Targeting lung cancer stem cells using combination of Tel and Docetaxel liposomes in 3D cultures and tumor xenografts.

Cancer stem cells (CSCs) accounts for recurrence and resistance to chemotherapy in various tumors. Efficacy of chemotherapeutic drugs is limited by tumor stromal barriers, which hinder their penetration into deep tumor sites. We have earlier shown telmisartan (Tel) pretreatment prior to Docetaxel (DTX) administration enhances anti-cancer effects in non-small cell lung cancer (NSCLC). Herein, we demonstrated for the first time the efficacy of Docetaxel liposomes (DTXPL) in combination with Tel in 3D cultures of H460 cells by using polysaccharide-based hydrogels (TheWell Biosciences) and also in xenograft model of DTX resistant H460 derived CD133+ lung tumors. DTXPL and Tel combination showed enhanced cytotoxicity in H460 WT 3D cultures by two folds. In H460 3D cultures, Tel pretreatment showed increased liposomal uptake. DTXPL and Tel combination treated tumors showed reduction in tumor volume (p < .001), increased apoptosis and downregulation of CSC markers (p < .01) in H460 WT and DTX resistant CD133+ xenograft models.

Combination of UVB Absorbing Titanium Dioxide and Quercetin Nanogel for Skin Cancer Chemoprevention.

Sunscreens are widely prescribed and used to prevent skin cancer; however, they have been reported to contain various chemicals which mimic hormones and disrupt hormonal functioning in humans. The aim of this study was to develop topical nanogel for skin cancer prevention using an antioxidant compound quercetin (Qu) and inorganic titanium dioxide (TiO2). Two formulations of Qu nanocrystals were optimized with low and high concentration of drug using the Box-Behnken design with the quadratic response surface model and further homogenized with TiO2. Qu nanocrystal (0.08% and 0.12%) formulations showed a particle size of 249.65 ± 2.84 nm and 352.48 ± 3.56 nm with zeta potential of - 14.7 ± 0.41 mV and - 19.6 ± 0.37 mV and drug content of 89.27 ± 1.39% and 90.38 ± 1.81% respectively. Scanning electron microscopy (SEM) images showed rod-shaped nanocrystals with a particle size below 400 nm. Qu (0.08%), Qu (0.12%), Qu (0.12%) + TiO2 (5%), and Qu (0.12%) + TiO2 (15%) nanogels showed over 70% drug release with significantly (p < 0.001) enhanced skin deposition of Qu as compare with Qu suspension within 24 h. The average numbers of tumor, tumor volume, and percentage of animals with tumors at onset in the Qu (0.12%) + TiO2 (15%) nanogel-pretreated group was found to be significantly (p < 0.05) less as compared with the UV only exposed group. Further, Qu (0.12%) + TiO2 (15%) nanogel significantly (p < 0.001) downregulated COX-2, EP3, EP4, PCNA, and cyclin D1 expressions in contrast to Qu and TiO2 only pretreated groups. Therefore, novel combination of Qu (0.12%) + TiO2 (15%) with enhanced skin deposition can be used as a chemopreventive strategy in UVB-induced skin photocarcinogenesis.

Role of Exosomes for Delivery of Chemotherapeutic Drugs.

Exosomes are endogenous extracellular vesicles (30-100 nm) composed with membrane lipid bilayer which carry vesicular proteins, enzymes, mRNA, miRNA and nucleic acids. They act as messengers for intra- and inter-cellular communication. In addition to their physiological roles, exosomes have the potential to encapsulate and deliver small chemotherapeutic drugs and biological molecules such as proteins and nucleic acid-based drugs to the recipient tissue or organs. Due to their biological properties, exosomes have better organotropism, homing capacity, cellular uptake and cargo release ability than other synthetic nano-drug carriers such as liposomes, micelles and nanogels. The secretion of tumor-derived exosomes is increased in the hypoxic and acidic tumor microenvironment, which can be used as a target for nontoxic and nonimmunogenic drug delivery vehicles for various cancers. Moreover, exosomes have the potential to carry both hydrophilic and hydrophobic chemotherapeutic drugs, bypass RES effect and bypass BBB. Exosomes can be isolated from other types of EVs and cell debris based on their size, density and specific surface proteins through ultracentrifugation, density gradient separation, precipitation, immunoaffinity interaction and gel filtration. Drugs can be loaded into exosomes at the biogenesis stage or with the isolated exosomes by incubation, electroporation, extrusion or sonication methods. Finally, exosomal cargo vehicles can be characterized by ultrastructural microscopic analysis. In this review we intend to summarize the inception, structure and function of the exosomes, role of exosomes in immunological regulation and cancer, methods of isolation and characterization of exosomes and products under clinical trials. This review will provide an inclusive insight of exosomes in drug delivery.