@article { ISI:000266208900051,
	title = {Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {106},
	number = {19},
	year = {2009},
	month = {MAY},
	pages = {7957-7961},
	publisher = {NATL ACAD SCIENCES},
	address = {2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA},
	abstract = {<p>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.</p>},
	keywords = {cancer, Signal transduction},
	issn = {0027-8424},
	doi = {10.1073/pnas.0902857106},
	author = {Basu, Sudipta and Harfouche, Rania and Soni, Shivani and Chimote, Geetanjali and Mashelkar, Raghunath Anant and Sengupta, Shiladitya}
}
@article { ISI:000279843200010,
	title = {Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {107},
	number = {28},
	year = {2010},
	month = {JUL},
	pages = {12435-12440},
	publisher = {NATL ACAD SCIENCES},
	address = {2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA},
	abstract = {<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 {\textendash}\&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>},
	keywords = {cancer, chemotherapy, nanomedicine},
	issn = {0027-8424},
	doi = {10.1073/pnas.1007026107},
	author = {Paraskar, Abhimanyu S. and Soni, Shivani and Chin, Kenneth T. and Chaudhuri, Padmaparna and Muto, Katherine W. and Berkowitz, Julia and Handlogten, Michael W. and Alves, Nathan J. and Bilgicer, Basar and Dinulescu, Daniela M. and Mashelkar, Raghunath Anant and Sengupta, Shiladitya}
}
