Rohit Srivastava

Nanodrug delivery in reversing multidrug resistance in cancer cells

Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance (MDR) which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp), multidrug resistance-associated proteins (MRP1, MRP2), and breast cancer resistance protein (BCRP). Currently nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective, and promising platforms for treatment of drug resistant cancer cells. Nanocarriers have potential to improve drug therapeutic index, ability for multifunctionality, divert ABC-transporter mediated drug efflux mechanism and selective targeting to tumor cells, cancer stem cells, tumor initiating cells, or cancer microenvironment. Selective nanocarrier targeting to tumor overcomes dose-limiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses, and emergence of multiple drug resistance with conventional or combination chemotherapy. Current review highlights various nanodrug delivery systems to overcome mechanism of MDR by neutralizing, evading, or exploiting the drug efflux pumps and those independent of drug efflux pump mechanism by silencing Bcl-2 and HIF1α gene expressions by siRNA and miRNA, modulating ceramide levels and targeting NF-κB. “Theragnostics” combining a cytotoxic agent, targeting moiety, chemosensitizing agent, and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR. Physical approaches such as combination of drug with thermal/ultrasound/photodynamic therapies to overcome MDR are focused. The review focuses on newer drug delivery systems developed to overcome MDR in cancer cell.

Thermoresponsive polymeric gel as an on-demand transdermal drug delivery system for pain management.

The main aim of this work is to design a heat triggered transdermal drug delivery system (TDDS) using a thermoresponsive polymer, poly (N-vinyl caprolactam) [PNVCL] based gel, where in patients can themselves administer a pulse of drug on mere application of heat pad over the TDDS, whenever pain is experienced. The phase transition temperature of PNVCL was tuned to 35 °C by grafting it onto a pH sensitive biopolymer, Chitosan, to synthesize Chitosan-g-PNVCL (CP) co-polymer which render the gel both thermo- and pH-responsive property. The application of triggered delivery was explored by loading acetamidophenol (a model hydrophilic drug) and etoricoxib (a model hydrophobic drug). In vitro drug release experiments were performed at three different temperatures (25, 32 and 39 °C) at two different pH (5.5 and 7) to study its drug release with response to temperature and pH. Drug release profiles obtained were found to have enhanced release for both the drugs respectively at 39 °C (above LCST) and pH5.5 when compared to other release conditions. In vitro skin permeation of both the drugs performed in rat abdominal skin using Franz diffusion cell showed enhanced drug release when the skin was subjected to higher temperature (39 °C). Moreover, it was also found that skin permeation for hydrophobic drug was better than that of hydrophilic drug. The in vivo biocompatibility studies of the CP gel in rat skin proved that the gel is biocompatible. The results obtained demonstrated the potential use of the thermoresponsive CP gel as an on-demand localized drug delivery system.

Poly (caprolactone) microparticles and chitosan thermogels based injectable formulation of etoricoxib for the potential treatment of osteoarthritis.

This study aimed to evaluate Poly (caprolactone) microparticles (MPs) loaded composite injectable Chitosan gel (CICGs) as a dual purpose (visco-supplement and intra articular drug delivery depot) therapeutic agent for the treatment of Osteoarthritis. Etoricoxib (COX-2 inhibitor), a highly hydrophobic drug was chosen as a model drug for the study. When administered orally, Etoricoxib poses severe cardiovascular toxicity issues. So, we have attempted to deliver this drug intra-articularly, which could retain the drug longer in the joint region and thus could ameliorate these toxicity issues. CICGs were prepared by dispersing MPs in the chitosan-Ammonium hydrogen phosphate solution and incubated at 37 °C. Rheology studies proved that gels were stable and had visco-elastic properties comparable to that of existing visco-supplements. The in vitro drug release profiles of CICGs were found to be more controlled when compared to MPs and bare chitosan gel (BCGs). In vitro and in vivo biocompatibility studies proved that the gels were biocompatible. In vivo synovial drug clearance studies proved that CICGs had a better drug retention capacity than BCGs and MPs. In vivo fluorescence imaging results confirmed that CICGs could stay longer in the joint region when compared to BCGs and MPs. Thus this novel CICGs could be a potential dual purpose gel for the treatment of diseased joint regions especially for Osteoarthritis.

Partial penile amputation due to penile tourniquet syndrome in a child troubled with primary nocturnal enuresis--a rare emergency.

Penile tourniquet syndrome (PTS) or acquired constriction ring syndrome (ACRS) is a rare emergency that can lead to a wide range of vascular and soft tissue injuries in the penis. We are presenting a case of penile tourniquet syndrome in an 8-year-old child who had tied a thread around his penis due to primary nocturnal enuresis. On exploration, a constricting thread ring was noticed that was causing partial circumferential distal penile amputation. The thread ring was cut and debridement with primary repair of the wound was done in layers. Prevention of complications needs early diagnosis, timely intervention, and removal of the constriction.

CdTe quantum dots: aqueous phase synthesis, stability studies and protein conjugation for development of biosensors

Synthesis of quantum dots (QDs) in aqueous medium is advantageous as compared to the organic solvent mediated synthesis, as the aqueous synthesis is less toxic, reagent effective, easily reproducible and importantly, synthesized QDs have biological compatibility. The QDs should be aqueous in nature for use in cell imaging, drug labeling, tracking and delivery. Structural modifications are necessary to enable their use in biosensing application. In this work, mercaptopropionic acid capped cadmium telluride QDs (MPA-CdTe QDs) were synthesized by hydrothermal method and characterized by various techniques. Water and various biochemical buffers were used to study the fluorescence intensity stability of the QDs at different physicochemical conditions. QDs stored in 4° C showed excellent stability of fluorescence intensity values as compared to the samples stored at room temperature. Staphylococcal protein A (SPA) was conjugated with the QDs (SPA-QDs) and characterized using UV and fluorescence spectroscopy, zeta potential, HRTEM, FTIR, and AFM. Blue shift was observed in the fluorescence emission spectra that may be due to reduction in the surface charge as carboxyl groups on QDs were replaced by amino groups of SPA. This SPA conjugated to QDs enables binding of the C-terminal of antibodies on its surface allowing N-terminal binding site remain free to bind with antigenic biomarkers. Thus, the biosensor i.e. antibody bound on SPA-QDs would bind to the antigenic biomarkers in sample and the detection system could be developed. As QDs have better fluorescence properties than organic dyes, this biosensor will provide high sensitivity and quantitative capability in diagnostics.

Tubercular thyroid abscess.

We encountered a patient who presented with neck swelling, difficulty in swallowing, voice change along with systemic features such as evening rise of temperature, chronic cough and weight loss. Ultrasonography of the thyroid gland revealed two cystic swellings. An ultrasound guided fine needle aspiration cytology was suggestive of tubercular abscess. The patient responded well to antigravity aspiration of the swellings and antitubercular treatment.

Studies on field efficacy of newer insecticides on population dynamics of major insect pests and mite infesting tomato crop

Bio-efficacy experiments on newer insecticides against insect pest of tomato were carried out by using seven different insecticides applied at different dose at 60 and 80 Days after planting. The bio efficacy of these insecticides were evaluated against major insect pests infesting tomato crop viz., tomato fruit borer, Helicoverpa armigera (Hubner), aphid, Aphis gossypii (Glover) and Myzus persica (Sulzer), leafminer, Liriomyza trifolii (Burgess), whitefly, Bemisia tabaci (Gennadius) and mite pest i.e. red spider mite, Tetranychus urticae (Koch). Based on the findings of the present study, it can be inferred that the newer insecticide Emamectin benzoate 1.9% EC @ 300 ml a.i./ha proved to be more effective against tomato fruit borer, whitefly and leaf miner. Other insecticides or mixtures of insecticides were moderately effective.

Hollow silicon microneedle array based trans-epidermal antiemetic patch for efficient management of chemotherapy induced nausea and vomiting

Chemotherapy Induced Nausea and Vomiting (CINV) is a serious health concern in the treatment of cancer patients. Conventional routes for administering anti-emetics (i.e. oral and parenteral) have several drawbacks such as painful injections, poor patient compliance, dependence on skilled personnel, non-affordability to majority of population (parenteral), lack of programmability and suboptimal bioavailability (oral). Hence, we have developed a trans-epidermal antiemetic drug delivery patch using out-of-plane hollow silicon microneedle array. Microneedles are pointed micron-scale structures that pierce the epidermal layer of skin to reach dermal blood vessels and can directly release the drug in their vicinity. They are painless by virtue of avoiding significant contact with dermal sensory nerve endings. This alternate approach gives same pharmacodynamic effects as par- enteral route at a sparse drug-dose requirement, hence negligible side-effects and improved patient compliance. Microneedle design attributes were derived by systematic study of human skin anatomy, natural micron-size structures like wasp-sting and cactus-spine and multi-physics simulations. We used deep reactive ion etching with Bosch process and optimized recipe of gases to fabricate high-aspect-ratio hollow silicon microneedle array. Finally, microneedle array and polydimethylsiloxane drug reservoir were assembled to make finished anti-emetic patch. We assessed microneedles mechanical stability, physico-chemical properties and performed in-vitro, ex- vivo and in-vivo studies. These studies established functional efficacy of the device in trans-epidermal delivery of anti-emetics, its programmability, ease of use and biosafety. Thus, out-of-plane hollow silicon microneedle array trans-epidermal antiemetic patch is a promising strategy for painless and effective management of CINV at low cost in mainstream healthcare.