03013nas 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-003180nas a2200301   4500008004100000022001400041245013900055210006900194260009800263300001400361490000700375520203500382100002502417700001702442700002202459700002302481700001902504700002902523700002202552700001902574700003102593700001802624700003202642700002102674700002702695700002502722856013102747       2013                        eng d  a0008-547200aSupramolecular nanoparticles that target phosphoinositide-3-kinase overcome insulin resistance and exert pronounced antitumor efficacy0 aSupramolecular nanoparticles that target phosphoinositide3kinase  a615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USAbAMER ASSOC CANCER RESEARCHcDEC  a6987-69970 v733 a<p>The centrality of phosphoinositide-3-kinase (PI3K) in cancer etiology is well established, but clinical translation of PI3K inhibitors has been limited by feedback signaling, suboptimal intratumoral concentration, and an insulin resistance ``class effect.'' This study was designed to explore the use of supramolecular nanochemistry for targeting PI3K to enhance antitumor efficacy and potentially overcome these limitations. PI3K inhibitor structures were rationally modified using a cholesterol-based derivative, facilitating supramolecular nanoassembly with L-alpha-phosphatidylcholine and DSPE-PEG [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polythylen e glycol)]. The supramolecular nanoparticles (SNP) that were assembled were physicochemically characterized and functionally evaluated in vitro. Antitumor efficacy was quantified in vivo using 4T1 breast cancer and K-Ras(LSL/+)/Pten(fl/fl) ovarian cancer models, with effects on glucose homeostasis evaluated using an insulin sensitivity test. The use of PI103 and PI828 as surrogate molecules to engineer the SNPs highlighted the need to keep design principles in perspective; specifically, potency of the active molecule and the linker chemistry were critical principles for efficacy, similar to antibody-drug conjugates. We found that the SNPs exerted a temporally sustained inhibition of phosphorylation of Akt, mTOR, S6K, and 4EBP in vivo. These effects were associated with increased antitumor efficacy and survival as compared with PI103 and PI828. Efficacy was further increased by decorating the nanoparticle surface with tumor-homing peptides. Notably, the use of SNPs abrogated the insulin resistance that has been associated widely with other PI3K inhibitors. This study provides a preclinical foundation for the use of supramolecular nanochemistry to overcome current challenges associated with PI3K inhibitors, offering a paradigm for extension to other molecularly targeted therapeutics being explored for cancer treatment. (C)2013 AACR.</p>1 aKulkarni, Ashish, A.1 aRoy, Bhaskar1 aRao, Poornima, S.1 aWyant, Gregory, A.1 aMahmoud, Ayaat1 aRamachandran, Madhumitha1 aSengupta, Poulomi1 aGoldman, Aaron1 aKotamraju, Venkata, Ramana1 aBasu, Sudipta1 aMashelkar, Raghunath, Anant1 aRuoslahti, Erkki1 aDinulescu, Daniela, M.1 aSengupta, Shiladitya  uhttps://library.ncl.res.in/content/supramolecular-nanoparticles-target-phosphoinositide-3-kinase-overcome-insulin-resistance-0