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

Yinjian Zhou, Ying Dong, Gang Huang, Yiguang Wang, Xiaonan Huang, Fayun Zhang, David A. Boothman, Jinming Gao, Wei Liang

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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 methemoglobinemia/hemolytic side-effects from the clinical formulation (β-lap-hydroxyl propyl-β-cyclodextrin complex) hindered its clinical translation. Here, we investigated 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 as 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. The β-lap aryl imine prodrug conjugated ultra-pH-sensitive (UPS) polymer reached high β-lap loading density (8.3%) and exhibited dual-stage responsiveness to pH variation. In pHs under pHt, at stage I, micelles immediately dissociate and subsequently, entering stage II, micelles start to quickly release β-lap. An in vitro release study showed that the micelles constantly release β-lap (14.9 ± 0.1%) at pHs above pHt in 72 h, whereas there was a boosted release of β-lap (79.4 ± 1.2%) at pH 5.0. The micelles' intracellular distribution being 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 the 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 cancer, as well as other NQO1+ cancer therapies.

Original languageEnglish (US)
Pages (from-to)7429-7440
Number of pages12
JournalJournal of Materials Chemistry B
Issue number46
StatePublished - 2016

ASJC Scopus subject areas

  • General Chemistry
  • Biomedical Engineering
  • General Materials Science


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