BITS Faculty Publications
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Item Design, synthesis and in vitro evaluation of primaquine and diaminoquinazoline hybrid molecules against the malaria parasite(Wiley, 2025-01) Sundriyal, Sandeep; Roy, AniruddhaIn this study, we built on the known inhibitory potential of diaminoquinazolines (DAQs) against different stages of Plasmodium development and designed a convenient two-step synthesis to combine DAQ with primaquine (PQ) pharmacophore. The PQ-DAQ hybrids displayed potent in vitro activities in the low nanomolar range (IC50 135.20–398.80 nM) against all intra-erythrocytic stages of the drug-sensitive 3D7 strain, with significant potency enhancement compared to PQ alone (IC50 9370 nM). These hybrids were also potent at killing drug-resistant strains (Dd2, Dd2 R539T, IPC4912, CamWT C580Y, and 7G8) in the nanomolar range, with 11 f being the most effective compound (IC50 172.20–396.60 nM). Notably, for the first time, we present evidence that the DAQ-based compound 8 and its hybrids can inhibit β-hematin formation in vitro with potency (IC50 0.90–27.80 μM), suggesting hemozoin formation to be one of the potential targets of this series. Lastly, two hybrids with potent antiplasmodial activity were also found to be safe up to 10 μM against human HepG2 cells, suggesting the possibility of achieving host vs parasite selectivity with this series.Item The power of synergism: a novel drug combination for improved therapy of glioblastoma(Wiley, 2024-05) Roy, AniruddhaOne of the biggest obstacles in treating glioblastoma multiforme (GBM) is the plasticity and adaptability of GBM cells, which renders monotherapy ineffective. Novel drug combinations that target multiple pathways are required to overcome this challenge. In the current study, the PI3K/AKT/mTOR pathway is identified as a crucial component in GBM cell survival using the KEGG database and literature search. Hence, it is hypothesized that a potential synergistic therapy can be achieved by targeting different stages of this pathway by combining disulfiram (DSF) and 7-ethyl-10-hydroxycamptothecin (SN-38). The efficacy of this drug combination is evaluated using 2D and 3D in vitro assays, which exhibited a significant synergism with 5 × 104 times lower IC50 than that of temozolomide (TMZ), the gold-standard drug. The combination treatment increases intracellular ROS (reactive oxygen species) production, and ROS inhibition by using N-Acetyl Cysteine (NAC) reduced the cytotoxicity substantially, indicating that ROS played a crucial role in the synergistic cytotoxicity. The combination treatment inhibited GBM cell proliferation, migration, and stem cell marker expression. Mechanistically, the DSF+SN-38 combination is found to increase p53 expression, inhibit PI3K signaling, and activate caspase 9. Altogether, this study demonstrates that the DSF+SN-38 combination can present a promising therapeutic strategy for treating GBM.Item Synergistic chemo-immunotherapy using ph-responsive nanoparticles in breast cancer treatment: in vitro and in vivo studies(ACS, 2024-10) Roy, AniruddhaRecent research underscores the pivotal role of the heterogeneous multicellular interactome within the tumor microenvironment (TME) in tumor progression and survival. Tumor-associated macrophages (TAMs), among other nonmalignant cells in the TME, promote an immunosuppressive environment, fostering tumor cell survival, proliferation, and resistance. Hence, combining chemotherapy with immunomodulatory agents to transition TAMs to an immunostimulatory phenotype holds immense therapeutic potential. The present study focuses on developing tumor-responsive nanoparticles (NPs) for combined chemo-immunotherapy using resiquimod (RSQ), a TLR 7/8 agonist as an immunomodulator, and paclitaxel (PTX) as chemotherapeutics. A pH-responsive NP known as PHNP, tailored with a star-shaped PLGA conjugated with poly histidine, was engineered to selectively deliver a consistent ratio of PTX and RSQ directly to the tumor site. In vitro studies demonstrate enhanced drug release at pH 6.4, increased penetration in tumor spheroids, and increased cytotoxic efficacy against breast cancer cells. Furthermore, PHNPs activate macrophages for antitumor activity. In vivo studies demonstrated a notable rise in plasma AUC and improved delivery of drugs to the tumor using PHNPs, resulting in enhanced effectiveness against tumor growth in a mouse orthotopic breast cancer model. Notably, PHNP treatment elevated intratumoral ROS and apoptosis levels and inhibited lung metastasis. Overall, this study underscores the potential of the PTX and RSQ combination as a prospective combined chemo-immunotherapeutic modality.Item Targeting tumor microenvironment with photodynamic nanomedicine(Wiley, 2025) Roy, AniruddhaPhotodynamic therapy (PDT) is approved for the treatment of certain cancers and precancer lesions. While early Photosensitizers (PS) have found their way to the clinic, research in the last two decades has led to the development of third-generation PS, including photodynamic nanomedicine for improved tumor delivery and minimal systemic or phototoxicity. In terms of nanoparticle design for PDT, we are witnessing a shift from passive to active delivery for improved outcomes with reduced PS dosage. Tumor microenvironment (TME) comprises of a complex and dynamic landscape with myriad potential targets for photodynamic nanocarriers that are surface-modified with ligands. Herein, we review ways to improvise PDT by actively targeting nanoparticles (NPs) to intracellular organelles such as mitochondria or lysosomes and so forth, overcoming the limitations caused by PDT-induced hypoxia, disrupting the blood vascular networks in tumor tissues—vascular targeted PDT (VTP) and targeting immune cells for photoimmunotherapy. We propose that a synergistic outlook will help to address challenges such as deep-seated tumors, metastasis, or relapse and would lead to robust PDT response in patients.Item Dual-emissive iridium(iii) complex with aggregation-induced emission: mechanistic insights into electron transfer for enhanced hypoxia detection in 3D tumor models(ACS, 2025-01) Roy, Aniruddha; Laskar, Inamur RahamanAccurate oxygen detection and measurement of its concentration is vital in biological and industrial applications, necessitating highly sensitive and reliable sensors. Optical sensors, valued for their real-time monitoring, nondestructive analysis, and exceptional sensitivity, are particularly suited for precise oxygen measurements. Here, we report a dual-emissive iridium(III) complex, IrNPh2, featuring “aggregation-induced emission” (AIE) properties and used for sensitive oxygen sensing. IrNPh2 exhibits dual emissions at 450 and 515 nm, with 515 nm triplet-state emission demonstrating remarkable oxygen sensitivity due to its long-lived excited state (12.12 μs) and high quantum yield (68%). Stern–Volmer analysis reveals a notable quenching constant (Ksv = 12.44%–1) and an ultralow detection limit of 0.0397%, emphasizing its superior performance. The oxygen quenching mechanism is driven by electron transfer (ET), supported by computational studies showing the lowest-unoccupied molecular orbital (LUMO) alignment of IrNPh2 with the πg* orbitals of triplet oxygen, leading to superoxide radical (O2•–) formation. Electron paramagnetic resonance (EPR) studies further confirm this pathway. Biological evaluations using a three-dimensional (3D) U87-MG glioma spheroid model highlight the ability of IrNPh2 to detect hypoxic regions, with significant fluorescence enhancement under hypoxia and minimal cytotoxicity (>80% viability at 100 μM). With high sensitivity, low detection limits, and biocompatibility, IrNPh2 emerges as a promising candidate for oxygen sensing in environmental and biomedical applications, especially tumor hypoxia detection.Item In vitro hemolysis and lipid peroxidation-inducing activity of the tentacle extract of the sea anemone (Paracondylactis indicus Dave) in rat erythrocytes(Wolters Kluwer, 2007-06) Roy, AniruddhaIn vitro hemolytic activity of the tentacle extract of Paracondylactis indicus (Dave), a sea anemone found in the eastern coastal region of West Bengal (India), was determined in rat erythrocytesItem Combined Chemo-immunotherapy as a Prospective Strategy To Combat Cancer: A Nanoparticle Based Approach(ACS, 2010-09) Roy, AniruddhaThe prime objective of this study was to develop a combined chemo-immunotherapeutic formulation which could directly kill cancer cells as well as activate the immunosuppressed tumor microenvironment to mount a robust antitumor immune response. Paclitaxel (PTX) and SP-LPS (nontoxic derivative of lipopolysaccharide) were selected as anticancer drug and immunostimulant respectively. Poly(lactic-co-glycolic acid) (PLGA) based PTX and SP-LPS containing nanoparticles (TLNP) were prepared by the double-emulsion method (w/o/w) and characterized in terms of size, zeta potential and transmission electron microscopy (TEM). The release behavior of PTX and SP-LPS from the TLNP exhibited a biphasic pattern characterized by an initial burst followed by slow continuous release. In vitro anticancer activity of TLNP was found to be higher compared to PTX when studied in a tumor cell−splenocyte coculture system. TLNP activated murine monocytes induced the secretion of various proinflammatory cytokines. After iv administration of TLNP in tumor bearing C57BL/6 mice, the amount of PTX in the tumor mass was found to be higher in TLNP treated mice as compared to commercial Taxol group at all time points studied. In vitro studies suggest that nanoparticles containing PTX and SP-LPS have both direct cytotoxicity and immunostimulatory activity. Hence this might have potential as a chemo-immunotherapeutic formulation against cancer with advantage over present day chemotherapy with Taxol, in terms of tumor targeting, less toxicity and immunostimulation.Item Anticancer and immunostimulatory activity by conjugate of paclitaxel and non-toxic derivative of lps for combined chemo-immunotherapy(Springer, 2012-05) Roy, AniruddhaCancer is a multifactorial syndrome; hence, multidimensional therapy with a chemo-immunotherapeutic conjugate could be more effective in curing the disease.Item Nanoparticle mediated co-delivery of paclitaxel and a TLR-4 agonist results in tumor regression and enhanced immune response in the tumor microenvironment of a mouse model(Elsevier, 2013-03) Roy, AniruddhaInefficiency of cancer chemotherapy to improve life expectancy in majority of patients raises serious concern and warrants development of novel therapeutic strategies. Immunotherapy in combination with chemotherapy has shown promising outcomes in recent years. Herein, we report better tumor regression and enhancement of antitumor immune response at the tumor microenvironment by co-delivery of paclitaxel and a TLR4 agonist through a PLGA based nanoparticle preparation (TLNP). Particle characterization showed high encapsulation of both components and retention of their biological activities. In vivo tumor regression studies demonstrated clear benefit of TLNP over the paclitaxel. The mean tumor volume of the TLNP treated animals was found to be 40% less than that of the Paclitaxel treated animals. Flow cytometric analysis of tumor infiltrating immune cells indicated activation of antigen presenting cells and T-cells providing evidence of Th1 immune response. In vivo results are promising and could pave way for novel chemo-immunotherapeutic treatment modality.Item Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles(Elsevier, 2013-12) Roy, AniruddhaNanoparticle drug delivery to the tumor is impacted by multiple factors: nanoparticles must evade clearance by renal filtration and the reticuloendothelial system, extravasate through the enlarged endothelial gaps in tumors, penetrate through dense stroma in the tumor microenvironment to reach the tumor cells, remain in the tumor tissue for a prolonged period of time, and finally release the active agent to induce pharmacological effect. The physicochemical properties of nanoparticles such as size, shape, surface charge, surface chemistry (PEGylation, ligand conjugation) and composition affect the pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. On the other hand, tumor biology (blood flow, perfusion, permeability, interstitial fluid pressure and stroma content) and patient characteristics (age, gender, tumor type, tumor location, body composition and prior treatments) also have impact on drug delivery by nanoparticles. It is now believed that both nanoparticles and the tumor microenvironment have to be optimized or adjusted for optimal delivery. This review provides a comprehensive summary of how these nanoparticle and biological factors impact nanoparticle delivery to tumors, with discussion on how the tumor microenvironment can be adjusted and how patients can be stratified by imaging methods to receive the maximal benefit of nanomedicine. Perspectives and future directions are also provided.