Browsing by Author "Uttam Gupta"

Now showing 1 - 11 of 11

ATP-Decorated Mesoporous Silica for Biomineralization of Calcium Carbonate and P2 Purinergic Receptor-Mediated Antitumor Activity against Aggressive Lymphoma
(American Chemical Society, 2018) Prateek Srivastava; Sumit Kumar Hira; Divesh Narayan Srivastava; Vivek Kumar Singh; Uttam Gupta; Ranjeet Singh; Ram Adhar Singh; Partha Pratim Manna
Adenosine triphosphate (ATP) is an important transmitter that mediates various biological effects via purinergic receptors (P2 receptors) in cancer. We investigated the antitumor activity of ATP-decorated and doxorubicin (DOX)-loaded mesoporous silica with biomineralization of calcium carbonate against a highly aggressive and metastatic murine lymphoma called Dalton's lymphoma (DL). Our results suggest that this nanocomposite has unique effects with respect to the morphology and properties of calcium carbonate on the surface of the nanoparticle. DOX in the nanoparticles was prevented from quick release via the interactions of the phosphate group present on ATP and calcium carbonate. This construct is significantly tumoricidal against parental and DOX-resistant DL cells and is thus a promising candidate for applications in drug delivery. The composite nanomaterial has excellent biocompatibility with higher uptake and acts via the participation of the purinergic receptor P2X7. The nanocomposite induces significantly higher apoptosis in tumor cells compared with DOX alone. Treatment of DL-bearing mice with the construct significantly reduces tumor burden, in addition to augmenting the lifespan of tumor-bearing mice as demonstrated by a sustained healthy life of the animals and improved histopathological parameters. © 2018 American Chemical Society.
Essential role of TNF-α in gamma c cytokine aided crosstalk between dendritic cells and natural killer cells in experimental murine lymphoma
(Elsevier B.V., 2020) Uttam Gupta; Sumit Kumar Hira; Ranjeet Singh; Ankush Paladhi; Prateek Srivastava; Partha Pratim Manna
Cooperative and cognitive interaction between the dendritic cells and natural killer cells was investigated for demonstrating the anti-tumor activity against an aggressive murine lymphoma, treated with doxorubicin. Crosstalk between the dendritic cells and the natural killer cells significantly reduced the proliferation of Dalton's lymphoma cells in a dose dependent manner. Treatment of Dalton's lymphoma cells with doxorubicin in vitro enhances the effects of crosstalk against the target cells. This crosstalk between the cells was regulated via stimulation with recombinant interleukin-15, and release of TNF-α which is critically important for the tumoricidal effects. Dendritic cells and the natural killer cells crosstalk activate both the cells and upregulate the expression of CD40, CD69 and CD86 on the dendritic cells. These findings provided new insight regarding these interactions and define a mechanism by which cellular immune response promotes tumoricidal activity against lymphoma in therapeutic setting. © 2019 Elsevier B.V.
In silico studies and evaluation of antiparasitic role of a novel pyruvate phosphate dikinase inhibitor in Leishmania donovani infected macrophages
(Elsevier B.V., 2019) Mohammad Kashif; Sumit Kumar Hira; Anurag Upadhyaya; Uttam Gupta; Ranjeet Singh; Ankush Paladhi; Faez Iqbal Khan; Abdur Rub; Partha Pratim Manna
The present work deals with the identification and characterization of a novel inhibitor Z220582104, specific to pyruvate phosphate dikinase, for leishmanicidal activities against free promastigotes and intracellular amastigotes. We have used structure-based drug designing approaches and performed homology modelling, virtual screening and molecular dynamics studies. Primary mouse macrophages and macrophage cell line J774A1 were infected with promastigotes of Leishmania donovani. Both promastigotes and infected macrophages were subjected to treatment with the varying concentrations of Z220582104 or miltefosine for assessment of leishmanicidal activity. The novel inhibitor Z220582104 demonstrated growth inhibitory potential and reduced the viability of the free promastigotes in a concentration- and time-dependent manner. Z220582104 was also effective against the intracellular form of the parasites and reduced the number of amastigotes in macrophages and also lowered the parasite index, compared with the untreated infected macrophages. Although less effective compared with the miltefosine, Z220582104 is well tolerated by the dividing cells and normal human lymphocytes and monocytes with no adverse effects on the growth kinetics or viability. Our in silico and in vitro studies suggested that Leishmania donovani pyruvate phosphate dikinase could be a potential new drug target. © 2018 Elsevier B.V. and International Society of Chemotherapy
In Vitro Anticancer Drug Delivery Using Amphiphilic Poly(N-vinylpyrrolidone)-b-Polyketal-b-Poly(N-vinylpyrrolidone) Block Copolymer as Micellar Nanocarrier
(Wiley-Blackwell, 2018) Kheyanath Mitra; Sumit Kumar Hira; Shikha Singh; Niraj Kumar Vishwakarma; Sambhav Vishwakarma; Uttam Gupta; Partha Pratim Manna; Biswajit Ray
We have first synthesized acid-degradable alkyne-terminated aliphatic polyketal and thereof synthesized novel pH-responsive double hydrophilic amphiphilic block copolymer of poly(N-vinyl pyrrolidone) (PNVP) and aliphatic polyketal (PK) (PNVP-b-PK-b-PNVP via click chemistry upon reaction with azide-terminated PNVP. Formation of block copolymer is confirmed by proton nuclear magnetic resonance, gel permeation chromatography, thermogravimetry, differential scanning calorimetry, and fluorescence spectroscopy techniques. pH-dependent degradation study of the block copolymer shows faster degradation at lower pH. Transmission electron microscopy (TEM) has revealed the formation of tiny (∼3.8 nm) micellar nanoparticles. Loading of the anticancer drugs doxorubicin (Dox) and imatinib in the micelle is confirmed from UV-Visible, and TEM studies. Drug release study from drug-loaded micelles has shown that imatinib is being released faster than Dox and both systems have shown higher load release at acidic pH of 6.4. Doxorubicin- and imatinib- loaded micelles demonstrate significant tumoricidal properties against parental and drug resistant human erythroleukemia K-562 and Dalton's lymphoma cells with respect to enhanced cellular uptake, cytotoxicity and growth inhibition. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Methotrexate-loaded four-arm star amphiphilic block copolymer elicits CD8+ T cell response against a highly aggressive and metastatic experimental lymphoma
(American Chemical Society, 2015) Sumit Kumar Hira; Kalyan Ramesh; Uttam Gupta; Kheyanath Mitra; Nira Misra; Biswajit Ray; Partha Pratim Manna
We have synthesized a well-defined four-arm star amphiphilic block copolymer [poly(DLLA)-b-poly(NVP)]4 [star-(PDLLA-b-PNVP)4] that consists of d,l-lactide (DLLA) and N-vinylpyrrolidone (NVP) via the combination of ring-opening polymerization (ROP) and xanthate-mediated reversible addition-fragmentation chain transfer (RAFT) polymerization. Synthesis of the polymer was verified by 1H NMR spectroscopy and gel permeation chromatography (GPC). The amphiphilic four-arm star block copolymer forms spherical micelles in water as demonstrated by transmission electron microscopy (TEM) and 1H NMR spectroscopy. Pyrene acts as a probe to ascertain the critical micellar concentration (cmc) by using fluorescence spectroscopy. Methotrexate (MTX)-loaded polymeric micelles of star-(PDLLA15-b-PNVP10)4 amphiphilic block copolymer were prepared and characterized by fluorescence and TEM studies. Star-(PDLLA15-b-PNVP10)4 copolymer was found to be significantly effective with respect to inhibition of proliferation and lysis of human and murine lymphoma cells. The amphiphilic block copolymer causes cell death in parental and MTX-resistant Dalton lymphoma (DL) and Raji cells. The formulation does not cause hemolysis in red blood cells and is tolerant to lymphocytes compared to free MTX. Therapy with MTX-loaded star-(PDLLA15-b-PNVP10)4 amphiphilic block copolymer micelles prolongs the life span of animals with neoplasia by reducing the tumor load, preventing metastasis and augmenting CD8+ T cell-mediated adaptive immune responses. © 2015 American Chemical Society.
Optimization of the bio-mechanical properties of Ti-8Si-2Mn alloy by 1393B3 bioactive glass reinforcement
(Institute of Physics Publishing, 2019) Vipul Saxena; Vijay Kumar; Amrendra Rai; Rishikesh Yadav; Uttam Gupta; Vinay Kumar Singh; Partha Pratim Manna
The low cost Ti-8Si-2Mn alloy matrix has been synthesized by powder metallurgical route. The alloy is reinforced with 1393 B3 bioactive glass to optimize the mechanical and biological properties. The reinforced weight percentage of glass is 0% (S1), 5% (S2), 10% (S3) and 20% (S4). The physical, mechanical, biological and corrosion properties of these composites were investigated. The cell culture suggests that composite S1 and S3 support the growth of the tumor cells when used at lower concentration. The hardness of samples decreases with the increasing percentage of reinforced glass; however, the respective hardness is still superior to the cortical bone. The composite S3 shows better compressive strength (339 MPa), low Young's modulus (76 GPa), optimum density (2.71 gm cm-3) and hardness (381 Hv) as compared to pre-existing Ti implants. So it can be proposed as a new novel load bearing bio implant which will potentially reduce the stress shielding effect, toxicity and will improve the Osseo conductivity. © 2019 IOP Publishing Ltd.
Pepsin Assisted Doxorubicin Delivery from Mesoporous Silica Nanoparticles Downsizes Solid Tumor Volume and Enhances Therapeutic Efficacy in Experimental Murine Lymphoma
(American Chemical Society, 2018) Prateek Srivastava; Sumit Kumar Hira; Uttam Gupta; Vivek Kumar Singh; Ranjeet Singh; Pankaj Pandey; Divesh Narayan Srivastava; Ram Adhar Singh; Partha Pratim Manna
Pepsin, a digestive enzyme, plays an important role in the metabolism of protein products in the stomach. The pH is regarded as the most pivotal criteria in appraising the pepsin's enzymatic activity. Pepsin is idle at the physiological pH (7.4) but dynamic in the acidic environments of the stomach (pH 2.0-4.0). Inspired by such pH regulatory actions, we have used pepsin as an enhancer, which is attached to silica nanoparticles for the doxorubicin release in the acidic tumor environment. Pepsin enzyme is transitional between the doxorubicin loaded silica nanoparticles and the biotin-avidin cap system, which intercedes the pores. The formed nanoplatform is poised at the physiological pH. However, when switched to low pH simulated conditions, the pepsin become vibrant and cleaves the avidin, rendering the clearance of the path for the diffusion of the drug. This design strategy augmented the drug bioavailability deep inside the solid tumor with enhanced uptake and apoptosis of the tumor cells in experimental lymphoma. Copyright © 2018 American Chemical Society.
Protease-Responsive Targeted Delivery of Doxorubicin from Bilirubin-BSA-Capped Mesoporous Silica Nanoparticles against Colon Cancer
(American Chemical Society, 2017) Prateek Srivastava; Sumit Kumar Hira; Divesh Narayan Srivastava; Uttam Gupta; Pradip Sen; Ram Adhar Singh; Partha Pratim Manna
Bilirubin is regarded as a toxic waste, produced from heme degradation and also acts as a potentially important antioxidant. Bilirubin causes arrest in cell cycle and lead to lesser occurrence of malignancies in individuals, having normal or slender increase in levels of serum bilirubin. Prompted by the dynamic interaction between bilirubin and bovine serum albumin (BSA), bilirubin-BSA complex was explored as a biocompatible cap system for protease responsive delivery device of anticancer drug against colon cancer. Bilirubin, conjugated to the amine terminated and doxorubicin loaded mesoporous silica nanoparticles were employed as a novel formulation against colon carcinoma cells. Compared to doxorubicin only, bilirubin in combination with doxorubicin-loaded mesoporous silica nanoparticle significantly inhibits tumor cell growth as assessed in MC-38 (murine) and HCT-116 (human) colon cancer cells. Bilirubin-doxorubicin combination potently inhibits proliferation of tumor cells and acted as cytotoxic and pro-apoptotic agent in vitro. Our result demonstrates that this novel cap system could play a precise role in defense against colon cancer by interrupting the pro-cancerogenic survival pathways during carcinogenesis. © 2017 American Chemical Society.
Structural characterization and in vitro bioactivity assessment of SiO2–CaO–P2O5–K2O–Al2O3 glass as bioactive ceramic material
(Elsevier Ltd, 2015) Himanshu Tripathi; Sumit Kumar Hira; Arepalli Sampath Kumar; Uttam Gupta; Partha Pratim Manna; S.P. Singh
The potassium based bioactive glasses have shown a better biocompatibility than soda containing bioactive glasses. Therefore, we have prepared a bioactive glass system containing potassium oxide and substituted with Al2O3 for further enhancement of bioactivity, physico-chemical properties, mechanical strength as well as its behavior to human osteosarcoma cells. The prepared bioactive glasses have a general formula, 42SiO2–34CaO-6 P2O5–(18−x) K2O, where x=0, 0.5, 1, 1.5 and 2.5 mol% of Al2O3. The in-vitro bioactivity of these samples was assessed by immersion in SBF solution for different time periods under physiological conditions. The formation of hydroxy carbonate apatite (HCA) layer on the surface of the glass samples after SBF treatment was confirmed by FTIR, XRD and SEM. The partial substitution of Al2O3 for K2O in glass demonstrated a significant increase in mechanical properties such as compressive strength and elastic modulus, respectively. The cytotoxicity, cell viability, proliferation, apoptosis and cell attachment were assessed using human osteosarcoma U2-OS cell lines. The cell culture studies demonstrated that the samples containing high concentration of Al2O3 showed a cytotoxic nature against cell lines. But the blood compatibility showed that all the samples were tolerant. Finally, this study clearly concludes that the optimization of Al2O3 in present potash based bioactive glasses would be potential biomaterials for biomedical applications. © 2015 Elsevier Ltd and Techna Group S.r.l.
Studies on interaction potency model based on drug synergy and therapeutic potential of triple stimuli-responsive delivery of doxorubicin and 5-fluoro-2-deoxyuridine against lymphoma using disulfide-bridged cysteine over mesoporous silica nanoparticles
(Royal Society of Chemistry, 2020) Prateek Srivastava; Sumit Kumar Hira; Ankush Paladhi; Ranjeet Singh; Uttam Gupta; Divesh Narayan Srivastava; Ram Adhar Singh; Partha Pratim Manna
A triple stimuli-responsive drug delivery platform involving doxorubicin, 5-fluoro-2-deoxy uridine and folic acid was fabricated on mesoporous silica nanoparticles for targeting delivery against a highly aggressive murine lymphoma called Dalton's lymphoma. Fabrication of the unique construct by amalgamating active and passive targeting mechanisms offers a novel hyper-chimeric platform for a stimuli-responsive drug delivery system. The novel construct enables efficient and precise delivery of the precious cargo to the tumor sites. Active targeting by folic acid directs the doxorubicin and 5-fluoro-2-deoxy uridine in the close proximities of the tumor cells, causing efficient killing and significant growth inhibition. Isobologram models, zero interaction potency dose-response surface plots and matrices were generated to evaluate the combination synergism of the two drugs. Therapy with the dual drug-bearing construct in mice with established tumors significantly reduced the tumor load and enhanced the survival of the animals compared with the untreated control. Therapy with the dual delivery system also augmented the innate and adaptive immune defense mechanisms of the treated animals. CD8+ T cells, natural killer cells and the dendritic cells from the treated group following successful therapy with the novel construct showed enhanced cytotoxicity and growth inhibitory capacities against DL tumor cells. This journal is © The Royal Society of Chemistry.
γc cytokine-aided crosstalk between dendritic cells and natural killer cells together with doxorubicin induces a healer response in experimental lymphoma by downregulating FOXP3 and programmed cell death protein 1
(Elsevier B.V., 2022) Ranjeet Singh; Uttam Gupta; Prateek Srivastava; Ankush Paladhi; Ugir Hossain Sk; Sumit Kumar Hira; Partha Pratim Manna
Background aims: The stimulatory natural killer–dendritic cell axis in the tumor microenvironment could play a critical role in stimulating cytotoxic T cells and driving immune responses against cancer. Methods: We established a novel treatment protocol by adroitly combining chemotherapy with doxorubicin and immunotherapy with dendritic cells and natural killer cells against a highly aggressive and malignant lymphoma called Dalton's lymphoma. Results: Our data suggest that binary application of adoptive cell therapy and chemotherapy nearly cures (95%) early-stage experimental lymphoma. In the case of mid-stage cancer, the success rate was significantly lower but still impressive (75%). Our results demonstrated that the application of combination therapy in early-stage cancer significantly reduced the tumor volume and extended the lifespan of the experimental animal in addition to reinvigorating the immune system, including restoring the effector functions of dendritic cells and natural killer cells. The novel protocol limits the metastasis of tumor cells in vascularized organs and rearms the adaptive immune response mediated by dendritic cells and CD4+ and CD8+ T cells. Conclusions: Combination therapy in the early stage alters the cytokine profile, increases interferon-γ and tumor necrosis factor-α in the serum of treated animals and downregulates programmed cell death protein 1 expression in CD8+ T cells. Thus, cooperative and cognitive interactions between dendritic cells and natural killer cells in addition to therapy with doxorubicin promote the immune response and tumoricidal activities against lymphoma. © 2022 International Society for Cell & Gene Therapy