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dc.contributor.authorSengupta, Poulomi
dc.contributor.authorBasu, Sudipta
dc.contributor.authorSoni, Shivani
dc.contributor.authorPandey, Ambarish
dc.contributor.authorRoy, Bhaskar
dc.contributor.authorOh, Michael S.
dc.contributor.authorChin, Kenneth T.
dc.contributor.authorParaskar, Abhimanyu S.
dc.contributor.authorSarangi, Sasmit
dc.contributor.authorConnor, Yamicia D.
dc.contributor.authorSabbisetti, Venkata
dc.contributor.authorKopparam, Jawahar
dc.contributor.authorKulkarni, Ashish
dc.contributor.authorMuto, Katherine
dc.contributor.authorAmarasiriwardena, Chitra
dc.contributor.authorJayawardene, Innocent
dc.contributor.authorLupoli, Nicola
dc.contributor.authorDinulescu, Daniela M.
dc.contributor.authorBonventre, Joseph V.
dc.contributor.authorMashelkar, Raghunath Anant
dc.contributor.authorSengupta, Shiladitya
dc.date.accessioned2013-02-12T21:22:58Z
dc.date.available2013-02-12T21:22:58Z
dc.date.issued2012-07
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/76785
dc.description.abstractNanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC50 values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-RasLSL/+/Ptenfl/fl ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics.en_US
dc.description.sponsorshipUnited States. Dept. of Defense (Breast Cancer Research Program Era of Hope Scholar Award W81XWH-07-1- 0482)en_US
dc.description.sponsorshipUnited States. Dept. of Defense (Collaborative Innovator Grant)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant R01 CA135242-01A2)en_US
dc.description.sponsorshipMedical Foundation, inc. (Charles A. King Trust Postdoctoral Research Fellowship Program)en_US
dc.description.sponsorshipUnited States. Dept. of Defense (Breast Cancer Research Program Postdoctoral Fellowship Award)en_US
dc.description.sponsorshipDana-Farber/Harvard Cancer Center (Ovarian Cancer SPORE award)en_US
dc.description.sponsorshipCanary Foundationen_US
dc.description.sponsorshipMary Kay Foundationen_US
dc.description.sponsorshipV Foundation for Cancer Researchen_US
dc.language.isoen_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1203129109en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePNASen_US
dc.titleCholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicityen_US
dc.typeArticleen_US
dc.identifier.citationSengupta, P. et al. “Cholesterol-tethered Platinum II-based Supramolecular Nanoparticle Increases Antitumor Efficacy and Reduces Nephrotoxicity.” Proceedings of the National Academy of Sciences 109.28 (2012): 11294–11299. Web.en_US
dc.contributor.departmentHarvard University--MIT Division of Health Sciences and Technologyen_US
dc.contributor.mitauthorConnor, Yamicia D.
dc.contributor.mitauthorSengupta, Shiladitya
dc.relation.journalProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsSengupta, P.; Basu, S.; Soni, S.; Pandey, A.; Roy, B.; Oh, M. S.; Chin, K. T.; Paraskar, A. S.; Sarangi, S.; Connor, Y.; Sabbisetti, V. S.; Kopparam, J.; Kulkarni, A.; Muto, K.; Amarasiriwardena, C.; Jayawardene, I.; Lupoli, N.; Dinulescu, D. M.; Bonventre, J. V.; Mashelkar, R. A.; Sengupta, S.en
dc.identifier.orcidhttps://orcid.org/0000-0002-5436-389X
mit.licensePUBLISHER_POLICYen_US


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