Department of Pharmacy
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Item A novel PEGylated carbon nanotube conjugated mangiferin: An explorative nanomedicine for brain cancer cells(Elsevier, 2019-10) Mittal, AnupamaIn the present study, polyethylene glycol-linked conjugate of carbon nanotubes with Mangiferin was synthesized and characterized by means of Fourier transform infrared and nuclear magnetic resonance spectroscopic techniques. Studies for the determination of particle size, polydispersity index and zeta potential were performed. Morphological characterization was performed using transmission electron microscopy. Phytochemical conjugated nanotubes were also evaluated for hemo-compatibility, protein binding capacity and in-vitro drug release. Cytotoxicity studies and flow cytometry were performed on U-87 cell lines. Drug release studies confirmed a spatiotemporal pattern of release at the cancer cell pH. Cytotoxicity studies proved that there was 1.28 folds decrease in the IC50 value indicating effective anticancer activity, whereas hemolytic profile established the safety. Flow cytometry confirmed effective induction of apoptosis with minimum necrosis by the nano-conjugate vis-à-vis the naïve drug. The pharmacokinetic study showcased that there was 4 times escalation in the area under the curve, i.e., bioavailability of the drug after the conjugation to that of plain mangiferin. From the obtained results, it can be concluded that these functionalized nanocarriers are capable of the effective and safer delivery of phytochemicals to the brain cancerous cells.Item Belinostat loaded lipid–polymer hybrid nanoparticulate delivery system for breast cancer: improved pharmacokinetics and biodistribution in a tumor model(RSC, 2023-10) Chitkara, Deepak; Mittal, AnupamaDespite various treatment modalities for breast cancer, it still persists as one of the most diagnosed types of cancer in females. The recent investigations in the epigenetics of breast cancer reveal several aberrations in the expression levels of various HDAC enzymes. Henceforth, the present work entails the formulation and characterization of a lipid polymer-based hybrid nanoparticulate (LPN) system for delivery of an epigenetic modulator drug, Belinostat, for its clinical application in breast cancer. The size of Belinostat nanoparticles prepared using a modified hot homogenization method was found to be 166.6 ± 19.95 nm with an encapsulation efficiency of 94.5 ± 5.1%. In vitro characterization for cytotoxicity, cellular uptake, and protein expression in two different breast cancer cells, 4T1 and MCF 7, revealed the superiority of the formulation in comparison with the free drug in MCF 7 cells. Subsequently, the behaviour of the formulation in in vivo settings of healthy and breast cancer xenograft bearing animals was analyzed using pharmacokinetic and biodistribution studies. The results revealed that the formulation demonstrated multi-fold improvement in the pharmacokinetic parameters in tumor bearing animals when compared with the free drug while no difference in pharmacokinetic behaviour was observed in healthy animals indicating the altered biodistribution and specificity of the formulation in breast tumor. This was confirmed by the biodistribution studies exhibiting 20-fold improved uptake and retention of the nanoparticulate formulation in tumor tissues of the animal model at the end of 4 h. Thus, the developed LPN system holds potential to act as a novel drug delivery system for Belinostat with several advantages over the free drug.Item Self-assembling lisofylline-fatty acid conjugate for effective treatment of diabetes mellitus(Elsevier, 2019-01) Mittal, Anupama; Chitkara, DeepakLisofylline is an anti-inflammatory agent with proven anti-diabetic activity. Its high solubility and rapid metabolism results in poor bioavailability and short half-life, limiting its clinical utility. We have synthesized Lisofylline-Linoleic acid (LSF-LA) conjugate which self-assembled into micelles (156.9 nm; PDI 0.187; CMC 1 μg/mL; aggregation number 54) without any surfactant and showed enhanced cellular uptake. It protected MIN6 insulinoma cells from cytokine induced cell death and enhanced insulin production under inflammatory conditions. It also suppressed the proliferation of activated peripheral blood mononuclear cells and reduced the production of inflammatory cytokines, IFN-γ and TNF-α. LSF-LA micelles exhibited reduced protein binding, significantly higher half-life (5.7-fold) and higher apparent volume of distribution (5.3-fold) than free LSF. In T1D animals, reduced blood glucose levels were observed at a reduced dose (~15 mg/kg, once daily of LSF-LA micelles vs. 25 mg/kg, twice daily of free LSF) that was further confirmed by immunohistochemical analysis.Item Simultaneous estimation of lisofylline and pentoxifylline in rat plasma by high performance liquid chromatography-photodiode array detector and its application to pharmacokinetics in rat(Elsevier, 2017-09) Chitkara, Deepak; Mittal, AnupamaLisofylline (LSF) is an anti-inflammatory and immunomodulatory agent with proven activity in serious infections associated with cancer chemotherapy, hyperoxia-induced acute lung injury, autoimmune disorders including type-1 diabetes (T1DM) and islet rejection after islet transplantation. It is also an active metabolite of another anti-inflammatory agent, Pentoxifylline (PTX). LSF bears immense therapeutic potential in multiple pharmacological activities and hence appropriate and accurate quantification of LSF is very important. Although a number of analytical methods for quantification of LSF and PTX have been reported for pharmacokinetics and metabolic studies, each of these have certain limitations in terms of large sample volume required, complex extraction procedure and/or use of highly sophisticated instruments like LC–MS/MS.Item Effective cellular internalization, cell cycle arrest and improved pharmacokinetics of Tamoxifen by cholesterol based lipopolymeric nanoparticles(Elsevier, 2018-05) Mittal, Anupama; Chitkara, DeepakThe present study aims at the development of cholesterol based lipopolymeric nanoparticles for improved entrapment, better cell penetration and improved pharmacokinetics of Tamoxifen (TMX). Self-assembling cholesterol grafted lipopolymer, mPEG-b-(CB-{g-chol}-co-LA) was synthesized from poly(ethyleneglycol)-block-2-methyl-2-carboxyl-propylenecarboxylic acid-co-poly (l-lactide) [mPEG-b-(CB-{g-COOH}-co-LA)] copolymer followed by carbodiimide coupling for attaching cholesterol. Lipopolymeric nanoparticles were prepared using o/w solvent evaporation technique, which were subsequently characterized to determine its particle size, entrapment efficiency, release pattern and compared with mPEG-PLA nanoparticles. Further, in order to assess the in vitro efficacy, cytotoxicity studies, uptake, apoptosis assay and cell cycle analysis were performed in breast cancer cell lines (MCF-7 and 4T1). Finally, the pharmacokinetic profile of TMX loaded mPEG-b-(CB-{g-chol}-co-LA) lipopolymeric nanoparticles was also performed. TMX loaded lipopolymeric nanoparticles of particle size 151.25 ± 3.74 (PDI 0.123) and entrapment efficiency of 73.62 ± 3.08% were formulated. The haemolytic index, protein binding and in vitro drug release of the optimized nanoparticles were found to be comparable to that of the TMX loaded mPEG-PLA nanoparticles. Lipopolymeric nanoparticles demonstrated improved IC50 values in breast cancer cells (22.2 μM in 4T1; 18.8 μM in MCF-7) than free TMX (27.6 μM and 23.5 μM respectively) and higher uptake efficiency. At IC50 values, TMX loaded lipopolymeric nanoparticles induced apoptosis and cell cycle arrest (G0/G1 phase) to similar extent as that of free drug. Pharmacokinetic studies indicated ∼2.5-fold increase in the half-life (t1/2) (p < 0.001) and ∼2.7-fold (p < 0.001) increase in the mean residence time (MRT) of TMX following incorporation into lipopolymeric nanoparticles. Thus, mPEG-b-(CB-{g-chol}-co-LA) lipopolymeric nanoparticles offer a more promising approach for delivery of Tamoxifen in breast cancer by improving drug internalization and prolonging the mean residence time of the drug indicating possibility of dose reduction and hence bypassing the adverse effects of TMX therapy.