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Nanoparticle-mediated delivery of multinuclear platinum(IV) prodrugs with enhanced drug uptake and the activity of overcoming drug resistance

Gao, Yinga; Jiang, Mob; Ma, Yuqina; Wu, Shuanga,d; Li, Wenliangb,c; Yang, Xiaoguangb; Li, Yuxinb; Jing, Xiabinc; Jiang, Hongyud

doi: 10.1097/CAD.0000000000000302
PRECLINICAL REPORTS
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Here, a nanoparticle-mediated delivery of multinuclear platinum(IV) prodrugs [biodegradable polymer-di-cisPt(IV)] for overcoming cisplatin drug resistance is reported. From the MTT assays, lower IC50 values of polymer-di-cisPt(IV) on A2780DDP cells than A2780 were observed with the lowest resistance factor of 0.7. Inductively coupled plasma mass spectroscopy results showed that more drugs were delivered into cancer cells and greater number of Pt–DNA adducts were formed with the use of the polymer-di-cisPt(IV) conjugate nanoparticles. By a mechanistic study with endocytosis inhibitors to treat A2780 cells, we proved that polymer-di-cisPt(IV) conjugate nanoparticles were internalized by the cancer cells through endocytosis rather than through passive diffusion or copper transporter 1-mediated active transportation. This well illustrates the way how the polymer-di-cisPt(IV) micelles overcome cisplatin resistance.

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aSchool of Chemistry & Environmental Engineering, Changchun University of Science & Technology

bNational Engineering Laboratory for Druggable Gene and Protein Screening, School of Life Science, Northeast Normal University

cState Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences

dDepartment of General Internal Medicine, The First Hospital of Jilin University, Changchun, China

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.anti-cancerdrugs.com).

Correspondence to Wenliang Li, PhD, National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China Tel: +86 431 8916 5937; fax: +86 431 8916 5917; e-mail: liwl100@nenu.edu.cn

Received March 20, 2015

Accepted September 8, 2015

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