Cargando…
Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery
Stability in systemic circulation, effective tumor accumulation, and the subsequent crucial subcellular targeting are significant elements that maximize the therapeutic efficacy of a drug. Accordingly, novel nanoparticles based on polysaccharides that simultaneously presented prolonged systemic circ...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882447/ https://www.ncbi.nlm.nih.gov/pubmed/31736389 http://dx.doi.org/10.1080/10717544.2019.1687614 |
_version_ | 1783474164107051008 |
---|---|
author | Fang, Lei Zhang, Wei Wang, Zhen Fan, Xinxin Cheng, Ziting Hou, Xiaoya Chen, Daquan |
author_facet | Fang, Lei Zhang, Wei Wang, Zhen Fan, Xinxin Cheng, Ziting Hou, Xiaoya Chen, Daquan |
author_sort | Fang, Lei |
collection | PubMed |
description | Stability in systemic circulation, effective tumor accumulation, and the subsequent crucial subcellular targeting are significant elements that maximize the therapeutic efficacy of a drug. Accordingly, novel nanoparticles based on polysaccharides that simultaneously presented prolonged systemic circulation and mitochondrial-targeted drug release were synthesized. First, the mitochondrial-targeted polymer, 3,4-dihydroxyphenyl propionic acid-chitosan oligosaccharide-dithiodipropionic acid-berberine (DHPA-CDB), was synthesized, which was used to form self-assembled curcumin (Cur)-encapsulated cationic micelles (DHPA-CDB/Cur). Negatively charged oligomeric hyaluronic acid-3-carboxyphenylboronic acid (oHA-PBA), a ligand to sialic acid and CD44, was further added to the surface of the preformed DHPA-CDB/Cur core to shield the positive charges and to prolong blood persistence. oHA-PBA@DHPA-CDB/Cur formed a covalent polyplex of oHA-PBA and DHPA-CDB/Cur via the pH-responsive borate ester bond between PBA and DHPA. The mildly acidic tumor environment led to the degradation of borate ester bonds, thereby realizing the exposure of the cationic micelles and causing a charge reversal from −19.47 to +12.01 mV, to promote cell internalization and mitochondrial localization. Compared with micelles without the oHA-PBA modification, the prepared oHA-PBA@DHPA-CDB/Cur showed enhanced cytotoxicity to PANC-1 cells and greater cellular uptake via receptor-mediated endocytosis. oHA-PBA@DHPA-CDB/Cur was effectively targeted to the mitochondria, which triggered mitochondrial membrane depolarization. In mice xenografted with PANC-1 cells, compared with control mice, oHA-PBA@DHPA-CDB/Cur resulted in more effective tumor suppression and greater biosafety with preferential accumulation in the tumor tissue. Thus, the long-circulating oHA-PBA@DHPA-CDB/Cur, with mitochondrial targeting and tumor environment charge-reversal capabilities, was shown to be an excellent candidate for subcellular-specific drug delivery. |
format | Online Article Text |
id | pubmed-6882447 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-68824472019-12-09 Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery Fang, Lei Zhang, Wei Wang, Zhen Fan, Xinxin Cheng, Ziting Hou, Xiaoya Chen, Daquan Drug Deliv Research Article Stability in systemic circulation, effective tumor accumulation, and the subsequent crucial subcellular targeting are significant elements that maximize the therapeutic efficacy of a drug. Accordingly, novel nanoparticles based on polysaccharides that simultaneously presented prolonged systemic circulation and mitochondrial-targeted drug release were synthesized. First, the mitochondrial-targeted polymer, 3,4-dihydroxyphenyl propionic acid-chitosan oligosaccharide-dithiodipropionic acid-berberine (DHPA-CDB), was synthesized, which was used to form self-assembled curcumin (Cur)-encapsulated cationic micelles (DHPA-CDB/Cur). Negatively charged oligomeric hyaluronic acid-3-carboxyphenylboronic acid (oHA-PBA), a ligand to sialic acid and CD44, was further added to the surface of the preformed DHPA-CDB/Cur core to shield the positive charges and to prolong blood persistence. oHA-PBA@DHPA-CDB/Cur formed a covalent polyplex of oHA-PBA and DHPA-CDB/Cur via the pH-responsive borate ester bond between PBA and DHPA. The mildly acidic tumor environment led to the degradation of borate ester bonds, thereby realizing the exposure of the cationic micelles and causing a charge reversal from −19.47 to +12.01 mV, to promote cell internalization and mitochondrial localization. Compared with micelles without the oHA-PBA modification, the prepared oHA-PBA@DHPA-CDB/Cur showed enhanced cytotoxicity to PANC-1 cells and greater cellular uptake via receptor-mediated endocytosis. oHA-PBA@DHPA-CDB/Cur was effectively targeted to the mitochondria, which triggered mitochondrial membrane depolarization. In mice xenografted with PANC-1 cells, compared with control mice, oHA-PBA@DHPA-CDB/Cur resulted in more effective tumor suppression and greater biosafety with preferential accumulation in the tumor tissue. Thus, the long-circulating oHA-PBA@DHPA-CDB/Cur, with mitochondrial targeting and tumor environment charge-reversal capabilities, was shown to be an excellent candidate for subcellular-specific drug delivery. Taylor & Francis 2019-11-18 /pmc/articles/PMC6882447/ /pubmed/31736389 http://dx.doi.org/10.1080/10717544.2019.1687614 Text en © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Fang, Lei Zhang, Wei Wang, Zhen Fan, Xinxin Cheng, Ziting Hou, Xiaoya Chen, Daquan Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery |
title | Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery |
title_full | Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery |
title_fullStr | Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery |
title_full_unstemmed | Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery |
title_short | Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery |
title_sort | novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882447/ https://www.ncbi.nlm.nih.gov/pubmed/31736389 http://dx.doi.org/10.1080/10717544.2019.1687614 |
work_keys_str_mv | AT fanglei novelmitochondrialtargetingchargereversalpolysaccharidehybridshellcorenanoparticlesforprolongedsystemiccirculationandantitumordrugdelivery AT zhangwei novelmitochondrialtargetingchargereversalpolysaccharidehybridshellcorenanoparticlesforprolongedsystemiccirculationandantitumordrugdelivery AT wangzhen novelmitochondrialtargetingchargereversalpolysaccharidehybridshellcorenanoparticlesforprolongedsystemiccirculationandantitumordrugdelivery AT fanxinxin novelmitochondrialtargetingchargereversalpolysaccharidehybridshellcorenanoparticlesforprolongedsystemiccirculationandantitumordrugdelivery AT chengziting novelmitochondrialtargetingchargereversalpolysaccharidehybridshellcorenanoparticlesforprolongedsystemiccirculationandantitumordrugdelivery AT houxiaoya novelmitochondrialtargetingchargereversalpolysaccharidehybridshellcorenanoparticlesforprolongedsystemiccirculationandantitumordrugdelivery AT chendaquan novelmitochondrialtargetingchargereversalpolysaccharidehybridshellcorenanoparticlesforprolongedsystemiccirculationandantitumordrugdelivery |