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, including acylhydrazone, ketal and
imine bonds for β-lap
prodrug syntheses result in an aryl
imine linkage the most optimal linkage. The conversion to β-lap was 2.8%, 4.5% and 100% at pH 7.4, 6.5 and 5.0 in 8 h, respectively. β-lap aryl
imine prodrug conjugated ultra pH-sensitive (UPS)
polymer reached high β-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 β-lap. In vitro release study showed that the
micelles constantly release β-lap (14.9 ± 0.1%) at pHs above pHt in 72 h, whereas boosted release of β-lap (79.4 ± 1.2%) at pH 5.0.
Micelle intracellular distribution predominantly in the lysosome organelle guaranteed their pH responsive dissociation and subsequently β-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 β-lap
prodrug micelles potentially offer an alternative nanotherapeutic strategy for lung, as well as other NQO1+
cancer therapies.