Department of Pharmacy
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Item Anticancer and immunostimulatory activity by conjugate of paclitaxel and non-toxic derivative of lps for combined chemo-immunotherapy(Springer, 2012-05) Roy, AniruddhaCancer is a multifactorial syndrome; hence, multidimensional therapy with a chemo-immunotherapeutic conjugate could be more effective in curing the disease.Item Modifying the tumor microenvironment using nanoparticle therapeutics(Wiley, 2016-04) Roy, AniruddhaTreatment of cancer has come a long way from the initial ‘radical surgeries’ to the multimodality treatments. For the major part of the last century, cancer was considered as a monocellular disorder, and treatment strategies were designed according to that hypothesis. However, the mortality rate from cancer continued to be high and a comprehensive treatment remained elusive. Recent progress in research has demonstrated that tumors are a complex network of neoplastic and non-neoplastic cells. The non-neoplastic cells, which are collectively called stroma, assist in tumor survival and progression. It has been shown that disrupting the tumor-stromal balance leads to significant effects on the tumor survival, and effective treatment can be achieved by targeting one or more of the stromal components. In this review, we summarize the roles of various stromal components in promoting tumor progression, and discuss innovative nanoparticle-mediated drug targeting strategies for stromal depletion and the subsequent effects on the tumors. Perspectives and the future directions are also provided.Item Comparison of Tumor Penetration of Podophyllotoxin–Carboxymethylcellulose Conjugates with Various Chemical Compositions in Tumor Spheroid Culture and In Vivo Solid Tumor(ACS, 2017-04) Roy, AniruddhaPolymer conjugation is an attractive approach for delivering insoluble and highly toxic drugs to tumors. However, most reports in the literature only disclose the optimal composition without emphasizing rational design or composition optimization to achieve maximized biological effects. In this study, we aimed to demonstrate that composition of a polymer conjugate would determine its physiochemical characteristics, tumor penetration, and, ultimately, the in vivo efficacy. We also aimed to examine whether the tumor spheroid model could generate comparable results with the in vivo tumor model in terms of tumor penetration and efficacy of the various polymer conjugates. We have designed a polymer conjugate delivery system for a chemotherapeutic drug podophyllotoxin (PPT) by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose to yield conjugates containing various amounts of PPT and PEG. Depending on the composition, these conjugates self-assembled into nanoparticles (NPs) with different physicochemical properties. Conjugates with an increased PPT content formed particles with an increased diameter. In the present study, we selected three conjugates representing compositions containing high, medium, and low drug content, and compared their particle formation, drug release kinetics, their ability to penetrate tumor spheroid and in vivo s.c. tumor, and finally their antitumor efficacy in spheroid culture and an in vivo s.c. tumor model. We found that the low drug content conjugate formed smaller NPs (20 nm) compared to the high drug content conjugates (30–120 nm), and displayed faster drug release kinetics (5%/day vs 1–3%/day), improved tumor penetration, and enhanced antitumor efficacy in both the spheroid model and s.c. tumor model. In particular, the low drug content conjugate preferentially accumulated in the hypovascular region within the tumor, inducing complete regression of s.c. tumors and the metastasis to the lungs. Our data indicate composition optimization is needed to select the optimal conjugate, and tumor spheroid culture is a robust screening tool to help select the optimal formulationItem 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.Item Nano-natural Products as Anticancer Agents(Springer, 2018-07) Paul, Atish Tulshiram; Jindal, Anil B.Cancer is one of the noxious diseases and is a major public health problem worldwide. The clinical management of cancer involves various approaches, but the most common one is chemotherapy. Natural products such as paclitaxel, camptothecin, podophyllotoxin, etc. have been used as major sources of anticancer drugs in many clinical trials. In spite of availability of these drugs for treatment of cancer, failure in chemotherapy is very common due to dose-limited toxicities and occurrence of drug resistance. In this regard, the nano-delivery systems directly target and deliver the selective drug to the cancerous sites and increase the permeability and intracellular accretion of anticancer drugs. Thus, the aim of this chapter is to focus on the application of nanotechnology to develop nano-natural products for effective treatment of cancer.Item Evaluation of Apoptosis and Autophagy Inducing Potential of Berberis aristata, Azadirachta indica, and Their Synergistic Combinations in Parental and Resistant Human Osteosarcoma Cells(Frontiers, 2017-12) Paul, Atish Tulshiram; Chowdhury, RajdeepCancer is a multifactorial disease and hence can be effectively overcome by a multi-constituently therapeutic strategy. Medicinal plant extracts represent a perfect example of such stratagem. However, minimal studies have been done till date that portray the effect of extraction techniques on the phyto-constituent profile of plant extracts and its impact on anticancer activity. In the present study, we have evaluated the anticancer potential of methanolic extracts of Berberis aristata root and Azadirachta indica seeds prepared by various extraction techniques in human osteosarcoma (HOS) cells. Soxhlation extract of B. aristata (BAM-SX) and sonication extract of A. indica (AIM-SO) were most effective in inducing apoptosis in parental drug sensitive, as well as resistant cell type developed by repeated drug exposure. Generation of reactive oxygen species and cell cycle arrest preceded caspase-mediated apoptosis in HOS cells. Interestingly, inhibition of autophagy enhanced cell death suggesting the cytoprotective role of autophagy. Combination studies of different methanolic extracts of BAM and AIM were performed, among which, the combination of BAM-SO and AIM-SO (BAAISO) was found to show synergism (IC50 10.27 µg/ml) followed by combination of BAM-MC and AIM-MC (BAAIMC) with respect to other combinations in the ratio of 1:1. BAAISO also showed synergism when it was added to cisplatin-resistant HOS cells (HCR). Chromatographic profiling of BAM-SX and AIM-SO by high performance thin layer chromatography resulted in identification of berberine (Rf 0.55), palmitine (Rf 0.50) in BAM-SX and azadirachtin A (Rf 0.36), azadirachtin B (Rf 0.56), nimbin (Rf 0.80), and nimbolide (Rf 0.43) in AIM-SO. The cytotoxic sensitivity obtained can be attributed to the above compounds. Our results highlight the importance of extraction technique and subsequent mechanism of action of multi-constituential B. aristata and A. indica against both sensitive and drug refractory HOS cells.Item Natural HDAC Inhibitors: Nature’s Answer to the Cancer(NMIMS, 2015) Gaikwad, Anil BhanudasPost translational modifications of histones play a significant role in regulation of physiological and pathological processes in the body. Acetylation is one of the most important chromatin modifying mechanisms being controlled by histone acetyl transferases and histone deacetylases. The histone deacetylases (HDAC) are basically responsible for silencing of gene transcription. Cancer involves silencing of a large number of genes. Inhibition of such gene silencing could possibly lead us to alleviatin or control of cancer progression. Natural HDAC inhibitors, a highly researched topic thus seems an attractive method to conquer the kingdom of cancer and thus prove to be the ‘bull’s eye’ like target for cancer treatment