01987nas a2200253   4500008004100000022001400041245006000055210005900115260007100174300001400245490000600259520116700265653001701432653001601449653001801465653001501483653001701498100002601515700002401541700001801565700003201583700002501615856009301640       2009                        eng d  a1936-085100aFullerenol-cytotoxic conjugates for cancer chemotherapy0 aFullerenolcytotoxic conjugates for cancer chemotherapy  a1155 16TH ST, NW, WASHINGTON, DC 20036 USAbAMER CHEMICAL SOCcSEP  a2505-25140 v33 a<p>In the present study, we report the novel application of polyhydroxylated fullerenes (fullerenols) in cancer drug delivery. The facile synthetic procedure for generating multiple hydroxyl groups on the fullerene cage offers scope for high drug loading in addition to conferring hydrophilicity. Doxorubicin, a first line cancer chemotherapeutic, was conjugated to fullerenols through a carbamate linker, achieving ultrahigh loading efficiency. The drug-fullerenol conjugate was found to be relatively stable in phosphate buffer saline but temporally released the active drug when incubated with tumor cell lysate. The fullerenol-doxorubicin conjugate suppressed the proliferation of cancer cell-lines in vitro through a G2-M cell cycle block, resulting in apoptosis. Furthermore, in an in vivo murine tumor model, fullerenol-doxorubicin exhibited Comparable antitumor efficacy as free drug without the systemic toxicity of free doxorubicin. Additionally, we demonstrate that the fullerenol platform can be extended to other chemotherapeutic agents, such as the slightly water-soluble cisplatin, and can emerge as a new paradigm in the management of cancer.</p>10achemotherapy10adoxorubicin10adrug delivery10afullerenol10ananoparticle1 aChaudhuri, Padmaparna1 aParaskar, Abhimanyu1 aSoni, Shivani1 aMashelkar, Raghunath, Anant1 aSengupta, Shiladitya  uhttps://library.ncl.res.in/content/fullerenol-cytotoxic-conjugates-cancer-chemotherapy-001870nas a2200229   4500008004100000022001400041245008800055210006900143260008000212300001400292490000800306520103400314653001101348653002401359100001801383700002101401700001801422700002401440700003201464700002501496856011901521       2009                        eng d  a0027-842400aNanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy0 aNanoparticlemediated targeting of MAPK signaling predisposes tum  a2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USAbNATL ACAD SCIENCEScMAY  a7957-79610 v1063 a<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>10acancer10aSignal transduction1 aBasu, Sudipta1 aHarfouche, Rania1 aSoni, Shivani1 aChimote, Geetanjali1 aMashelkar, Raghunath, Anant1 aSengupta, Shiladitya  uhttps://library.ncl.res.in/content/nanoparticle-mediated-targeting-mapk-signaling-predisposes-tumor-chemotherapy-002140nas a2200361   4500008004100000022001400041245008800055210006900143260008000212300001600292490000800308520092900316653002701245653001101272653002101283653001701304653002401321100002601345700001801371700002101389700002501410700001901435700001901454700001701473700002401490700002401514700002301538700002201561700002201583700003201605700002501637856011601662       2010                        eng d  a0027-842400aCoupling growth-factor engineering with nanotechnology for therapeutic angiogenesis0 aCoupling growthfactor engineering with nanotechnology for therap  a2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USAbNATL ACAD SCIENCEScAUG  a13608-136130 v1073 a<p>Therapeutic angiogenesis is an emerging paradigm for the management of ischemic pathologies. Proangiogenic Therapy is limited, however, by the current inability to deliver angiogenic factors in a sustained manner at the site of pathology. In this study, we investigated a unique nonglycosylated active fragment of hepatocyte growth factor/scatter factor, 1K1, which acts as a potent angiogenic agent in vitro and in a zebrafish embryo and a murine matrigel implant model. Furthermore, we demonstrate that nanoformulating 1K1 for sustained release temporally alters downstream signaling through the mitogen activated protein kinase pathway, and amplifies the angiogenic outcome. Merging protein engineering and nanotechnology offers exciting possibilities for the treatment of ischemic disease, and furthermore allows the selective targeting of downstream signaling pathways, which translates into discrete phenotypes.</p>10acardiovascular disease10aHGF/SF10aischemic disease10ananoparticle10aprotein engineering1 aRoy, Rituparna, Sinha1 aSoni, Shivani1 aHarfouche, Rania1 aVasudevan, Pooja, R.1 aHolmes, Oliver1 ade Jonge, Hugo1 aRowe, Arthur1 aParaskar, Abhimanyu1 aHentschel, Dirk, M.1 aChirgadze, Dimitri1 aBlundell, Tom, L.1 aGherardi, Ermanno1 aMashelkar, Raghunath, Anant1 aSengupta, Shiladitya  uhttps://library.ncl.res.in/content/coupling-growth-factor-engineering-nanotechnology-therapeutic-angiogenesis-002646nas 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-003013nas a2200409   4500008004100000022001400041245012700055210006900182260008000251300001600331490000800347520160500355653001701960653001701977100002201994700001802016700001802034700002102052700001702073700002002090700002202110700002802132700002002160700002002180700002802200700002202228700002102250700002002271700002902291700002602320700001902346700002702365700002602392700003202418700002502450856012802475       2012                        eng d  a0027-842400aCholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity0 aCholesteroltethered platinum IIbased supramolecular nanoparticle  a2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USAbNATL ACAD SCIENCEScJUL  a11294-112990 v1093 a<p>Nanoscale 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 -&gt; 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-Ras(LSL/+/)Pten(fl/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 nextgeneration platinum-based agent in the clinics.</p>10achemotherapy10ananomedicine1 aSengupta, Poulomi1 aBasu, Sudipta1 aSoni, Shivani1 aPandey, Ambarish1 aRoy, Bhaskar1 aOh, Michael, S.1 aChin, Kenneth, T.1 aParaskar, Abhimanyu, S.1 aSarangi, Sasmit1 aConnor, Yamicia1 aSabbisetti, Venkata, S.1 aKopparam, Jawahar1 aKulkarni, Ashish1 aMuto, Katherine1 aAmarasiriwardena, Chitra1 aJayawardene, Innocent1 aLupoli, Nicola1 aDinulescu, Daniela, M.1 aBonventre, Joseph, V.1 aMashelkar, Raghunath, Anant1 aSengupta, Shiladitya  uhttps://library.ncl.res.in/content/cholesterol-tethered-platinum-ii-based-supramolecular-nanoparticle-increases-antitumor-0