Improving Drug Potency and Efficacy by Nanocarrier-Mediated Subcellular Targeting

被引：217

作者：

Murakami, Mami ^{[2
]}

Cabral, Horacio ^{[1
,2
]}

Matsumoto, Yu ^{[3
]}

Wu, Shourong ^{[3
]}

Kano, Mitsunobu R. ^{[4
]}

Yamori, Takao ^{[5
]}

Nishiyama, Nobuhiro ^{[1
,3
]}

Kataoka, Kazunori ^{[1
,2
,3
,6
]}

机构：

[1] Univ Tokyo, Ctr NanoBio Integrat, Tokyo 1138656, Japan

[2] Univ Tokyo, Grad Sch Engn, Dept Bioengn, Bunkyo Ku, Tokyo 1138656, Japan

[3] Univ Tokyo, Grad Sch Med, Ctr Dis Biol & Integrat Med, Tokyo 1130033, Japan

[4] Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan

[5] Japanese Fdn Canc Res, Ctr Canc Chemotherapy, Div Mol Pharmacol, Koto Ku, Tokyo 1358550, Japan

[6] Univ Tokyo, Grad Sch Engn, Dept Mat Engn, Tokyo 1138656, Japan

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2011年 / 3卷 / 64期

基金：

日本科学技术振兴机构; 日本学术振兴会;

关键词：

INCORPORATED POLYMERIC MICELLES; BLOCK-COPOLYMER MICELLES; CANCER CELL-LINES; ANTITUMOR-ACTIVITY; SOLID TUMORS; PHASE-I; MULTIDRUG-RESISTANCE; ANTICANCER DRUGS; OXALIPLATIN; DELIVERY;

D O I：

10.1126/scitranslmed.3001385

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Nanocarrier-mediated drug targeting is an emerging strategy for cancer therapy and is being used, for example, with chemotherapeutic agents for ovarian cancer. Nanocarriers are selectively accumulated in tumors as a result of their enhanced permeability and retention of macromolecules, thereby enhancing the antitumor activity of the nanocarrier-associated drugs. We investigated the real-time subcellular fate of polymeric micelles incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt/m), the parent complex of oxaliplatin, in tumor tissues by fluorescence-based assessment of their kinetic stability. These observations revealed that DACHPt/m was extravasated from blood vessels to the tumor tissue and dissociated inside each cell. Furthermore, DACHPt/m selectively dissociated within late endosomes, enhancing drug delivery to the nearby nucleus relative to free oxaliplatin, likely by circumvention of the cytoplasmic detoxification systems such as metallothionein and methionine synthase. Thus, these drug-loaded micelles exhibited higher antitumor activity than did oxaliplatin alone, even against oxaliplatin-resistant tumors. These findings suggest that nanocarriers targeting subcellular compartments may have considerable benefits in clinical applications.

引用

页数：11