Department of Pharmacy
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Item New strategies for cancer management: how can temozolomide carrier modifications improve its delivery?(Future Science Group, 2017-06) Chitkara, Deepak; Mittal, AnupamaGlioblastoma multiform (GBM) is the most devastating, highly aggressive astrocytic cell neoplasm having a median survival of 12–15 months and a 5-year survival rate of <3% [1]. Surgery along with radiation therapy and/or chemotherapy is the standard treatment strategy for primary brain tumors wherein, the survival advantages are only palliative. Despite clinical and technological advances, a cure for GBM remains elusive due to its diffuse infiltrative pattern of growth (hindering complete surgical resection), cytogenetic heterogeneity (limiting the use of pathway-specific targeted agents) and location (need to cross the blood–brain barrier [BBB]). Temozolomide (TMZ) is the first-line chemotherapy for GBM used in conjunction with radiotherapy or as a single agent for maintenance therapy [1]. It is an imidazotetrazine class DNA alkylating agent that methylates guanine and adenine bases of DNA leading to DNA double-strand breaks, cell cycle arrest and eventual cell death [1]. An autophagy induction leading to cell death has also been reported as a putative mechanism of action of TMZ in cancer cells and GBM patients [2]. Looking at the current therapy for GBM, there is still an unmet medical need resulting due to its inefficient delivery of TMZ to the cancer tissue. Only a modest activity is seen for TMZ, particularly in high-grade gliomas, which is further limited by the development of resistance leaving no viable therapeutic option for recurrent glioblastoma [3]. Further, TMZ is an unstable molecule that undergoes rapid hydrolysis and has significant dose-limiting hematological toxicity that prevents dosage increase [1]. Currently, TMZ is given orally or intravenously (TEMODAR®) at a dose of 75 mg/m2 concomitant with radiotherapy for 49 days followed by 150 mg/m2 (cycle 1) and 200 mg/m2 (cycle 2–6) as a maintenance dose.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.Item Multi-component clobetasol-loaded monolithic lipid-polymer hybrid nanoparticles ameliorate imiquimod-induced psoriasis-like skin inflammation in Swiss albino mice(Elsevier, 2020-10) Chitkara, Deepak; Mittal, AnupamaLipid-polymer hybrid nanoparticles (LPNs) exhibit several advantages over polymeric and non-polymeric systems in terms of improved drug loading, controlled release, stability, and cellular uptake. Herein we report a scalable and stable monolithic lipid-polymer hybrid nanoparticles (LPNs) consisting of a combination of lipids (solid and liquid) and an amphiphilic copolymer, mPEG-PLA. Clobetasol propionate, a topical corticosteroid, was encapsulated in the hydrophobic core of these LPNs that showed spherical shaped particles with a z-average size of 94.8 nm (PDI = 0.213) and encapsulation efficiency of 84.3%. These clobetasol loaded LPNs (CP/LPNs) were formulated into a topical hydrogel using carbopol 974P. CP/LPNs gel showed a sustained in vitro clobetasol release for 7 days with no burst release and 6 month stability at 2-8°C and room temperature. Further, CP/LPNs showed an improved cellular uptake with significant growth inhibition of HaCaT cells. In ex vivo studies, these LPNs penetrated into the viable epidermis and dermis region of the psoriatic skin with undetectable quantities leaching to the reservoir. Further, the topical application of CP/LPNs gel on Swiss albino mice with psoriasis-like inflammation showed negligible leaching of clobetasol into the systemic circulation. Efficacy assessment showed significantly improved PASI score, reduced skin damage and proliferation after treatment with CP/LPNs gel as compared to marketed product (Clobetamos™). Collectively, the enhanced cellular uptake, high skin penetration with increased skin retention, and improved efficacy demonstrate the potential of these LPNs for future clinical application.Item Development of quercetin nanoformulation and in vivo evaluation using streptozotocin induced diabetic rat model(Springer, 2012-02) Chitkara, Deepak; Mittal, AnupamaQuercetin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Qu-NP) were prepared by emulsion–diffusion–evaporation method and characterized as 179.9 ± 11.2 nm in size with 0.128 as polydispersity index, more than 86% drug entrapment efficiency, and zeta potential was −6.06 ± 1.51 mV. d-Trehalose (5% w/v) was found to be a suitable cryoprotectant for lyophilization of Qu-NP, and antioxidant assays indicated that Qu-NP were able to retain the antioxidant property similar to that of free drug at equivalent concentration after formulation development. In vitro release study of Qu-NP showed a controlled release pattern of quercetin. An enhanced oral bioavailability (523% relative increase) was observed in pharmacokinetic study with a 6-day sustained release from Qu-NP as compared to quercetin suspension, which indicated the reduced dosing frequency. Efficacy in diabetic rats suggested that same dose of Qu-NP on every fifth day was sufficient to bring effect similar to daily dose of oral quercetin suspension, and the same effect was also observed for catalase and superoxide dismutase levels in pancreas and kidneys. Thus, the system offers an efficacious oral therapy with reduced dose and dosing frequency for treatment of diabetes and is hence patient compliant.Item Exploration and insights into the cellular internalization and intracellular fate of amphiphilic polymeric nanocarriers(Elsevier, 2021-04) Chitkara, Deepak; Mittal, AnupamaThe beneficial or deleterious effects of nanomedicines emerge from their complex interactions with intracellular pathways and their subcellular fate. Moreover, the dynamic nature of plasma membrane accounts for the movement of these nanocarriers within the cell towards different organelles thereby not only influencing their pharmacokinetic and pharmacodynamic properties but also bioavailability, therapeutic efficacy and toxicity. Therefore, an in-depth understanding of underlying parameters controlling nanocarrier endocytosis and intracellular fate is essential. In order to direct nanoparticles towards specific sub-cellular organelles the physicochemical attributes of nanocarriers can be manipulated. These include particle size, shape and surface charge/chemistry. Restricting the particle size of nanocarriers below 200 nm contributes to internalization via clathrin and caveolae mediated pathways. Similarly, a moderate negative surface potential confers endolysosomal escape and targeting towards mitochondria, endoplasmic reticulum (ER) and Golgi. This review aims to provide an insight into these physicochemical attributes of nanocarriers fabricated using amphiphilic graft copolymers affecting cellular internalization. Fundamental principles understood from experimental studies have been extrapolated to draw a general conclusion for the designing of optimized nanoparticulate drug delivery systems and enhanced intracellular uptake via specific endocytic pathway.Item Lipid-polymer hybrid nanocarriers for delivering cancer therapeutics(Elsevier, 2018-02) Chitkara, Deepak; Mittal, AnupamaCancer remained a major cause of death providing diversified challenges in terms of treatment including non-specific toxicity, chemoresistance and relapse. Nanotechnology- based delivery systems grabbed tremendous attention for delivering cancer therapeutics as they provide benefits including controlled drug release, improved biological half-life, reduced toxicity and targeted delivery. Majority of the nanocarriers consists of either a polymer or a lipid component along with other excipients to stabilize the colloidal system. Lipid-based systems provide advantages like better entrapment efficiency, scalability and low- cost raw materials, however, suffer from limitations including instability, a burst release of the drug, and limited surface functionalization. On the other hand, polymeric systems provide an excellent diversity of chemical modifications, stability, controlled release, however limited drug loading capacities and scale up limit their use. Hybrid nanocarriers consisting of lipid and polymer were able to overcome some of these disadvantages while retaining the advantages of both the systems. Designing a stable lipid-polymer hybrid system requires a thorough understanding of the material properties and their behavior in in vitro and in vivo environments. This review highlights the current status and future prospects of lipid-polymer hybrid systems with a particular focus on cancer nanotherapeutics