BITS Faculty Publications

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    Studies on cytotoxic activity of Camel milk whey protein as a nutraceutical against HeLa cells
    (Camel Publishing House, 2023) Dubey, Uma S.
    Camel milk is an adapted dietary supplement with multiple antimicrobial and immuno-stimulatory properties. Diabetes, infant diarrhoea, hepatitis, allergy, lactose intolerance, and alcohol- induced liver damage have been treated with it (Galil et al, 2016). Numerous immunologically essential molecules, such as lysozymes, lactoferrin, lactoperoxidase, serum albumin, acidic whey protein, peptidoglycan recognition protein, and small peptides, contribute to its health benefits (Dubey et al, 2016). Recently, the anti-microbial and antioxidant properties of camel milk and its role as an anti-cancer and anti-hepatitis agent has been demonstrated (Khan et al, 2021). Camel milk also has the normal isotypes of antibodies shared with other mammalian species. Actually not only camel’s milk but even its urine is among such natural products enriched with molecules that are safe to humans and endowed with profound anti-cancer properties (Alebie et al, 2017). Aryl hydrocarbon receptor (AhR) is an endogenous transcription factor with known preventative and therapeutic benefits for patients with cancer associated with organs like the liver, breast, prostate, etc. (Xie et al, 2012; Richmond et al, 2014). Aberrant AhR expression is involved in carcinogenesis (Korzeniewski et al, 2010).
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    Formulating ternary inclusion complex of sorafenib tosylate using β-cyclodextrin and hydrophilic polymers: physicochemical characterization and in vitro assessment
    (Springer, 2022-09) Marathe, Sandhya Amol; Singhvi, Gautam
    Sorafenib tosylate (SFNT) is the first-line drug for hepatocellular carcinoma. It exhibits poor solubility leading to low oral bioavailability subsequently requiring intake of large quantities of drug to exhibit desired efficacy. The present investigation was aimed at enhancing the solubility and dissolution rate of SFNT using complexation method. The binary inclusion complex was prepared with β-cyclodextrin (β-CD). The molecular docking studies confirmed the hosting of SFNT into hydrophobic cavity of β-CD, while the phase solubility studies revealed the stoichiometry of complexation with a stability constant of 735.8 M−1. The ternary complex was prepared by combining the SFNT-β-CD complex with PEG-6000 and HPMC polymers. The results from ATR-IR studies revealed no interaction between drug and excipients. The decreased intensities in ATR-IR peaks and changes in chemical shifts from NMR of SFNT in complexes indicate the possibility of SFNT hosting into the hydrophobic cavity of β-CD. The disappearance of SFNT peak in DSC and XRD studies revealed the amorphization upon complexation. The ternary complexes exhibited improved in vitro solubility (17.54 µg/mL) compared to pure SFNT (0.19 µg/mL) and binary inclusion complex (1.52 µg/mL). The dissolution profile of ternary inclusion complex in 0.1 N HCl was significantly higher compared to binary inclusion complex and pure drug. In cytotoxicity studies, the ternary inclusion complex has shown remarkable effect than the binary inclusion complex and pure drug on HepG2 cell lines.
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    Synthesis of carbohydrazides and carboxamides as anti-tubercular agents
    (Elsevier, 2018-08) Kumar, Gautam
    A novel series of furan/thiophene carbohydrazides and carboxamides were synthesized and evaluated for anti-TB and cytotoxic activities. All the synthesized compounds were characterized using 1H and 13C NMR and mass spectral techniques. Among the 23 compounds tested for anti-tubercular activity, seven compounds (3e, 3g, 3h, 9b, 9c, 9e and 9h) showed minimum inhibitory concentration value less than 1 μg/mL against Mycobacterium tuberculosis H37Rv and they were found to be non-toxic. Molecular docking and dynamics simulation studies of these compounds with an enzyme enoyl ACP reductase revealed the probable mechanism of action, which is similar to isoniazid. Further, all these tested compounds exhibited good absorption, distribution, metabolism and excretion and drug-likeness in-silico and thus may be considered as potential leads for further drug development.
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    Exosomal fragment enclosed polyamine-salt nano-complex for co-delivery of docetaxel and mir-34a exhibits higher cytotoxicity and apoptosis in breast cancer cells
    (Springer Nature, 2024-09) Chitkara, Deepak
    A novel core–shell nanocarrier system has been designed for co-delivery of a small anticancer drug, docetaxel (DTX) and tumor suppressor (TS) miR-34a named as Exo(PAN34a+DTX). The core is formed by pH dependent polyamine salt aggregates (PSA) containing both the payloads and the shell is formed by RAW 264.7 cell derived exosomal fragments. Herein, phosphate driven polyallylamine hydrochloride (PAH, MW:17,500 Da) PSA was formed in presence of miR-34a and DTX to form PAN34a+DTX. The formulation exhibited pH dependent DTX release with only 33.55 ± 2.12% DTX release at pH 7.2 and 75.21 ± 1.8% DTX release till 144 h at pH 5.5. At 1.21 molar ratio of phosphate to the amine (known as R value), efficient complexation of miR-34a (3.6 μM) in the PAN particles was obtained. PAN34a+DTX demonstrated particle size (163.86 ± 12.89 nm) and zeta-potential value of 17.53 ± 5.10 mV which upon exosomal fragment layering changed to − 7.23 ± 2.75 mV which is similar to the zeta-potential of the exosomal fragments, i.e., − 8.40 ± 1.79 mV. The final formulation Exo(PAN34a+DTX), loaded with 40 ng/mL DTX and 50 nM miR-34a exhibited 48.20 ± 4.59% cytotoxicity in triple negative breast cancer (TNBC) cells, 4T1. Co-localization of CM-DiI (red fluorescence) stained exosomal fragments and FAM-siRNA (green fluorescence) in the cytoplasm of 4T1 cells after 6 h of Exo(PANFAM) treatment confirmed the efficiency of the designed system to co-deliver two actives. Exo(PAN34a+DTX) also reduced BCL-2 expression (target gene for miR-34a) by 8.98 folds in comparison to free DTX confirming promising co-delivery and apoptosis inducing effect of Exo(PAN34a+DTX) in 4T1.
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    Indolyl-α-keto-1,3,4-oxadiazoles: Synthesis, anti-cell proliferation activity, and inhibition of tubulin polymerization
    (Elsevier, 2021-04) Kumar, Anil; Kumar, Dalip
    A series of novel indolyl-α-keto-1,3,4-oxadiazole derivatives have been synthesized by employing molecular iodine-mediated oxidative cyclization of acylhydrazones. In vitro anti cell proliferation activity of these derivatives against various cancer cells lines such as human lymphoblast (U937), leukemia (Jurkat & SB) and human breast (BT474) was investigated. Among the synthesized indolyl-α-keto-1,3,4-oxadiazoles 19a-p, only one compound (19e) exhibited significant antiproliferative activity against a panel of cell lines. The compound 19e with 3,4,5-trimethoxyphenyl motif, endowed strong cytotoxicity against U937, Jurkat, BT474 and SB cancer cells with IC50 values of 7.1, 3.1, 4.1, and 0.8 µM, respectively. Molecular docking studies suggested a potential binding mode for 19e in the colchicine binding site of tubulin. When tested for in vitro tubulin polymerizaton, 19e inhibited tubulin polymezations (IC50 = 10.66 µM) and induced apoptosis through caspase 3/7 activation. Further, the derivative 19e did not cause necrosis when measured using lactate dehydrogenase assay.
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    Synthesis and Biological Evaluation of 5′-O-Fatty Acyl Ester Derivatives of 3′-Fluoro-2′,3′-dideoxythymidine as Potential Anti-HIV Microbicides
    (MDPI, 2022-05) Kumar, Anil
    A number of 5′-O-fatty acyl derivatives of 3′-fluoro-2′,3′-dideoxythymidine (FLT, 1) were synthesized. These conjugates were evaluated for their potential as topical microbicides with anti-HIV activity against cell-free (X4 and R5), cell-associated, and multidrug-resistant viruses. Compared to FLT and 3′-azido-2′,3′-dideoxythymidine (AZT), 5′-O-(12-azidododecanoyl) (5), 5′-O-myristoyl (6), and 5′-O-(12-thioethyldodecanoyl) (8) derivatives of FLT were found to be more active against both cell-free viruses (lymphocytotropic and monocytotropic strains) with EC50 values of 0.4 μM, 1.1 μM, and <0.2 μM, respectively, as well as cell-associated virus with EC50 values of 12.6, 6.4, and 2.3 μM, respectively. Conjugates 5, 6, and 8 exhibited >4 and >30 times better antiviral index than FLT and AZT, respectively. Conjugates 5 and 8 were significantly more potent than FLT against many multidrug-resistant strains. A comparison of the anti-HIV activity with the corresponding non-hydrolyzable ether conjugates suggested that ester hydrolysis to FLT and fatty acids is critical to enable anti-HIV activity. Cellular uptake studies were conducted using fluorescent derivatives of FLT attached with 5(6)-carboxyfluorescein through either β-alanine (23) or 12-aminododecanoic acid (24) spacers. The lipophilic fluorescent analog with a long chain (24) showed more than 12 times higher cellular uptake profile than the fluorescent analog with a short chain (23). These studies further confirmed that the attachment of fatty acids improved the cellular uptake of nucleoside conjugates. In addition, 5, 6, and 8 were the least cytotoxic and did not alter vaginal cell and sperm viability compared to the positive control, a commercial topical spermicide (N-9), which significantly decreased sperm and vaginal cell viability inducing the generation of proinflammatory cytokines.
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    New Antimicrobial Hexapeptides: Synthesis, Antimicrobial Activities, Cytotoxicity, and Mechanistic Studies
    (Wiley, 2009-12) Sundriyal, Sandeep
    The lead optimization of an antimicrobial hexapeptide Orn-D-Trp-D-Phe-Ile-D-Phe-His(1-Bzl)-NH2 depending on the hydrophobic or positive-charge character of amino acids at various positions along its sequence was performed, followed by biological evaluation and mechanistic studies. This led to the identification of a new class of antimicrobial hexapeptides that interact preferentially with the negatively charged phospholipids of a model bacterial membrane.
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    Exploring temozolomide encapsulated PEGylated liposomes and lyotropic liquid crystals for effective treatment of glioblastoma: in-vitro, cell line, and pharmacokinetic studies
    (Elsevier, 2023-05) Singhvi, Gautam; Roy, Aniruddha
    Temozolomide (TMZ) is one of the best choices for treating glioblastoma. However, due to the short plasma half-life, only 20–30 % brain bioavailability can be achieved using traditional formulations. In the present study, PEGylated liposomes and lyotropic liquid crystals (LLCs) were developed and investigated to prolong the plasma circulation time of TMZ. Industrially feasible membrane extrusion and modified hot melt emulsification techniques were utilized during the formulation. Liposomes and LLCs in the particle size range of 80–120 nm were obtained with up to 50 % entrapment efficiency. The nanocarriers were found to show a prolonged release of up to 72 h. The cytotoxicity studies in glioblastoma cell lines revealed a ∼1.6-fold increased cytotoxicity compared to free TMZ. PEGylated liposomes and PEGylated LLCs were found to show a 3.47 and 3.18-fold less cell uptake in macrophage cell lines than uncoated liposomes and LLCs, respectively. A 1.25 and 2-fold increase in the plasma t1/2 was observed with PEGylated liposomes and PEGylated LLCs, respectively, compared to the TMZ when administered intravenously. Extending plasma circulation time of TMZ led to significant increase in brain bioavailability. Overall, the observed improved pharmacokinetics and biodistribution of TMZ revealed the potential of these PEGylated nanocarriers in the efficient treatment of glioblastoma.
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    Nanoscale Pluronic® micellar templates with varying %EO content for controlled drug release and cytotoxicity
    (Elsevier, 2023-08) Roy, Aniruddha; Singhvi, Gautam
    This study investigates the self-assembly in ethylene oxide (EO)-propylene oxide (PO)-based block copolymers (BCPs) with various molecular features like molecular weight, EO/PO ratio, HLB (Hydrophobic lipophilic balance) in aqueous solution environment. Our BCP solution systems exhibit significant changes in solution behaviour that showed micellization, micelle growth/ transition, and progressively phase separation (2ϕ), all of which are well explained by clear solution, blue point (BP) and cloud Point (CP) respectively. The solubilization of the highly hydrophobic anticancer drug-Quercetin (QCT) in such BCPs is examined using UV–Visible spectroscopy. The spectral findings inferred the dissolution capability of QCT in the examined copolymeric micellar systems in terms of drug loading efficiency (DL%), encapsulation efficiency (EE%), partition coefficient (P), and standard free energy of solubilization (ΔGo). Amongst the varied tested BCPs, it was observed that Pluronics® P123 and F127 exhibited an enhanced QCT solubilization capability than others and is explained in terms of hydrophobicity and hydrophilicity. The micellar size distribution profile expressed as hydrodynamic diameter (Dh) was determined for QCT-loaded and QCT-unloaded BCP micelles employing dynamic light scattering (DLS). The drug release profile was fitted employing various kinetic models, allowing this study to serve as an excellent foundation for QCT delivery. Reversed-phase High-performance liquid chromatography (HPLC) system determined the retention period in the QCT-loaded micelle while the structural alterations involved in Pluronics®-QCT system is inferred using small-angle neutron scattering (SANS). Fourier transform infrared spectroscopy (FT-IR) depicted the compatibility between Pluronics® and QCT which was validated further from the evaluated optimum descriptors using Gaussian 09 computational simulation framework. It was discovered that the QCT-loaded micelles exhibited a greater anticancer effect than free drug when tested in vivo on cancer cells. The anticancer activity of QCT-loaded F127 micelles was determined to be the strongest. Thus, the current study on QCT solubilization in Pluronics® will benefit considerably from its investigated outcomes.
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    Nanocarriers as Potential Targeted Drug Delivery for Cancer Therapy
    (Springer, 2020-01) Singhvi, Gautam
    Cancer is a disease characterized by the uncontrolled growth of cells and is the leading cause of death worldwide with an incidence of 11 million new cases each year. Nanotechnology-based drug delivery systems have received much attention for cancer treatment. Nanocarriers are the delivery systems which are prepared by alteration of the size (1–1000 nm) and shape of a material to the nano-range level. Nanocarriers are prepared by utilizing natural, polymeric, inorganic magnetic silica-based materials. Various nanocarriers including liposomes, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, magnetic nanoparticles, and other inorganic nanoparticles have been investigated for diagnostic, therapeutic, and drug targeting in cancer therapy. Nanocarriers act as a cancer-specific drug delivery or diagnostic agent by inherent passive targeting mechanism or adopted active targeting strategies by altering the surface properties with specific ligands. Targeted nanoparticulate systems increase the accumulation of the chemotherapeutic agent in the tumor tissue and reduce the toxicity to healthy cells. Nanocarriers extend the drug release for a longer duration and protect the drug from degradation. Nanocarriers are also proven effective for improving the pharmacokinetics of poorly soluble hydrophobic drugs by solubilizing or permeating them through lipophilic biological barriers.