02646nas a2200313   4500008004100000022001400041245011600055210006900171260008000240300001600320490000800336520152500344653001101869653001701880653001701897100002801914700001801942700002201960700002601982700002402008700002102032700002802053700002202081700002002103700002702123700003202150700002502182856012502207       2010                        eng d  a0027-842400aHarnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy0 aHarnessing structureactivity relationship to engineer a cisplati  a2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USAbNATL ACAD SCIENCEScJUL  a12435-124400 v1073 a<p>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 –&gt; 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 mu M) comparable to that of free cisplatin (3.87 +/- 0.37 mu M), and superior to carboplatin (14.75 +/- 0.38 mu M). 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.</p>10acancer10achemotherapy10ananomedicine1 aParaskar, Abhimanyu, S.1 aSoni, Shivani1 aChin, Kenneth, T.1 aChaudhuri, Padmaparna1 aMuto, Katherine, W.1 aBerkowitz, Julia1 aHandlogten, Michael, W.1 aAlves, Nathan, J.1 aBilgicer, Basar1 aDinulescu, Daniela, M.1 aMashelkar, Raghunath, Anant1 aSengupta, Shiladitya  uhttps://library.ncl.res.in/content/harnessing-structure-activity-relationship-engineer-cisplatin-nanoparticle-enhanced-0