Department of Pharmacy
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Item Molecular medicines for cancer: concepts and applications of nanotechnology(CRC Press, 2019) Chitkara, Deepak; Mittal, AnupamaThe field of molecular medicine covers the medical interventions targeting molecular structures and mechanisms that are involved in disease progression. In cancer, several molecular mechanisms have been shown to impact its progression, aggressiveness and chemoresistance. Increasing evidence demonstrates the role of nanotechnology and outcome of molecular therapy. Several books have discussed molecular biology and mechanisms involved in cancer, but this text gives an account of molecular therapeutics in cancer relating to advancements of nanotechnology. It provides a description of the multidisciplinary field of molecular medicines and its targeted delivery to cancer using nanotechnology. Key Features: Provides current information in the multidisciplinary field of molecular medicines and its targeted delivery to cancer using nanotechnology Presents important aspects of nanotechnology in the site-specific delivery of anticancer agents Includes up to date information on oligonucleotide and gene based therapies in cancer Describes small targeted molecules, antibodies and oligonucleotides which have shown to selectively target the molecular structures thereby influencing signal transduction Facilitates discussion between researchers involved in cancer therapy and nanoscientistsItem Regional Drug Therapy: Polymeric Carriers for(CRC Press, 2015) Chitkara, Deepak; Mittal, AnupamaItem Advancements in Polymeric Systems for Nucleic Acid Delivery(CRC Press, 2018) Chitkara, Deepak; Mittal, AnupamaRNA interference (RNAi) has been suggested as a potential treatment method to improve current chemotherapeutic regimens. It is a sequence-specific, post-transcriptional gene silencing mechanism in animals and plants that targets mRNA encoded by the mutant gene. RNA-based strategies are useful in targeting the mutations that results in a gain of function wherein RNA levels are modified and includes the use of antisense oligonucleotide, triplex-forming oligonucleotides, aptamers, trans-splicing, segmental trans-splicing, ribozymes, DNAzymes, siRNA, and miRNA (Chitkara, Singh, & Mittal, 2016). Among these, siRNA and miRNA have generated a lot of interest as they could be easily synthesized, do not require genome integration, and thus could curtail potential problems of insertional mutagenesis. These are 20–25 base pair-long RNA oligonucleotides that are incorporated into the pre-RISC (RNA-inducedItem In vitro release behavior of paclitaxel and carboplatin from poly(l-lactide) microspheres dispersed in thermosensitive biodegradable gel for combination therapy(International Journal of Drug Delivery, 2011) Chitkara, Deepak; Mittal, AnupamaThe objective of the current work was to design an injectable, sustained release formulation of a combination of anticancer drugs, carboplatin and paclitaxel, for localized delivery. In this combination formulation, carboplatin was encapsulated into poly(L-lactide) (PLA) microspheres and paclitaxel was dissolved in thermosensitive biodegradable gel of PLGA-PEG-PLGA (poly (DL-lactide-co-glycolide- polyethylene glycol- poly (DL-lactide-co-glycolide)); no external solvent like cremophorEL was used in the formulation, further, these carboplatin microspheres were dispersed in the gel containing paclitaxel to achieve a single delivery system. The combined formulation was assessed for various parameters for sustained release of both the drugs. Release profiles of carboplatin from PLA microspheres; paclitaxel from hydrogel alone and in combination with carboplatin and carboplatin microspheres dispersed in paclitaxel loaded gel were studied. In vitro release of both the drugs from PLGA-PEG-PLGA hydrogel showed that carboplatin was released with 40-50% burst release and paclitaxel was released in biphasic manner for 50-60 days. Initial burst of carboplatin was controlled by incorporating it in PLA microspheres which were then dispersed in paclitaxel loaded hydrogel and the new formulation did not exhibit any burst release of the drug. Release pattern of combination formulations revealed that the two drugs were co-eluting from a single delivery system and the rate of release of each of the individual drugs was significantly affected. Thus, a novel injectable combination formulation for sustained and simultaneous delivery of carboplatin and paclitaxel was developed which provided sustained release of each of the drugs and could be further explored in tumor models.Item Scalable Self-Assembling Micellar System for Enhanced Oral Bioavailability and Efficacy of Lisofylline for Treatment of Type-I Diabetes(ACS, 2019-10) Mittal, Anupama; Chitkara, Deepak; Shrivastava, RichaThe study summarizes the development of an orally active nanoformulation of a potent but one of the least explored molecules, lisofylline (LSF), in type 1 diabetes (T1D). LSF undergoes rapid metabolism, resulting in poor oral bioavailability and short half-life. In this work, to improve its pharmacokinetic (PK) properties, LSF was encapsulated in the form of its ester prodrug [LSF–linoleic acid (LA) prodrug] into biodegradable self-assembling polymeric micelles [LSF–LA PLM, size: 149.3 nm; polydispersity index: 0.209; critical micelle concentration (cmc); 5.95 μg/mL and Nagg: 14.82 at 10 cmc] of methoxypoly(ethylene glycol)-b-poly(carbonate-co-l-lactide) (mPEG-b-P(CB-co-LA)) block copolymer. LSF–LA PLM was found to be equally effective as the LSF–LA prodrug in cell culture studies in insulin-secreting MIN6 cells and showed excellent stability in simulating biological fluids and plasma. PK of LSF–LA PLM (10 mg/kg dose) revealed a significant improvement in oral bioavailability of LSF (74.86%; 3.3-fold increase in comparison to free LSF) and drastic reduction in the drug metabolism. Further, LSF–LA PLM showed a significant reduction in fasting glucose levels and increase in insulin levels by intraperitoneal as well oral routes in a streptozotocin (STZ)-induced T1D rat model. Production of inflammatory cytokines (TNF-α and IFN-γ) and different biochemical markers for liver and kidney functions were much reduced in diabetic animals after treatment with LSF–LA PLM. LSF–LA PLM-treated pancreatic sections showed minimal infiltration of CD4+ and CD8+ T-cells as indicated by hematoxylin/eosin staining and immunohistochemical analysis.Item Core-shell nanoparticulate formulation of gemcitabine: lyophilization, stability studies, and in vivo evaluation(Springer, 2014-10) Chitkara, Deepak; Mittal, AnupamaCore-shell nanoparticulate formulation of gemcitabine was prepared by incorporating gemcitabine in a hydrophilic bovine serum albumin (BSA) core surrounded by hydrophobic poly(dl-lactic acid-co-glycolic acid) (PLGA) shell with a particle size of 243 nm and encapsulation efficiency of 40.5 %. Prepared formulations were lyophilized, wherein several cryoprotectants were screened for product attributes such as cake appearance, reconstitution with water, and size constancy. Trehalose was screened as a lyoprotectant, which showed stability for 6 months at 5 °C and 25 °C/60 % relative humidity (RH) conditions. However, an increase in particle size was observed at accelerated conditions (40 °C/75 % RH). In vitro evaluation of these nano-formulations in MCF-7 breast cancer cells showed enhanced cellular uptake (90 %) as compared to GEMCITE® uptake (51 %) in 6 h along with reduced IC50 value at 72 h (16 μM versus 30 μM). In vivo studies in Sprague Dawley rats showed C max, t 1/2, and area under the curve (AUC) at 2.55 μg/ml, 13.6 h, and 28,322.5 μg/l/h, respectively, whereas GEMCITE® at the same dose showed significantly lower corresponding values at 1.94 μg/ml, 6.89 h, and 13,967 μg/l/h. In the same study, AUC and C max of inactive metabolite of gemcitabine (dFdU) were reduced by 33 and 42 %, respectively, for these nanoparticles compared to GEMCITE®. In 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer model, significantly reduced tumor growth was observed in gemcitabine-loaded-nanoparticle-treated animals compared with GEMCITE®-treated animal at equivalent dose (121 versus 243 % in 30 days). The results indicated that our core-shell nanoparticles are more effective for tumor reduction compared to marketed formulation of gemcitabine, GEMCITE®.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 Structural modifications in polymeric micelles to impart multifunctionality for improved drug delivery(Future Science Group, 2016-01) Mittal, Anupama; Chitkara, DeepakPolymeric micelles are macromolecular nanoconstructs which are formed by self-assembly of synthetic amphiphilic block copolymers. These copolymers could be chemically modified to expand their functionality and hence obtain a multifunctional micelle which could serve several functions simultaneously, for example, long circulation time along with active targeting, smart polymeric micelles providing on-demand drug release for example, pH responsive micelles, redox- and light-sensitive micelles, charge-conversion micelles and core/shell cross-linked micelles. Additionally, micelles could be tailored to carry a contrast agent or siRNA/miRNA along with the drug for greater clinical benefit. The focus of the current commentary would be to highlight such chemical modifications which impart multifunctionality to a single carrier and discuss challenges involved in clinical translation of these multifunctional micelles.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 A Rapid and Precise Liquid Chromatographic Method for Simultaneous Determination of Alpha Lipoic Acid and Docetaxel in Lipid-Based Nanoformulations(OUP, 2018-07) Chitkara, Deepak; Mittal, AnupamaCombinational drug delivery successfully merges the benefits of nanotechnology and combination therapy by providing diversity to improve the carrier properties and better control over tailoring them as per the need of cancer treatment. A combination of conventional chemotherapeutic agent; docetaxel (DTX) and antioxidant agent; alpha lipoic acid (ALA) which acts by preventing metastasis may fulfill idealness of control and targeted drug delivery against breast cancer. The objective of the current study is to develop a reverse-phase HPLC-UV method for simultaneous determination of DTX and ALA in lipid-based nanoformulations. DTX and ALA were separated on Intersil® ODS (C18) column (250 × 4.6 mm, 5 μm) with a mobile phase consisting of acetonitrile: sodium acetate buffer (pH 3.5; 10 mM) (65:35% v/v) run in isocratic mode at a flow rate of 1 mL/min. The developed method was validated as per ICH guidelines. The method showed linearity in the concentration range of 1–15 μg/mL for DTX and 2–30 μg/mL for ALA. It can detect minimum 200 ng/mL of DTX and 500 ng/mL of ALA. The method was further successfully applied in lipid-based formulation characterization. In conclusion, a simple, accurate and precise reverse-phase HPLC-UV method was established for simultaneous determination of DTX and ALA in nanoformulations.