Department of Pharmacy
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Item Downregulation of microRNA-29b in cancer and fibrosis: molecular insights and clinical implications(Elsevier, 2024-11) Chitkara, DeepakMicroRNA-29b (miR-29b) is known for its therapeutic potential as an antifibrotic and anticancer agent. In fibrotic conditions, miR-29b inhibits fibrogenesis by downregulating crucial regulators such as collagens, extracellular matrix proteins and the transforming growth factor-β pathway. Similarly, in cancer, it acts as a tumor suppressor by downregulating various oncogenes and signaling pathways involved in cancer progression, such as Wnt–β-catenin, p38–mitogen-activated protein kinase and nuclear factor-κB. However, the upregulation of these pathways suppresses miR-29b, contributing to fibrosis and cancer development. Preclinical research and clinical trials have shown that delivering exogenous miR-29b mimics can restore its expression, attenuating tumorigenesis and fibrogenesis. This review discusses miR-29b’s potential and its possible therapeutic development for cancer and fibrotic disorders.Item Docetaxel and its nanoformulations: how delivery strategies could impact the therapeutic outcome?(Future Science Group, 2020-09) Mittal, Anupama; Chitkara, DeepakTo overcome problems associated with current conventional formulations of DTX, efforts have been made to develop a variety of DTX-loaded nanosystems. These systems have improved water solubility, bioavailability and antitumor efficacy with a specific accumulation of drugs at tumor sites. Some of the novel DTX nanoformulations, which demonstrated exciting in vivo anticancer efficacy results, have grabbed the attention of pharmaceutical companies and successfully entered clinical trialsItem 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 Self-Assembling, Amphiphilic Polymer–Gemcitabine Conjugate Shows Enhanced Antitumor Efficacy Against Human Pancreatic Adenocarcinoma(ACS, 2013-06) Chitkara, DeepakThe therapeutic efficacy of gemcitabine is severely compromised due to its rapid plasma metabolism. Moreover, its hydrophilicity poses a challenge for its efficient entrapment in nanosized delivery systems and to provide a sustained release profile. In this study, gemcitabine was covalently conjugated to poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate) (PEG-PCC) which could self-assemble into micelles of 23.6 nm. These micelles afforded protection to gemcitabine from plasma metabolism as evident by negligible amount of gemcitabine and its metabolite dFdU detected in the plasma after 24 h. A controlled release of gemcitabine from the micelles was observed with 53.89% drug release in 10 days in the presence of protease enzyme Cathepsin B. Gemcitabine conjugated micelles were cytotoxic, showed internalization, and induced cell apoptosis in MIA PaCa-2 and L3.6pl pancreatic cancer cell lines. These micelles efficiently inhibited tumor growth when injected intravenously into MIA PaCa-2 cell derived xenograft tumor bearing NSG mice at a dose of 40 mg/kg in terms of reduced tumor volume and tumor weight (0.38 g vs 0.58 g). TUNEL assay revealed that gemcitabine conjugated micelles induced a much higher extent of apoptosis in the tumor tissues compared to free gemcitabine. In conclusion, gemcitabine conjugated micelles were able to enhance the drug payload, protect it from rapid plasma metabolism, and provide a sustained release and showed enhanced antitumor activity, and thus have the potential to provide a better therapeutic alternative for treating pancreatic cancer.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 nanotherapeuticsItem Efficacy of gemcitabine conjugated and miRNA-205 complexed micelles for treatment of advanced pancreatic cancer(Elsevier, 2014-08) Chitkara, Deepak; Mittal, AnupamaClinical effectiveness of gemcitabine in pancreatic cancer is hindered due to its rapid plasma metabolism and development of chemo-resistance. We have previously delineated the significant role of miRNAs in mediating the growth and proliferation of cancer stem cells (CSCs) which in turn result in chemo-resistance, invasion and metastasis. Here, we designed self-assembling, gemcitabine conjugated cationic copolymers for co-delivery of a tumor suppressor miRNA-205 (miR-205) and evaluated their in vivo efficacy in a pancreatic cancer ectopic tumor model developed using gemcitabine resistant MIA PaCa-2R cells. Combination formulations showed mean a particle size of <100 nm and gemcitabine payload of >10% w/w, exhibited miRNA complexation at N/P ratio of 4/1, sustained release of gemcitabine for >10 days, transfection efficiency of >90%, extended miRNA and drug stability in serum. Functional assays in gemcitabine resistant MIA PaCa-2R and CAPAN-1R pancreatic cancer cells revealed that the combination formulations effectively reversed chemo-resistance, invasion and migration. In pancreatic tumor model, the combination formulation treated group showed significant inhibition of tumor growth. Immuno-hiostochemical analysis revealed decreased tumor cell proliferation with increased apoptosis in the animals treated with miR-205 and gemcitabine combination.