">PLGA nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Cisplatin-resistant A2780CP ovarian cancer and metastatic MDA-MB-231 breast cancer cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Apoptosis<break></break>↓Proliferation and colony formation</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b42-ijn-12-2689" ref-type="bibr">42</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">PNIPAAm-COOH nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Human prostate cancer PC3, human breast cancer MCF-7 cells, and human nasopharyngeal cancer KB cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Curcumin uptake<break></break>↓Cell viability in cancerous cells but not in normal cells<break></break>↑Apoptosis in PC3 cells<break></break>↓Mitochondrial membrane potential in PC3 cells</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b46-ijn-12-2689" ref-type="bibr">46</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Cyclodextrin/cellulose nanocrystals</td><td valign="top" align="left" rowspan="1" colspan="1">Human prostate cancer PC-3 and DU145, as well as human colorectal carcinoma HT-29 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Curcumin uptake<break></break>↓Proliferation</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b47-ijn-12-2689" ref-type="bibr">47</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Folate-modified PLA-PEG micelles</td><td valign="top" align="left" rowspan="1" colspan="1">Human hepatocellular carcinoma HepG2 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Cell growth</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b23-ijn-12-2689" ref-type="bibr">23</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">PLGA nanoparticles by conjugation with anti-P-glycoprotein</td><td valign="top" align="left" rowspan="1" colspan="1">Human cervical carcinoma KB-VI and KB-3-1 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Curcumin uptake<break></break>↓Cell viability</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b44-ijn-12-2689" ref-type="bibr">44</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Dextran micelles</td><td valign="top" align="left" rowspan="1" colspan="1">C6 glioma cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Curcumin uptake<break></break>↓Cell viability</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b107-ijn-12-2689" ref-type="bibr">107</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Dendrosomal nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">BALB/c metastatic breast cancer in mice</td><td valign="top" align="left" rowspan="1" colspan="1">↓Tumor size<break></break>↓<italic>STAT3</italic>, <italic>IL-10</italic>, and arginase 1 gene expression<break></break>↑<italic>STAT4</italic> and <italic>IL-12</italic> gene expression</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b48-ijn-12-2689" ref-type="bibr">48</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">F68-Cis-curcumin conjugate micelles</td><td valign="top" align="left" rowspan="1" colspan="1">Human ovarian carcinoma A2780 and hepatocellular carcinoma SMMC 7721 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓MMP<break></break>↑Curcumin cellular uptake<break></break>↑Apoptosis</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b106-ijn-12-2689" ref-type="bibr">106</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">PLGA nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Diethylnitrosamine-induced hepatocellular carcinoma in Swiss albino rat</td><td valign="top" align="left" rowspan="1" colspan="1">↑Apoptosis<break></break>↓Mitochondrial ROS generation<break></break>↑GSH, SOD, and CAT<break></break>↑Mitochondrial cyt c release<break></break>↓iNOS<break></break>↓ALP, AST, and ALT</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b108-ijn-12-2689" ref-type="bibr">108</xref></td></tr><tr><td rowspan="7" valign="top" align="left" colspan="1"></td><td rowspan="7" valign="top" align="left" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">PCL nanodroplets</td><td valign="top" align="left" rowspan="1" colspan="1">S180 cancer-bearing mice</td><td valign="top" align="left" rowspan="1" colspan="1">↓Tumor growth</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b49-ijn-12-2689" ref-type="bibr">49</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">PHEMA nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Ovarian cancer SKOV-3 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Tumor growth<break></break>↑Apoptosis</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b109-ijn-12-2689" ref-type="bibr">109</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Colloidal nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Esophageal Barrett cancer OE19 and OE33 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Proliferation in cancerous cells but not in normal cells<break></break>No significant effect on apoptosis<break></break>↓Activated T-cell apoptosis and production of TNF-α, IL-8, IL-6, IL-10, and IL-Iβ</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b110-ijn-12-2689" ref-type="bibr">110</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Nanoparticles prepared by ultrasonic spray</td><td valign="top" align="left" rowspan="1" colspan="1">Human embyronic kidney HEK and human PC3 prostate cancer cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Cell viability (more obvious on HEK cells)</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b51-ijn-12-2689" ref-type="bibr">51</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Nanostructured lipid carriers</td><td valign="top" align="left" rowspan="1" colspan="1">Human neuroblastoma LAN5 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Cell viability<break></break>↑Hsp70</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b52-ijn-12-2689" ref-type="bibr">52</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Polymer–coated magnetic nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Human ovarian carcinoma SKOv-3 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Cell viability</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b53-ijn-12-2689" ref-type="bibr">53</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Lipid-polymer hybrid nanoparticles in combination with docetaxel</td><td valign="top" align="left" rowspan="1" colspan="1">Human PC3 prostate adenocarcinoma cells, BALB/c nude mice</td><td valign="top" align="left" rowspan="1" colspan="1">↑Adherence ability of the nanocarriers to cell membrane in PC3<break></break>↑Antitumor effects in PC3<break></break>↓Tumor growth in vivo</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b54-ijn-12-2689" ref-type="bibr">54</xref></td></tr><tr><td rowspan="10" valign="top" align="left" colspan="1">Flavonoid</td><td valign="top" align="left" rowspan="1" colspan="1">Baicalein
<graphic xlink:href="ijn-12-2689Fig5"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">Paclitaxel–baicalein dual-targeted ligands of folate and hyaluronic acid</td><td valign="top" align="left" rowspan="1" colspan="1">Human lung cancer A549 and drug-resistant lung cancer A549/PTX cells, xenograft mouse model of A549/PTX drug-resistant human lung cancer</td><td valign="top" align="left" rowspan="1" colspan="1">↓Cell viability<break></break>↓Tumor growth in vivo</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b82-ijn-12-2689" ref-type="bibr">82</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Chrysin
<graphic xlink:href="ijn-12-2689Fig6"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">Nanosuspension</td><td valign="top" align="left" rowspan="1" colspan="1">Human hepatocellular carcinoma HepG2 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Cell growth</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b85-ijn-12-2689" ref-type="bibr">85</xref></td></tr><tr><td rowspan="2" valign="top" align="left" colspan="1">EGCG
<graphic xlink:href="ijn-12-2689Fig7"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">Ca/AlNO<sub>3</sub>-layered double-hydroxide nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Human prostate cancer PC-3 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Apoptosis<break></break>↓Cell viability<break></break>↓Colony formation</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b87-ijn-12-2689" ref-type="bibr">87</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Chitosan nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Human melanoma Mel 928 cells, xenograft athymic nu/nu mouse model of melanoma</td><td valign="top" align="left" rowspan="1" colspan="1">↓Apoptosis<break></break>↓Cell viability<break></break>↑Bax<break></break>↓Bcl-2<break></break>↓Caspase-3 and caspase-9 protein expression<break></break>↑Cleaved caspase-9<break></break>↑PARP cleavage<break></break>G2/M phase cell cycle arrest<break></break>Induction of p21 and p27<break></break>Inhibition of cyclin DI and D3<break></break>↓Tumor growth and proliferation in vivo<break></break>Inhibition of CDK 4 and 6<break></break>↑Apoptosis</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b88-ijn-12-2689" ref-type="bibr">88</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">EGCG (+ paclitaxel)</td><td valign="top" align="left" rowspan="1" colspan="1">Core–shell PLGA–casein nanoparticles in targeted and nontargeted form</td><td valign="top" align="left" rowspan="1" colspan="1">Human breast cancer MDA-MB-231 and MCF-7 cells, breast cancer cells isolated from patients</td><td valign="top" align="left" rowspan="1" colspan="1">↑Apoptosis<break></break>↓NF-κB activation<break></break>Anticancer effects on patients samples</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b89-ijn-12-2689" ref-type="bibr">89</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Green tea polyphenols</td><td valign="top" align="left" rowspan="1" colspan="1">Graphene nanosheets</td><td valign="top" align="left" rowspan="1" colspan="1">Colon cancer HT29 and Sw48 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Photothermal destruction of Sw48</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b90-ijn-12-2689" ref-type="bibr">90</xref></td></tr><tr><td rowspan="2" valign="top" align="left" colspan="1">Luteolin
<graphic xlink:href="ijn-12-2689Fig8"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">Phytosome</td><td valign="top" align="left" rowspan="1" colspan="1">Human MDA-MB-231 breast cancer cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Cell viability<break></break>↑<italic>Nrf2 and related downstream genes HoI</italic> and <italic>MDRI</italic><break></break><italic>↑Sensitivity to doxorubicin</italic></td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b92-ijn-12-2689" ref-type="bibr">92</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">PLA-PEG-OMe nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Lung cancer H292 cells, squamous cell carcinoma of head-and-neck Tu212 cells, xenograft mouse model of head and neck cancer</td><td valign="top" align="left" rowspan="1" colspan="1">↓Tumor growth<break></break>↓Colony formation<break></break>↓Tumor size in animals</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b93-ijn-12-2689" ref-type="bibr">93</xref></td></tr><tr><td rowspan="2" valign="top" align="left" colspan="1">Quercetin
<graphic xlink:href="ijn-12-2689Fig9"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">Phytosome</td><td valign="top" align="left" rowspan="1" colspan="1">Human breast cancer MCF-7 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Apoptosis<break></break>No significant change in <italic>Nrf2</italic><break></break><italic>↓mRNA expression of Nrf2</italic> downstream genes <italic>NQOI</italic> and <italic>MRPi</italic></td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b95-ijn-12-2689" ref-type="bibr">95</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Liposome</td><td valign="top" align="left" rowspan="1" colspan="1">Human breast cancer MCF-7 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Cell proliferation<break></break>↑Antitoxic effect</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b96-ijn-12-2689" ref-type="bibr">96</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Flavonolignan</td><td valign="top" align="left" rowspan="1" colspan="1">Silibinin (+ glycyrrhizic acid)
<graphic xlink:href="ijn-12-2689Fig10"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">Pegylated nanoliposomes</td><td valign="top" align="left" rowspan="1" colspan="1">Human hepatocellular carcinoma HepG2 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Cell viability in cancerous cells but not in normal cells</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b55-ijn-12-2689" ref-type="bibr">55</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Lignan</td><td valign="top" align="left" rowspan="1" colspan="1">Honokiol
<graphic xlink:href="ijn-12-2689Fig11"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">MPEG micelles</td><td valign="top" align="left" rowspan="1" colspan="1">Mouse Lewis lung cancer cell lines LL/2</td><td valign="top" align="left" rowspan="1" colspan="1">↓Cell growth<break></break>Induction of cell cycle arrest in G0/G1 phase</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b60-ijn-12-2689" ref-type="bibr">60</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Naphthoquinone</td><td valign="top" align="left" rowspan="1" colspan="1">Plumbagin
<graphic xlink:href="ijn-12-2689Fig12"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">Silver nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Human skin HaCaT and A431 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Pyruvate kinase activity (more obvious in A431)<break></break>↑Apoptosis by production of free radicals</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b66-ijn-12-2689" ref-type="bibr">66</xref></td></tr><tr><td rowspan="5" valign="top" align="left" colspan="1">Stilbene</td><td rowspan="5" valign="top" align="left" colspan="1">Resveratrol
<graphic xlink:href="ijn-12-2689Fig13"></graphic></td><td valign="top" align="left" rowspan="1" colspan="1">PLGA-PEG-COOH nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Human prostate cancer DU-145, PC-3, and LNCaP cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Cell growth and proliferation</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b68-ijn-12-2689" ref-type="bibr">68</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">PCL nanocapsules<break></break>MPEG-PCL nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Murine melanoma B16F10 cells<break></break>Rat C6 glioma cells</td><td valign="top" align="left" rowspan="1" colspan="1">↓Tumor growth<break></break>↓Cell viability</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b69-ijn-12-2689" ref-type="bibr">69</xref><break></break><xref rid="b70-ijn-12-2689" ref-type="bibr">70</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Pegylated coencapsulation with 5-FU</td><td valign="top" align="left" rowspan="1" colspan="1">Human NT8e head and neck cancer</td><td valign="top" align="left" rowspan="1" colspan="1">Synergistic antineoplastic effect at high concentrations and antagonistic effect at low concentrations of resveratrol<break></break>↑Bax<break></break>↑Bcl-2</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b72-ijn-12-2689" ref-type="bibr">72</xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Bovine serum albumin<break></break>Nanoparticles</td><td valign="top" align="left" rowspan="1" colspan="1">Human ovarian cancer SKOV3 cells</td><td valign="top" align="left" rowspan="1" colspan="1">↑Apoptosis<break></break>↑Bax<break></break>↑DNA fragmentation<break></break>↑Cyt <italic>c</italic> and apoptosis-inducing factor release</td><td valign="top" align="left" rowspan="1" colspan="1"><xref rid="b71-ijn-12-2689" ref-type="bibr">71</xref></td></tr></tbody></table><table-wrap-foot><fn id="tfn1-ijn-12-2689"><p><bold>Abbreviations:</bold> ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CAT, catalase; cyt c, cytochrome c; 5-FU, 5-fluorouracil; GSH, glutathione; HPV, human papillomavirus; IL, interleukin; iNOS, inducible nitric oxide synthase; miRNA, microRNA; MMP, mitochondrial membrane potential; MPEG, methoxy polyethylene glycol; MPEG-PLA-PAE, (MPEG)-poly(lactide)-poly(b-amino ester); OMe, methoxy group; PAE, poly(b-amino ester); PARP, poly(ADP-ribose) polymerase; PCL, poly(ε-caprolactone); PEG, polyethylene glycol; pegylated, conjugated with PEG; PHEMA, poly(2-hydroxyethyl methacrylate); PLA, polylactic acid; PLGA, poly(lactic-<italic>co</italic>-glycolic acid); PNIPAAm, poly(<italic>N</italic>-isopropylacrylamide); ROS, reactive oxygen species; SOD, superoxide dismutase; TNF, tumor necrosis factor.</p></fn></table-wrap-foot></table-wrap><table-wrap id="t2-ijn-12-2689" position="float"><label>Table 2</label><caption><p>Advantages and disadvantages of conventional formulations versus nanoformulations</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="2" valign="top" align="left" rowspan="1">Nanoformulations
<hr></hr></th><th colspan="2" valign="top" align="left" rowspan="1">Conventional formulations
<hr></hr></th></tr><tr><th valign="top" align="left" rowspan="1" colspan="1">Advantages</th><th valign="top" align="left" rowspan="1" colspan="1">Disadvantages</th><th valign="top" align="left" rowspan="1" colspan="1">Advantages</th><th valign="top" align="left" rowspan="1" colspan="1">Disadvantages</th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">Higher surface area-to-volume ratio</td><td valign="top" align="left" rowspan="1" colspan="1">Short shelf life<break></break>Unpredictable toxicity, stability, and pharmacokinetics</td><td valign="top" align="left" rowspan="1" colspan="1">Specified safety profile, predictable toxicity, stability, and pharmacokinetics</td><td valign="top" align="left" rowspan="1" colspan="1">Untargeted drug delivery<break></break>Uncontrollable release</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Improved bioavailability<break></break>Targeted drug delivery<break></break>Sustained drug release</td><td valign="top" align="left" rowspan="1" colspan="1">More expensive</td><td valign="top" align="left" rowspan="1" colspan="1">Less expensive</td><td valign="top" align="left" rowspan="1" colspan="1">Undesirable pharmacokinetics</td></tr></tbody></table></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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