Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy

被引：98

作者：

Basu, Sudipta ^{[1
]}

Harfouche, Rania ^{[1
]}

Soni, Shivani ^{[1
]}

Chimote, Geetanjali ^{[1
]}

Mashelkar, Raghunath A. ^{[1
,2
]}

Sengupta, Shiladitya ^{[1
]}

机构：

[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Harvard Mit Div Hlth Sci & Technol,Dept Med, Boston, MA 02115 USA

[2] Natl Chem Labs, Pune 411008, Maharashtra, India

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 19期

基金：

加拿大健康研究院;

关键词：

cancer; signal transduction; MUTATIONS; CANCER; GROWTH; BRAF; PENETRATION; ACTIVATION; LIPOSOMES; PATHWAY; GENE;

D O I：

10.1073/pnas.0902857106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The MAPK signal transduction cascade is dysregulated in a majority of human tumors. Here we report that a nanoparticle-mediated targeting of this pathway can optimize cancer chemotherapy. We engineered nanoparticles from a unique hexadentate-polyD, L-lactic acid-co-glycolic acid polymer chemically conjugated to PD98059, a selective MAPK inhibitor. The nanoparticles are taken up by cancer cells through endocytosis and demonstrate sustained release of the active agent, resulting in the inhibition of phosphorylation of downstream extracellular signal regulated kinase. We demonstrate that nanoparticle-mediated targeting of MAPK inhibits the proliferation of melanoma and lung carcinoma cells and induces apoptosis in vitro. Administration of the PD98059-nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Our study shows the nanoparticle-mediated delivery of signal transduction inhibitors can emerge as a unique paradigm in cancer chemotherapy.

引用

页码：7957 / 7961

页数：5

共 25 条

[11] The pharmacology of PEGylation: Balancing PD with PK to generate novel therapeutics [J].