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