Co-delivery of cisplatin and siRNA through hybrid nanocarrier platform for masking resistance to chemotherapy in lung cancer.

The resistance of cancer cells to chemotherapy has presented a formidable challenge. The current research aims at evaluating whether silencing of the cisplatin efflux promoter gene ABCC3 using siRNA co-loaded with the drug in a nanocarrier improves its efficacy in non-small cell lung cancer (NSCLC). Hybrid nanocarriers (HNCs) comprising lipids and poly(lactic acid-polyethylene glycol) di-block copolymer (PEG-PLA) were prepared for achieving the simultaneous delivery of cisplatin caprylate and ABCC3-siRNA to the cancer cells.

Lipid-nucleic acid nanoparticles of novel ionizable lipids for systemic BMP-9 gene delivery to bone-marrow mesenchymal stem cells for osteoinduction.

Rational design of novel ionizable lipids for development of lipid-nucleic acid nanoparticles (LNP) is required for safe and effective systemic gene delivery for osteoporosis. LNPs require suitable characteristics for intravenous administration and effective accumulation in bone marrow for enhanced transfection. Hence, lipids with C18 tail and ionizable headgroup (Boc-His-ODA/BHODA and His-ODA/HODA) were synthesized and characterized physicochemically.

Hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of siRNA therapeutics.

Linear polyethylenimine (LPEI) has been well reported as a carrier for siRNA delivery. However, its applications are limited due to its highly ionized state at physiologic pH and the resultant charge mediated toxicity. The presence of ionizable secondary amines in LPE are responsible for its unique characteristics such as pH dependent solubility and positive charge.

Development of Hot Melt Extruded Solid Dispersion of Tamoxifen Citrate and Resveratrol for Synergistic Effects on Breast Cancer Cells.

Primary standard therapy for ER-positive breast cancer being tamoxifen, newer delivery approach for enhancement of dissolution and therapeutic efficiency of tamoxifen through oral route could be a possible solution. In the present study, we investigated combination of tamoxifen (TAM) with resveratrol (RES) and observed that the combination is effective on MCF-7 breast cancer cells. To ensure co-delivery of the drugs, we explored the hot melt extrusion technique for simultaneously extruding two drugs together in order to enhance their bioavailability.

Colloidally Stable Small Unilamellar Stearyl Amine Lipoplexes for Effective BMP-9 Gene Delivery to Stem Cells for Osteogenic Differentiation.

The biocompatibility of cationic liposomes has led to their clinical translation in gene delivery and their application apart from cancer to cardiovascular diseases, osteoporosis, metabolic diseases, and more. We have prepared PEGylated stearyl amine (pegSA) lipoplexes meticulously considering the physicochemical properties and formulation parameters to prepare single unilamellar vesicles (SUV) of < 100 nm size which retain their SUV nature upon complexation with pDNA rather than the conventional lipoplexes which show multilamellar nature. The developed PEGylated SA lipoplexes (pegSA lipoplexes) showed a lower N/P ratio (1.

A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers.

Non-small cell lung cancers (NSCLC) account for 85% of all lung cancers, and the epidermal growth factor receptor (EGFR) is highly expressed or activated in many NSCLC that permit use of EGFR tyrosine kinase inhibitors (TKIs) as frontline therapies. Resistance to EGFR TKIs eventually develops that necessitates development of improved and effective therapeutics. CARP-1/CCAR1 is an effector of apoptosis by Doxorubicin, Etoposide, or Gefitinib, while CARP-1 functional mimetic (CFM) compounds bind with CARP-1, and stimulate CARP-1 expression and apoptosis.

Tacrolimus Loaded PEG-Cholecalciferol Based Micelles for Treatment of Ocular Inflammation.

Purpose: Poor corneal permeability, nasolacrimal drainage and requirement of chronic administration are major drawbacks of existing therapies for ocular inflammation. Hence, we designed topical micelles of PEG conjugated with cholecalciferol (PEGCCF).

Methods: Integrin targeted tacrolimus loaded PEGCCF micelles (TTM) were prepared by solvent diffusion evaporation method and characterized for particle size, osmolality, encapsulation efficiency and drug loading.

Liposomes encapsulating native and cyclodextrin enclosed paclitaxel: Enhanced loading efficiency and its pharmacokinetic evaluation.

Combination strategy involving cyclodextrin (CD) complexation and liposomal system was investigated for Paclitaxel (PTX) to improve loading. Complexation was done using 2,6-di-O-methylbetacyclodextrin (DMβCD). Sterically stabilized double loaded PEGylated liposomes (DLPLs) containing PTX and PTX-DMβCD complex were prepared by thin film hydration.

Cholecalciferol-PEG Conjugate Based Nanomicelles of Doxorubicin for Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the leading cancer in women. Chemotherapeutic agents used for TNBC are mainly associated with dose-dependent toxicities and development of resistance. Hence, novel strategies to overcome resistance and to offer dose reduction are warranted.

Liposomes co-Loaded with 6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3 (PFKFB3) shRNA Plasmid and Docetaxel for the Treatment of non-small Cell Lung Cancer.

Purpose: Non-small cell lung cancer is the leading cause of cancer related deaths globally. Considering the side effects and diminishing chemosensitivity to chemotherapy, novel treatment approaches are sought. Hence, we aim to develop a liposomal co-delivery system of pDNA expressing shRNA against PFKFB3 (pshPFKFB3) and docetaxel (DTX).

Role of antibodies in diagnosis and treatment of ovarian cancer: Basic approach and clinical status.

Ovarian cancer is the second most leading gynecological cancer after endometrial cancer in women. Chemotherapy and cyto-reductive surgery are currently the mainstays for treatment of ovarian cancer in early stages. However, the overall 5years of survival rate in advanced stage is just 20-30%.

Liposomes and Lipid Envelope-Type Systems for Systemic siRNA Delivery.

The 'RNA interference' has emerged as a potential therapeutic strategy owing to its high specificity to silent any malfunctioned gene in diseases with genetic background. Currently intravenous delivery of siRNA has been a preferred way of administration due to high access of blood to the organs where direct delivery is not possible. Among non-viral delivery systems enabling systemic delivery of siRNA, liposomes and lipid envelope systems appear to be promising due to their biocompatibility over other systems.

Role of Nanotechnology in Delivery of Protein and Peptide Drugs.

The advent of recombinant DNA technology and computational designing has fueled the emergence of proteins and peptides as a new class of modern therapeutics such as vaccines, antigens, antibodies and hormones. Demand for such therapeutics has increased recently due to their distinct pharmacodynamic characteristics of specificity of action and high potency. However, their potential clinical applications are often hindered by involvement of factors which impact their therapeutic potential negatively.

Protein- and Peptide-drug conjugates: an emerging drug delivery technology.

Protein- and peptide-drug conjugates hold a promising stance in the delivery of therapeutic agents by providing distinct advantage of improving therapeutic potential of drugs. Recent advancements in the proteomics and recombinant DNA technology, by enabling identification of distinct structural features of proteins and making it feasible to introduce specific functionalities in protein/peptide structure, has made it possible to synthesize high quality protein- and peptide-drug conjugates though a wide variety of coupling techniques. Additionally, use of specialized linkers makes them unique in their in vivo therapeutic application by providing target tissue-specific release of drug.

Surface-modified Epirubicin-HCl liposomes and its in vitro assessment in breast cancer cell-line: MCF-7.

Background: Epirubicin-HCl is highly efficient for breast cancer management at a concentration of 60-90 mg/m(2). However, its application is limited due to cumulative dose-dependent cardio-toxicity.

Purpose: The main aim of this study was to formulate breast cancer-targeted liposomal carrier by surface conjugation of transferrin to minimize cardio-toxicity of drug along with improved pharmacokinetic profile.

Receptor-targeted drug delivery: current perspective and challenges.

Receptor-targeted drug delivery has been extensively explored for active targeting. However, the scarce clinical applications of such delivery systems highlight the implicit hurdles in development of such systems. These hurdles begin with lack of knowledge of differential expression of receptors, their accessibility and identification of newer receptors.

Development and characterization of siRNA lipoplexes: Effect of different lipids, in vitro evaluation in cancerous cell lines and in vivo toxicity study.

Cationic liposomes have long been used as non-viral vectors for small interfering RNA (siRNA) delivery but are associated with high toxicity, less transfection efficiency, and in vivo instability. In this investigation, we have developed siRNA targeted to RRM1 that is responsible for development of resistance to gemcitabine in cancer cells. Effect of different lipid compositions has been evaluated on formation of stable and less toxic lipoplexes.

PEG - a versatile conjugating ligand for drugs and drug delivery systems.

Polyethylene glycol (PEG) conjugation is a rapidly evolving strategy to solve hurdles in therapeutic delivery and is being used as an add-on tool to the traditional drug delivery methods. Chemically, PEGylation is a term used to denote modification of therapeutic molecules by conjugation with PEG. Efforts are constantly being made to develop novel strategies for conjugation of PEG with these molecules in order to increase its current applications.

Caprylate-conjugated Cisplatin for the development of novel liposomal formulation.

Cisplatin, first (platinum) compound to be evolved as an anticancer agent, has found its important place in cancer chemotherapy. However, the dose-dependent toxicities of cisplatin, namely nephrotoxicity, ototoxicity, peripheral neuropathy, and gastrointestinal toxicity hinder its widespread use. Liposomes can reduce the toxicity of cisplatin and provide a better therapeutic action, but the low lipid solubility of cisplatin hinders its high entrapment in such lipid carrier.

cRGD grafted liposomes containing inorganic nano-precipitate complexed siRNA for intracellular delivery in cancer cells.

Development of effective vector for intracellular delivery of siRNA has always been a challenge due to its hydrophilicity, net negative surface charge and sensitivity against nucleases in biological milieu. The present investigation was aimed to develop a novel non-viral liposomal carrier for siRNA delivery. Nano-precipitate of calcium phosphate was entrapped in liposomes composed of a neutral lipid (DPPC), a fusogenic lipid (DOPE), a PEGylated lipid (DSPE-mPEG2000) and cholesterol.

Epidermal growth factor receptor targeting in cancer: a review of trends and strategies.

The epidermal growth factor receptor (EGFR) is a cell-surface receptor belonging to ErbB family of tyrosine kinase and it plays a vital role in the regulation of cell proliferation, survival and differentiation. However; EGFR is aberrantly activated by various mechanisms like receptor overexpression, mutation, ligand-dependent receptor dimerization, ligand-independent activation and is associated with development of variety of tumors. Therefore, specific EGFR inhibition is one of the key targets for cancer therapy.

Proteins: emerging carrier for delivery of cancer therapeutics.

Introduction: Over the past decades, proteins have emerged as versatile carriers for the diagnosis and treatment of cancer, diabetes, rheumatoid arthritis, and many more diseases. Proteins have gained considerable attention in formulation of several delivery systems for anticancer drugs due to their nontoxic, non-immunogenic, biocompatible and biodegradable nature. Proteins are good candidates for conjugation with drugs as they provide good pharmacokinetics as well as better cancer tissue accumulation.

Physiologically activated phase transition systems for improved ocular retention of ketorolac tromethamine.

In present investigation, novel physiologically activated phase transition systems for Ketorolac Tromethamine was developed. In-situ gelling systems: pH sensitive gel using carbopol 980 and HPMC K100LV, ion sensitive gel using gallan gum and temperature sensitive gel using Poloxamer 407 and Poloxamer 188 were developed. The drug content, content uniformity, pH, optical transmittance, rheological property, bioadhesive strength, in-vitro drug release, ocular irritation and stability study were evaluated.