Re-assembled Casein Micelles for Oral Delivery of Chemotherapeutic Combinations to Overcome Multidrug Resistance in Gastric Cancer

Abstract

Multidrug resistance (MDR) mediated by ATP-dependent efflux transporters continues to be a dominant obstacle towards curative cancer therapy. We have previously demonstrated the ability of β-casein micelles (β-CM) to orally deliver a combination of individually encapsulated hydrophobic cargo of drugs and chemosensitizers designed to overcome MDR in gastric cancer. Herein we investigated the potential of reassembled casein micelles (rCM) to serve as a target-activated delivery platform comprising a synergistic duo of a chemotherapeutic drug (paclitaxel) and a P-glycoprotein-specific transport inhibitor (tariquidar). The high binding affinity of paclitaxel and tariquidar to rCM was demonstrated by spectrofluorometry. Furthermore, solubilization of the drugs and suppression of crystal growth was shown by light microscopy and dynamic light scattering. A remarkable antitumor activity and complete MDR reversal were demonstrated in the in vitro cytotoxicity assay against MDR human gastric carcinoma cells overexpressing P-glycoprotein. The structure and cytotoxic activity of drug-loaded rCM were completely retained after freeze-drying and reconstitution as in β-CM. Hence, our findings highlight the great potential of casein-based nanovehicles as efficient platforms for oral delivery and local target-activated release of synergistic hydrophobic drug combinations to treat gastric cancer, and overcome of cancer chemoresistance, and for the possible treatment of non-malignant gastric disorders.

Crosslinked casein micelles bound paclitaxel as enzyme activated intracellular drug delivery systems for cancer therapy

“…For this reason, casein is regarded as an excellent candidate as excipient for pharmaceutical applications in drug delivery. [20] Although other authors have previously reported the use of casein micelles (CM) as carriers for oral delivery of PTX in gastric carcinoma therapy [21][22][23][24][25][26], the parenteral application of this system in cancer therapy has not been reported in literature and could be of great interest for the pharmaceutical industry. CM are of particular importance due to their nanometric size in dispersion for intracellular drug delivery.…”