01870nas 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-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-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-001789nas a2200205   4500008004100000245014600041210006900187260000800256300001400264490000600278520103400284100002401318700001601342700001701358700002201375700001901397700002501416700001801441856012401459       2016                        eng d00aEngineering and in vitro evaluation of acid labile cholesterol tethered MG132 nanoparticle fortargeting ubiquitin-proteasome system in cancer0 aEngineering and in vitro evaluation of acid labile cholesterol t  cOCT  a5099-51060 v13 aIn recent years, proteasome has evolved as one of the important alternative targets in cancer chemotherapy. However, selective targeting of proteasome system in cancer cells still remains a major challenge. To address this, a potent peptide based proteasome inhibitor MG132 was chemically conjugated with biocompatible-biodegradable cholesterol by acid cleavable hydrazone linkage. Spherical nanoparticles (MG132-NPs) were engineered from cholesterol-MG132 conjugate. Increased amount of free MG132 was released from these nanoparticles in acidic environment compared to physiological milieu in a slow and controlled manner. These MG132-NPs were taken up by breast cancer MCF7 cells into lysosomes within 6 h. Proteasome system was inhibited by these MG132-NPs leading to stabilization of beta-catenin, cyclin A and cyclin B in HEK-293T cells. Interestingly, MG132-NPs induced much improved cell death in drug resistant MDA-MB-231 cells with insignificant toxicity in healthy cells (HEK293 and L929) even in higher concentration.1 aGhosh, Chandramouli1 aGupta, Neha1 aMore, Piyush1 aSengupta, Poulomi1 aMallick, Abhik1 aSantra, Manas, Kumar1 aBasu, Sudipta  uhttps://library.ncl.res.in/content/engineering-and-vitro-evaluation-acid-labile-cholesterol-tethered-mg132-nanoparticle01296nas a2200193   4500008004100000245012000041210006900161260000800230300001400238490000700252520059900259100001700858700001900875700001700894700002200911700002100933700001800954856013000972       2017                        eng d00aCisplatin-induced self-assembly of graphene oxide sheets into spherical nanoparticles for damaging sub-cellular DNA0 aCisplatininduced selfassembly of graphene oxide sheets into sphe  cJAN  a1409-14120 v533 aThis report describes the hitherto unobserved cisplatin induced self-assembly of 2D-graphene oxide sheets into 3D-spherical nano-scale particles. These nanoparticles can encompass dual DNA damaging drugs simultaneously. A combination of confocal microscopy, gel electrophoresis and flow cytometry studies clearly demonstrated that these novel nanoparticles can internalize into cancer cells by endocytosis, localize into lysosomes, and damage DNA, leading to apoptosis. Cell viability assays indicated that these nanoparticles were more cytotoxic towards cancer cells compared to healthy cells.1 aNandi, Aditi1 aMallick, Abhik1 aMore, Piyush1 aSengupta, Poulomi1 aBallav, Nirmalya1 aBasu, Sudipta  uhttps://library.ncl.res.in/content/cisplatin-induced-self-assembly-graphene-oxide-sheets-spherical-nanoparticles-damaging-sub02323nas a2200217   4500008004100000022001400041245015600055210006900211260000800280300001400288490000600302520153700308100002001845700001701865700001801882700002001900700001501920700002101935700001801956856013101974       2017                        eng d  a2470-134300aDrug-triggered self-assembly of linear polymer into nanoparticles for simultaneous delivery of hydrophobic and hydrophilic drugs in breast cancer cells0 aDrugtriggered selfassembly of linear polymer into nanoparticles   cDEC  a8730-87400 v23 a<p>Breast cancer is the most devastating disease among females globally. Conventional chemotherapeutic regimen relies on the use of highly cytotoxic drugs as monotherapy and combination therapy leading to severe side effects to the patients as collateral damage. Moreover, combining hydrophobic and hydrophilic drugs create erratic biodistribution and suboptimal medicinal outcome. Hence, packaging multiple drugs of diverse mechanisms of action and biodistribution for safe delivery into tumor tissues with optimal dosages is indispensable for next-generation breast cancer therapy. To address these, in this report, we describe a unique cisplatin-triggered self-assembly of linear polymer into 3D-spherical sub 200 nm particles. These nano-particles comprise a hydrophobic (paclitaxel) and hydrophilic drug (cisplatin) simultaneously in a single particle. Molecular dynamics simulation revealed hydrophilic-hydrophilic interaction and interchain H-bonding as underlying mechanisms of self-assembly. Confocal microscopy studies evidently demonstrated that these novel nanoparticles can home into lysosomes in breast cancer cells, fragment subcellular nuclei, and prevent cell division, leading to improved breast cancer cell death compared to free drug combination. Moreover, 3D-breast tumor spheroids were reduced remarkably by the treatment of these nanoparticles within 24 h. These dual-drug-loaded self-assembled polymeric nanoparticles have prospective to be translated into a clinical strategy for breast cancer patients.</p>1 aPalvai, Sandeep1 aAnandi, Libi1 aSarkar, Sujit1 aAugustus, Meera1 aRoy, Sudip1 aLahiri, Mayurika1 aBasu, Sudipta  uhttps://library.ncl.res.in/content/drug-triggered-self-assembly-linear-polymer-nanoparticles-simultaneous-delivery-hydrophobic02536nas a2200181   4500008004100000022001400041245010800055210006900163260000800232300001400240490000600254520188300260100002002143700002502163700002202188700001802210856012602228       2017                        eng d  a2470-134300aHyaluronic acid layered chimeric nanoparticles: targeting MAPK-P13K signaling hub in colon cancer cells0 aHyaluronic acid layered chimeric nanoparticles targeting MAPKP13  cNOV  a7868-78800 v23 a<p>Colon cancer has emerged as one of the most devastating diseases in the whole world. Mitogen-activated protein kinase (MAPK)-phosphatidylinsitol-3-kinase (PI3K) signaling hub has gained lots of attention due to its deregulation in colon cancer cells. However, selective targeting of oncogenic MAPK-PI3K hub in colon cancer has remained highly challenging, hence it has mostly been unexplored. To address this, we have engineered a hyaluronic acid layered lipid-based chimeric nanoparticle (HA-CNP) consisting of AZD6244 (MAPK inhibitor), PI103 (PI3K inhibitor), and cisplatin (DNA impairing drug) ratiometrically in a single particle. Electron microscopy (field emission scanning electron microscopy and atomic force microscopy) and dynamic light scattering were utilized to characterize the size, shape, morphology, and surface charge of the HA-CNPs. Fluorescent confocal laser scanning microscopy and flow cytometry analysis confirmed that HA-CNPs were taken up by HCT-116 colon cancer cells by merging of clathrin and CD44 receptor-mediated endocytosis along with macropinocytosis to home into acidic organelles (lysosomes) within 1 h. A gel electrophoresis study evidently established that HA-CNPs simultaneously inhibited MAPK-PI3K signaling hub with DNA damage in HCT-116 cells. These HA-CNPs stalled the cell cycle into G0/G1 phase, leading to induction of apoptosis (early and late) in colon cancer cells. Finally, these HA-CNPs exerted remarkable cytotoxicity in HCT-116 colon cancer cells at 24 h compared to that of the free triple drug cocktail as well as HA-coated dual drug-loaded nanoparticles without showing any cell death in healthy L929 fibroblast cells. These HA-coated CNPs have potential to be translated into clinics as a novel platform to perturb various oncogenic signaling hubs concomitantly toward next-generation targeted colon cancer therapy.</p>1 aPalvai, Sandeep1 aKuman, Meenu, Mahesh1 aSengupta, Poulonu1 aBasu, Sudipta  uhttps://library.ncl.res.in/content/hyaluronic-acid-layered-chimeric-nanoparticles-targeting-mapk-p13k-signaling-hub-colon02992nas a2200349   4500008004100000022001400041245010700055210006900162260000900231300001100240490000700251520191400258653000902172653001402181653001602195653001502211653001302226100001502239700001402254700002202268700002402290700002002314700001902334700002202353700001802375700002202393700002302415700002502438700002602463700002202489856013102511       2021                        eng d  a2234-943X00aUnbiased phenotype-based screen identifies therapeutic agents selective for metastatic prostate cancer0 aUnbiased phenotypebased screen identifies therapeutic agents sel  cMAR   a5941410 v103 a<p>In American men, prostate cancer is the second leading cause of cancer-related death. Dissemination of prostate cancer cells to distant organs significantly worsens patients' prognosis, and currently there are no effective treatment options that can cure advanced-stage prostate cancer. In an effort to identify compounds selective for metastatic prostate cancer cells over benign prostate cancer cells or normal prostate epithelial cells, we applied a phenotype-based in vitro drug screening method utilizing multiple prostate cancer cell lines to test 1,120 different compounds from a commercial drug library. Top drug candidates were then examined in multiple mouse xenograft models including subcutaneous tumor growth, experimental lung metastasis, and experimental bone metastasis assays. A subset of compounds including fenbendazole, fluspirilene, clofazimine, niclosamide, and suloctidil showed preferential cytotoxicity and apoptosis towards metastatic prostate cancer cells in vitro and in vivo. The bioavailability of the most discerning agents, especially fenbendazole and albendazole, was improved by formulating as micelles or nanoparticles. The enhanced forms of fenbendazole and albendazole significantly prolonged survival in mice bearing metastases, and albendazole-treated mice displayed significantly longer median survival times than paclitaxel-treated mice. Importantly, these drugs effectively targeted taxane-resistant tumors and bone metastases - two common clinical conditions in patients with aggressive prostate cancer. In summary, we find that metastatic prostate tumor cells differ from benign prostate tumor cells in their sensitivity to certain drug classes. Taken together, our results strongly suggest that albendazole, an anthelmintic medication, may represent a potential adjuvant or neoadjuvant to standard therapy in the treatment of disseminated prostate cancer.</p>
10abone10acarcinoma10adrug-screen10aMetastasis10aProstate1 aChung, Ivy1 aZhou, Kun1 aBarrows, Courtney1 aBanyard, Jacqueline1 aWilson, Arianne1 aRummel, Nathan1 aMizokami, Atsushi1 aBasu, Sudipta1 aSengupta, Poulomi1 aShaikh, Badaruddin1 aSengupta, Shiladitya1 aBielenberg, Diane, R.1 aZetter, Bruce, R.  uhttps://library.ncl.res.in/content/unbiased-phenotype-based-screen-identifies-therapeutic-agents-selective-metastatic-prostate