Metallofullerene Nanoparticles Circumvent Tumor Resistance to Cisplatin by Reactivating Endocytosis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Apr 7

PMID 20368438

Citations 47

Authors

Xing-Jie Liang

Huan Meng

Yingze Wang

Haiyong He

Jie Meng

Juan Lu

Paul C Wang

Yuliang Zhao

Xueyun Gao

Baoyun Sun

Chunying Chen

Genmei Xing

Dingwu Shen

Michael M Gottesman

Yan Wu

Jun-Jie Yin

Lee Jia

Affiliations

Soon will be listed here.

Abstract

Cisplatin is a chemotherapeutic drug commonly used in clinics. However, acquired resistance confines its application in chemotherapeutics. To overcome the acquired resistance to cisplatin, it is reasoned, based on our previous findings of mediation of cellular responses by [Gd@C(82)(OH)(22)](n) nanoparticles, that [Gd@C(82)(OH)(22)](n) may reverse tumor resistance to cisplatin by reactivating the impaired endocytosis of cisplatin-resistant human prostate cancer (CP-r) cells. Here we report that exposure of the CP-r PC-3-luc cells to cisplatin in the presence of nontoxic [Gd@C(82)(OH)(22)](n) not only decreased the number of surviving CP-r cells but also inhibited growth of the CP-r tumors in athymic nude mice as measured by both optical and MRI. Labeling the CP-r PC-3 cells with transferrin, an endocytotic marker, demonstrated that pretreatment of the CP-r PC-3-luc cells with [Gd@C(82)(OH)(22)](n) enhanced intracellular accumulation of cisplatin and formation of cisplatin-DNA adducts by restoring the defective endocytosis of the CP-r cancer cells. The results suggest that [Gd@C(82)(OH)(22)](n) nanoparticles overcome tumor resistance to cisplatin by increasing its intracellular accumulation through the mechanism of restoring defective endocytosis. The technology can be extended to other challenges related to multidrug resistance often found in cancer treatments.

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