ß-Casein micelles for oral delivery of SN-38 and elacridar to overcome BCRP-mediated multidrug resistance in gastric cancer.

Gastric cancer is the third leading cause of cancer-related mortality worldwide. A dominant hindrance towards curative cancer therapy is multidrug resistance (MDR) mediated by ATP-dependent efflux pumps. We have previously demonstrated the ability of ß-casein (ß-CN) micelles and re-assembled casein micelles to serve as nanovehicles for oral delivery and target-activated release of hydrophobic chemotherapeutics in the stomach, and to overcome P-glycoprotein-dependent MDR in gastric cancer. Herein we investigated the modularity and versatility of this ß-CN-based delivery system using a different synergistic drug duo to treat MDR gastric cancer cells overexpressing the breast cancer resistance protein (BCRP). The chemotherapeutic drug SN-38, a BCRP transport substrate, and the BCRP efflux transport inhibitor, elacridar, exhibited high binding affinity to ß-CN, as demonstrated by spectrophotometry and spectrofluorometry. Furthermore, light microscopy and dynamic light scattering confirmed that ß-CN solubilized these drugs and suppressed drug crystal growth. In vitro cytotoxicity against MDR human gastric carcinoma cells overexpressing BCRP revealed a synergistic activity of this drug combination and a complete MDR reversal. Hence, our findings highlight the great promise of casein-based nanovehicles, harboring hydrophobic synergistic drug combinations, as a modular and versatile oral delivery system for local drug release in the stomach to overcome chemoresistance in gastric cancer.

Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance.

Intrinsic anticancer drug resistance appearing prior to chemotherapy as well as acquired resistance due to drug treatment, remain the dominant impediments towards curative cancer therapy. Hence, novel targeted strategies to overcome cancer drug resistance constitute a key aim of cancer research. In this respect, targeted nanomedicine offers innovative therapeutic strategies to overcome the various limitations of conventional chemotherapy, enabling enhanced selectivity, early and more precise cancer diagnosis, individualized treatment as well as overcoming of drug resistance, including multidrug resistance (MDR). Delivery systems based on nanoparticles (NPs) include diverse platforms enabling a plethora of rationally designed therapeutic nanomedicines. Here we review NPs designed to enhance antitumor drug uptake and selective intracellular accumulation using strategies including passive and active targeting, stimuli-responsive drug activation or target-activated release, triggered solely in the cancer cell or in specific organelles, cutting edge theranostic multifunctional NPs delivering drug combinations for synergistic therapy, while facilitating diagnostics, and personalization of therapeutic regimens. In the current paper we review the recent findings of the past four years and discuss the advantages and limitations of the various novel NPs-based drug delivery systems. Special emphasis is put on in vivo study-based evidences supporting significant therapeutic impact in chemoresistant cancers. A future perspective is proposed for further research and development of complex targeted, multi-stage responsive nanomedical drug delivery systems for personalized cancer diagnosis and efficacious therapy.

ß-casein nanovehicles for oral delivery of chemotherapeutic Drug combinations overcoming P-glycoprotein-mediated multidrug resistance in human gastric cancer cells.

Multidrug resistance (MDR) is a primary obstacle to curative cancer therapy. We have previously demonstrated that ß-casein (ß-CN) micelles (ß-CM) can serve as nanovehicles for oral delivery and target-activated release of hydrophobic drugs in the stomach. Herein we introduce a novel nanosystem based on ß-CM, to orally deliver a synergistic combination of a chemotherapeutic drug (Paclitaxel) and a P-glycoprotein-specific transport inhibitor (Tariquidar) individually encapsulated within ß-CM, for overcoming MDR in gastric cancer. Light microscopy, dynamic light scattering and zeta potential analyses revealed solubilization of these drugs by ß-CN, suppressing drug crystallization. Spectrophotometry demonstrated high loading capacity and good encapsulation efficiency, whereas spectrofluorometry revealed high affinity of these drugs to ß-CN. In vitro cytotoxicity assays exhibited remarkable synergistic efficacy against human MDR gastric carcinoma cells with P-glycoprotein overexpression. Oral delivery of ß-CN - based nanovehicles carrying synergistic drug combinations to the stomach constitutes a novel efficacious therapeutic system that may overcome MDR in gastric cancer.