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Lysosome-oriented, dual-stage pH-responsive polymeric micelles for ?-Lapachone delivery.

ABSTRACT: ?-Lapachone (?-lap), a novel anticancer agent, is bioactivated by NADP(H):quinone oxidoreductase 1 (NQO1), an enzyme over-expressed in numerous tumors, including lung, pancreas, breast, and prostate cancers. Fast renal clearance and methemaglobinemia / hemolytic side-effects from the clinical formulation (?-lap-hydroxyl propyl-?-cyclodextrin complex) hindered its clinical translation. Here, we investigated a dual model pH responsive polymers for ?-lap delivery. Three pH-sensitive linkages, including acylhydrazone, ketal and imine bonds for ?-lap prodrug syntheses result in an aryl imine linkage the most optimal linkage. The conversion to ?-lap was 2.8%, 4.5% and 100% at pH 7.4, 6.5 and 5.0 in 8 h, respectively. ?-lap aryl imine prodrug conjugated ultra pH-sensitive (UPS) polymer reached high ?-lap loading density (8.3%) and exhibited dual-stages responsiveness to pH variation. In pHs under pHt, at stage I, micelle immediately dissociation and subsequently entering stage II, micelles start quickly release ?-lap. In vitro release study showed that the micelles constantly release ?-lap (14.9 ± 0.1%) at pHs above pHt in 72 h, whereas boosted release of ?-lap (79.4 ± 1.2%) at pH 5.0. Micelle intracellular distribution predominantly in the lysosome organelle guaranteed their pH responsive dissociation and subsequently ?-lap controlled release. The M-P micelles retained NQO1-dependent cytotoxicity in A549 lung cancer cells, similar to free drug in both efficacy and mechanism of cell death. The lysosome-oriented dual-stage ultra pH responsive ?-lap prodrug micelles potentially offer an alternative nanotherapeutic strategy for lung, as well as other NQO1+ cancer therapies.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC5452003 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Lysosome-oriented, dual-stage pH-responsive polymeric micelles for β-Lapachone delivery.

Zhou Yinjian Y Dong Ying Y Huang Gang G Wang Yiguang Y Huang Xiaonan X Zhang Fayun F Boothman David A DA Gao Jinming J Liang Wei W

Journal of materials chemistry. B 20161021 46

β-Lapachone (β-lap), a novel anticancer agent, is bioactivated by NADP(H):quinone oxidoreductase 1 (NQO1), an enzyme over-expressed in numerous tumors, including lung, pancreas, breast, and prostate cancers. Fast renal clearance and methemaglobinemia / hemolytic side-effects from the clinical formulation (β-lap-hydroxyl propyl-β-cyclodextrin complex) hindered its clinical translation. Here, we investigated a dual model pH responsive polymers for β-lap delivery. Three pH-sensitive linkages, inclu ...[more]

PMID: 28580145

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Project description:RNA interference (RNAi) drugs have significant therapeutic potential, but delivery systems with appropriate efficacy and toxicity profiles are still needed. Here, we describe a neutral, ampholytic polymeric delivery system based on conjugatable diblock polymer micelles. The diblock copolymer contains a hydrophilic poly[N-(2-hydroxypropyl)methacrylamide-co-N-(2-(pyridin-2-yldisulfanyl)ethyl)methacrylamide) (poly[HPMA-co-PDSMA]) segment to promote aqueous stability and facilitate thiol-disulfide exchange reactions and a second ampholytic block composed of propylacrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The poly[(HPMA-co-PDSMA)-b-(PAA-co-DMAEMA-co-BMA)] was synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization with an overall molecular weight of 22 000 g/mol and a PDI of 1.88. Dynamic light scattering and fluorescence measurements indicated that the diblock copolymers self-assemble under aqueous conditions to form polymeric micelles with a hydrodynamic radius and critical micelle concentration of 25 nm and 25 ?g/mL, respectively. Red blood cell hemolysis experiments show that the neutral hydrophilic micelles have potent membrane destabilizing activity at endosomal pH values. Thiolated siRNA targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was directly conjugated to the polymeric micelles via thiol exchange reactions with the pyridal disulfide groups present in the micelle corona. Maximum silencing activity in HeLa cells was observed at a 1:10 molar ratio of siRNA to polymer following a 48 h incubation period. Under these conditions 90% mRNA knockdown and 65% protein knockdown at 48 h was achieved with negligible toxicity. In contrast the polymeric micelles lacking a pH-responsive endosomalytic segment demonstrated negligible mRNA and protein knockdown under these conditions. The potent mRNA knockdown and excellent biocompatibility of the neutral siRNA conjugates demonstrate the potential utility of this carrier design for delivering therapeutic siRNA drugs.

Dataset Information

Lysosome-oriented, dual-stage pH-responsive polymeric micelles for ?-Lapachone delivery.

Publications

Lysosome-oriented, dual-stage pH-responsive polymeric micelles for β-Lapachone delivery.

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