Title : Casein-based nanovehicles for oral delivery of chemotherapeutic combinations to overcome multidrug resistance in gastric cancer
Abstract:
Gastrointestinal cancers are the third leading cause of cancer-related deaths worldwide. Moreover, multidrug resistance (MDR) mediated by ATP-dependent efflux transporters remains a dominant obstacle toward curative cancer therapy. Furthermore, most chemotherapeutic agents are lipid-soluble, administered intravenously using harmful solvents and surfactants. An effective and selective oral delivery system would significantly contribute to patients’ quality of life, reduce hospitalization costs and circumvent infection with antibiotic-resistant pathogens prevalent in hospitals. Bovine milk is comprised of 80% phosphoproteins known as Caseins. Their amphiphilic structure enables them to naturally self-assemble into casein micelles (CM). In previous studies we have demonstrated the potential of β-CN micelles (β-CM) and re-assembled casein micelles (rCM) to serve as nanovehicles for oral delivery and target-activated release of hydrophobic cargo, including nutraceuticals and chemotherapeutic agents, in the stomach. Herein we compared the rCM- and the β-CM- based oral delivery platforms. Each comprised an individually encapsulated synergistic duo of a chemotherapeutic drug along with its corresponding chemosensitizer, which counteract ATPdriven MDR efflux pumps (e.g. p-glycoprotein (P-gp)/ ABCB1, breast cancer resistance protein/ ABCG2), that expel a spectrum of anticancer drugs from cancer cells and therefore markedly suppresses the efficacy of numerous hydrophobic chemotherapeutics. Hence, the rationally designed encapsulated pair is expected to display enhanced efficacy and synergy in overcoming MDR phenomena in gastric cancer. This novel treatment strategy, can allow less painful treatment at the comfort of the patient’s home. The target-activated release mechanism, aimed to locally treat gastric cancer, can diminish untoward toxicity to the upper gastro-intestinal tract and minimize toxic side effects caused by systemic chemotherapy. This nanosystem could also be applied for the treatment of various non-malignant gastric disorders and tailored to individual drug combinations for personalized medicine. Audience Take Away: • Casein-based nanovehicles are an efficient platform for oral delivery and target-activated release of synergistic hydrophobic drug combinations in the stomach. • Casein-based delivery systems can release synergistic drug combinations to overcome two modalities of ATPdependent MDR in gastric cancer. • Casein based delivery systems may enable treatment at home, thus a
