Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy

Abhimanyu S. Paraskar, Shivani Soni, Kenneth T. Chin, Padmaparna Chaudhuri, Katherine W. Muto, Julia Berkowitz, Michael W. Handlogten, Nathan J. Alves, Basar Bilgicer, Daniela M. Dinulescu, Raghunath A. Mashelkar, Shiladitya Sengupta

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O → Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 ± 0.16 μM) comparable to that of free cisplatin (3.87 ± 0.37 μM), and superior to carboplatin (14.75 ± 0.38 μM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras LSL/+?Ptenfl/fl ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasmaspectroscopy. Given the universalneedfor a better platinate, we anticipate this coupling of nanotechnology and structureactivity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.

Original languageEnglish (US)
Pages (from-to)12435-12440
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number28
DOIs
StatePublished - Jul 13 2010
Externally publishedYes

Keywords

  • Cancer
  • Chemotherapy
  • Nanomedicine

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy'. Together they form a unique fingerprint.

  • Cite this

    Paraskar, A. S., Soni, S., Chin, K. T., Chaudhuri, P., Muto, K. W., Berkowitz, J., Handlogten, M. W., Alves, N. J., Bilgicer, B., Dinulescu, D. M., Mashelkar, R. A., & Sengupta, S. (2010). Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy. Proceedings of the National Academy of Sciences of the United States of America, 107(28), 12435-12440. https://doi.org/10.1073/pnas.1007026107