title: Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis.
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.
authors.affiliation: Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190, China. liangxj@nanoctr.cn
authors.forename: Xing-Jie
authors.initials: XJ
authors.lastname: Liang
authors.forename: Huan
authors.initials: H
authors.lastname: Meng
authors.forename: Yingze
authors.initials: Y
authors.lastname: Wang
authors.forename: Haiyong
authors.initials: H
authors.lastname: He
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.forename: Juan
authors.initials: J
authors.lastname: Lu
authors.forename: Paul C
authors.initials: PC
authors.lastname: Wang
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xueyun
authors.initials: X
authors.lastname: Gao
authors.forename: Baoyun
authors.initials: B
authors.lastname: Sun
authors.forename: Chunying
authors.initials: C
authors.lastname: Chen
authors.forename: Genmei
authors.initials: G
authors.lastname: Xing
authors.forename: Dingwu
authors.initials: D
authors.lastname: Shen
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Yin
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004358:Drug Therapy / Q000295:instrumentation / Q000379:methods; D004705:Endocytosis; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D050997:Nanomedicine; D036103:Nanotechnology / Q000379:methods; D014168:Transferrin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014168:Transferrin; D002945:Cisplatin