TY - JOUR
T1 - Lysosome-oriented, dual-stage pH-responsive polymeric micelles for β-lapachone delivery
AU - Zhou, Yinjian
AU - Dong, Ying
AU - Huang, Gang
AU - Wang, Yiguang
AU - Huang, Xiaonan
AU - Zhang, Fayun
AU - Boothman, David A.
AU - Gao, Jinming
AU - Liang, Wei
N1 - Publisher Copyright:
© The Royal Society of Chemistry.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84997637139&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84997637139&partnerID=8YFLogxK
U2 - 10.1039/c6tb02049f
DO - 10.1039/c6tb02049f
M3 - Article
AN - SCOPUS:84997637139
SN - 2050-7518
VL - 4
SP - 7429
EP - 7440
JO - Journal of Materials Chemistry B
JF - Journal of Materials Chemistry B
IS - 46
ER -