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...
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doaj-9596760dca244b7fbddffcca8d2c12d62020-11-25T01:10:23ZengTaylor & Francis GroupDrug Delivery1071-75441521-04642019-01-012611125113910.1080/10717544.2019.16876141687614Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug deliveryLei Fang0Wei Zhang1Zhen Wang2Xinxin Fan3Ziting Cheng4Xiaoya Hou5Daquan Chen6Universities of Shandong, Yantai UniversityAffiliated Yantai Yuhuangding Hospital of Qingdao UniversityUniversities of Shandong, Yantai UniversityUniversities of Shandong, Yantai UniversityUniversities of Shandong, Yantai UniversityUniversities of Shandong, Yantai UniversityUniversities of Shandong, Yantai UniversityStability 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.http://dx.doi.org/10.1080/10717544.2019.1687614tumor microenvironment-responsivelong-circulatingcharge-reversalpolysaccharide-based nanoparticlesmitochondrial targeting shell/core structure |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lei Fang Wei Zhang Zhen Wang Xinxin Fan Ziting Cheng Xiaoya Hou Daquan Chen |
spellingShingle |
Lei Fang Wei Zhang Zhen Wang Xinxin Fan Ziting Cheng Xiaoya Hou Daquan Chen Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery Drug Delivery tumor microenvironment-responsive long-circulating charge-reversal polysaccharide-based nanoparticles mitochondrial targeting shell/core structure |
author_facet |
Lei Fang Wei Zhang Zhen Wang Xinxin Fan Ziting Cheng Xiaoya Hou Daquan Chen |
author_sort |
Lei Fang |
title |
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_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_sort |
novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery |
publisher |
Taylor & Francis Group |
series |
Drug Delivery |
issn |
1071-7544 1521-0464 |
publishDate |
2019-01-01 |
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. |
topic |
tumor microenvironment-responsive long-circulating charge-reversal polysaccharide-based nanoparticles mitochondrial targeting shell/core structure |
url |
http://dx.doi.org/10.1080/10717544.2019.1687614 |
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