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

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 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). 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/+)/Pten(fl/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 plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer. -->
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Grant Information: R01 CA135242 United States CA NCI NIH HHS; 1R01CA135242-01A2 United States CA NCI NIH HHS
Substance Nomenclature: 0 (Polyenes)
0 (Polymers)
49DFR088MY (Platinum)
4F86W47BR6 (Raloxifene Hydrochloride)
9003-27-4 (polyisobutylene)
BG3F62OND5 (Carboplatin)
Q20Q21Q62J (Cisplatin)
Entry Date(s): Date Created: 20100710 Date Completed: 20100819 Latest Revision: 20211020
Update Code: 20221213
PubMed Central ID: PMC2906605
DOI: 10.1073/pnas.1007026107
PMID: 20616005
Autor: Paraskar AS; Department of Medicine, Brigham and Women's Hospital, Cambridge, MA 02139, USA., Soni S, Chin KT, Chaudhuri P, Muto KW, Berkowitz J, Handlogten MW, Alves NJ, Bilgicer B, Dinulescu DM, Mashelkar RA, Sengupta S
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2010 Jul 13; Vol. 107 (28), pp. 12435-40. Date of Electronic Publication: 2010 Jun 23.
DOI: 10.1073/pnas.1007026107
Abstrakt: 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 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). 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/+)/Pten(fl/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 plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.
Databáze: MEDLINE
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