Active targeting of block copolymer micelles with trastuzumab Fab fragments and nuclear localization signal leads to increased tumor uptake and nuclear localization in HER2-overexpressing xenografts.
Identifieur interne : 000892 ( Main/Exploration ); précédent : 000891; suivant : 000893Active targeting of block copolymer micelles with trastuzumab Fab fragments and nuclear localization signal leads to increased tumor uptake and nuclear localization in HER2-overexpressing xenografts.
Auteurs : RBID : pubmed:24066900Abstract
Block copolymer micelles (BCMs) have been employed as effective drug delivery systems to solid tumors by virtue of their capacity to transport large therapeutic payloads and passively target tumor sites. Active targeting of nanoparticles (NPs) has been exploited as a means to increase the therapeutic efficacy of NP-based drugs by promoting their delivery to cellular sites of action. Effective whole tumor accumulation and cellular uptake constitute key objectives in the success of preclinical drug formulations, although they have seldom been investigated concurrently in vivo. The current study aims to elucidate the in vivo fate of 31-nm-sized block copolymer micelles (BCMs) targeted to the nucleus of HER2-overexpressing breast cancer cells. Pharmacokinetics, biodistribution, tumor uptake, and intratumoral distribution of BCMs were investigated in mice bearing subcutaneous BT-474 and MDA-MB-231 xenografts expressing high and low levels of HER2, respectively. Radiolabeling with (111)indium enabled quantitative assessment of BCM distribution at the whole body, tissue, and cellular levels. Surface-grafted trastuzumab Fab fragments (TmAb-Fab) facilitated binding and internalization of BCMs by HER2-positive breast cancer cells, while synthetic 13-mer nuclear localization signal (NLS) peptides conjugated to the TmAb-Fab conferred nuclear translocation capability. Active targeting of BCMs led to a 5-fold increase in tumor uptake in HER2-overexpressing BT-474 tumors, alongside a correspondingly greater level of cellular uptake and nuclear localization, relative to the nontargeted formulations. This study distinctively highlights the quantitative evaluation of active targeting on tumor, cellular and subcellular uptake of BCMs and presents a promising platform for the effective delivery of chemo- and/or radiotherapy in vivo.
DOI: 10.1021/mp400315p
PubMed: 24066900
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Active targeting of nanoparticles (NPs) has been exploited as a means to increase the therapeutic efficacy of NP-based drugs by promoting their delivery to cellular sites of action. Effective whole tumor accumulation and cellular uptake constitute key objectives in the success of preclinical drug formulations, although they have seldom been investigated concurrently in vivo. The current study aims to elucidate the in vivo fate of 31-nm-sized block copolymer micelles (BCMs) targeted to the nucleus of HER2-overexpressing breast cancer cells. Pharmacokinetics, biodistribution, tumor uptake, and intratumoral distribution of BCMs were investigated in mice bearing subcutaneous BT-474 and MDA-MB-231 xenografts expressing high and low levels of HER2, respectively. Radiolabeling with (111)indium enabled quantitative assessment of BCM distribution at the whole body, tissue, and cellular levels. Surface-grafted trastuzumab Fab fragments (TmAb-Fab) facilitated binding and internalization of BCMs by HER2-positive breast cancer cells, while synthetic 13-mer nuclear localization signal (NLS) peptides conjugated to the TmAb-Fab conferred nuclear translocation capability. Active targeting of BCMs led to a 5-fold increase in tumor uptake in HER2-overexpressing BT-474 tumors, alongside a correspondingly greater level of cellular uptake and nuclear localization, relative to the nontargeted formulations. This study distinctively highlights the quantitative evaluation of active targeting on tumor, cellular and subcellular uptake of BCMs and presents a promising platform for the effective delivery of chemo- and/or radiotherapy in vivo.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="In-Process"><PMID Version="1">24066900</PMID><DateCreated><Year>2014</Year><Month>02</Month><Day>04</Day></DateCreated><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1543-8392</ISSN><JournalIssue CitedMedium="Internet"><Volume>10</Volume><Issue>11</Issue><PubDate><Year>2013</Year><Month>Nov</Month><Day>4</Day></PubDate></JournalIssue><Title>Molecular pharmaceutics</Title><ISOAbbreviation>Mol. Pharm.</ISOAbbreviation></Journal><ArticleTitle>Active targeting of block copolymer micelles with trastuzumab Fab fragments and nuclear localization signal leads to increased tumor uptake and nuclear localization in HER2-overexpressing xenografts.</ArticleTitle><Pagination><MedlinePgn>4229-41</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1021/mp400315p</ELocationID><Abstract><AbstractText>Block copolymer micelles (BCMs) have been employed as effective drug delivery systems to solid tumors by virtue of their capacity to transport large therapeutic payloads and passively target tumor sites. Active targeting of nanoparticles (NPs) has been exploited as a means to increase the therapeutic efficacy of NP-based drugs by promoting their delivery to cellular sites of action. Effective whole tumor accumulation and cellular uptake constitute key objectives in the success of preclinical drug formulations, although they have seldom been investigated concurrently in vivo. The current study aims to elucidate the in vivo fate of 31-nm-sized block copolymer micelles (BCMs) targeted to the nucleus of HER2-overexpressing breast cancer cells. Pharmacokinetics, biodistribution, tumor uptake, and intratumoral distribution of BCMs were investigated in mice bearing subcutaneous BT-474 and MDA-MB-231 xenografts expressing high and low levels of HER2, respectively. Radiolabeling with (111)indium enabled quantitative assessment of BCM distribution at the whole body, tissue, and cellular levels. Surface-grafted trastuzumab Fab fragments (TmAb-Fab) facilitated binding and internalization of BCMs by HER2-positive breast cancer cells, while synthetic 13-mer nuclear localization signal (NLS) peptides conjugated to the TmAb-Fab conferred nuclear translocation capability. Active targeting of BCMs led to a 5-fold increase in tumor uptake in HER2-overexpressing BT-474 tumors, alongside a correspondingly greater level of cellular uptake and nuclear localization, relative to the nontargeted formulations. This study distinctively highlights the quantitative evaluation of active targeting on tumor, cellular and subcellular uptake of BCMs and presents a promising platform for the effective delivery of chemo- and/or radiotherapy in vivo.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Hoang</LastName><ForeName>Bryan</ForeName><Initials>B</Initials><Affiliation>Leslie Dan Faculty of Pharmacy, ‡Department of Chemistry, and §Department of Medical Imaging, University of Toronto , 144 College St., Toronto, Ontario, M5S 3M2, Canada.</Affiliation></Author><Author ValidYN="Y"><LastName>Ekdawi</LastName><ForeName>Sandra N</ForeName><Initials>SN</Initials></Author><Author ValidYN="Y"><LastName>Reilly</LastName><ForeName>Raymond M</ForeName><Initials>RM</Initials></Author><Author ValidYN="Y"><LastName>Allen</LastName><ForeName>Christine</ForeName><Initials>C</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><Agency>Canadian Institutes of Health Research</Agency><Country>Canada</Country></Grant></GrantList><PublicationTypeList><PublicationType>Journal Article</PublicationType><PublicationType>Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2013</Year><Month>10</Month><Day>22</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mol Pharm</MedlineTA><NlmUniqueID>101197791</NlmUniqueID><ISSNLinking>1543-8384</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="aheadofprint"><Year>2013</Year><Month>10</Month><Day>22</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2013</Year><Month>9</Month><Day>27</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2013</Year><Month>9</Month><Day>27</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2013</Year><Month>9</Month><Day>27</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="doi">10.1021/mp400315p</ArticleId><ArticleId IdType="pubmed">24066900</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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