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Gupta N.,Invictus Oncology | Gupta N.,India Innovation Research Center | Gupta N.,Symbiosis International University | Kancharla J.,Invictus Oncology | And 23 more authors.
Chemical Science | Year: 2017

Despite the advances in the design of antibody-drug conjugates (ADCs), the search is still ongoing for novel approaches that lead to increased stability and homogeneity of the ADCs. We report, for the first time, an ADC platform technology using a platinum(ii)-based linker that can re-bridge the inter-chain cysteines in the antibody, post-reduction. The strong platinum-sulfur interaction improves the stability of the ADC when compared with a standard maleimide-linked ADC thereby reducing the linker-drug exchange with albumin significantly. Moreover, due to the precise conserved locations of cysteines, both homogeneity and site-specificity are simultaneously achieved. Additionally, we demonstrate that our ADCs exhibit increased anticancer efficacy in vitro and in vivo. The Pt-based ADCs can emerge as a simple and exciting proposition to address the limitations of the current ADC linker technologies. © The Royal Society of Chemistry.

Biswas G.,India Innovation Research Center | Kim W.,Pohang University of Science and Technology | Kim K.-T.,Pohang University of Science and Technology | Cho J.,Soonchunhyang University | And 3 more authors.
Journal of Chemistry | Year: 2017

Based on the strong evidences between inflammation and neurodegeneration, nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, are considered as effective agents to reduce the risk of Alzheimer's and Parkinson's disease. However, the clinical use of NSAIDs in these diseases is limited by low brain distribution. In this study, we had synthesized ibuprofen conjugate which has good brain penetration. S-(+)-Ibuprofen was covalently attached to a molecular transporter having FITC and eight terminal guanidine groups. This conjugate showed good cellular uptake property in live cells. It was also injected into a mouse and the distribution of the compound was examined in each organ. The conjugate was well delivered to mouse brain indicating the conjugate is able to cross the blood-brain barrier. Our novel synthetic ibuprofen conjugate will hopefully deliver other NSAIDs into brain and is therefore applicable to the neurodegenerative diseases treatment or prevention. Copyright © 2017 Goutam Biswas et al.

Majumder B.,Mitra Biotech | Baraneedharan U.,Mitra Biotech | Thiyagarajan S.,Mitra Biotech | Radhakrishnan P.,Mitra Biotech | And 26 more authors.
Nature Communications | Year: 2015

Predicting clinical response to anticancer drugs remains a major challenge in cancer treatment. Emerging reports indicate that the tumour microenvironment and heterogeneity can limit the predictive power of current biomarker-guided strategies for chemotherapy. Here we report the engineering of personalized tumour ecosystems that contextually conserve the tumour heterogeneity, and phenocopy the tumour microenvironment using tumour explants maintained in defined tumour grade-matched matrix support and autologous patient serum. The functional response of tumour ecosystems, engineered from 109 patients, to anticancer drugs, together with the corresponding clinical outcomes, is used to train a machine learning algorithm; the learned model is then applied to predict the clinical response in an independent validation group of 55 patients, where we achieve 100% sensitivity in predictions while keeping specificity in a desired high range. The tumour ecosystem and algorithm, together termed the CANScript technology, can emerge as a powerful platform for enabling personalized medicine. © 2015 Macmillan Publishers Limited. All rights reserved.

Goldman A.,Harvard University | Goldman A.,Harvard-MIT Division of Health Sciences and Technology | Goldman A.,Brigham and Women's Hospital | Majumder B.,India Innovation Research Center | And 11 more authors.
Nature Communications | Year: 2015

Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44 Hi CD24 Hi chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer. © 2014 Macmillan Publishers Limited. All rights reserved.

Mitra A.,North Bengal University | Pariyar A.,Indian Institute of Science | Bose S.,North Bengal University | Bandyopadhyay P.,North Bengal University | Sarkar A.,India Innovation Research Center
Sensors and Actuators, B: Chemical | Year: 2015

A novel phenalenone based molecular receptor, 1,1,1-tris(1-oxophenalenyl-9-N-ethyl)amine (3) bearing PLY moiety as the fluorophore has been synthesized and characterized. A thorough study on the binding behaviour of the compound with I- and other biologically relevant anions (viz. F-, Cl-, Br-, CH3COO-, N3-, HPO42-, H2PO4-, NO3-, SO42-) in solution was performed by quantitative UV-vis and fluorescence spectroscopy. The novel compound evolved as a highly selective sensor for I- ion, discriminating all other biologically important anions in solution. © 2015 Elsevier B.V. All rights reserved.

Connor Y.,Harvard-MIT Division of Health Sciences and Technology | Connor Y.,Massachusetts Institute of Technology | Connor Y.,Brigham and Women's Hospital | Connor Y.,Harvard University | And 28 more authors.
Nature Communications | Year: 2015

Metastasis is a major cause of mortality and remains a hurdle in the search for a cure for cancer. Not much is known about metastatic cancer cells and endothelial cross-talk, which occurs at multiple stages during metastasis. Here we report a dynamic regulation of the endothelium by cancer cells through the formation of nanoscale intercellular membrane bridges, which act as physical conduits for transfer of microRNAs. The communication between the tumour cell and the endothelium upregulates markers associated with pathological endothelium, which is reversed by pharmacological inhibition of these nanoscale conduits. These results lead us to define the notion of 'metastatic hijack': cancer cell-induced transformation of healthy endothelium into pathological endothelium via horizontal communication through the nanoscale conduits. Pharmacological perturbation of these nanoscale membrane bridges decreases metastatic foci in vivo. Targeting these nanoscale membrane bridges may potentially emerge as a new therapeutic opportunity in the management of metastatic cancer. © 2015 Macmillan Publishers Limited. All rights reserved.

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