Chitosan‑<i>g</i>‑TPGS Nanoparticles for Anticancer Drug Delivery and Overcoming Multidrug Resistance

To overcome the P-glycoprotein (P-gp)-induced multidrug resistance (MDR) of cancer cells, a novel copolymer, chitosan-<i>graft</i>-d-α-tocopheryl polyethylene glycol 1000 (TPGS) (CT) was synthesized for doxorubicin (DOX) delivery by the P-gp inhibiting virtue of TPGS. DOX-loaded CT nanoparticles (NPs) were fabricated by a modified solvent extraction/evaporation method combined with ionic cross-linking to form a uniform particle size of 140–180 nm with ∼40% DOX loading efficiency. These drug-loaded CT NPs demonstrated a pH-responsive release behavior, and DOX was released more quickly under low pH values. Significant cell cytotoxicity was observed on the human hepatocarcinoma cells (HepG2 and BEL-7402) and human breast adenocarcinoma cells (MCF-7). The cell cytotoxicity and apoptosis of drug-resistant cells (MCF-7/DOX and BEL-7402/5-Fu), was greatly enhanced as compared to Adriamycin. The IC₅₀ value showed that DOX-loaded CT NPs could be 1.5–199-fold more effective than Adriamycin. This can be attributed to the P-gp blocking and down-regulation of ATP levels by the CT NPs. The potential of these NPs to act as an oral delivery system was also investigated. Both the pharmacokinetic properties and <i>in vivo</i> antitumor activity of DOX-loaded CT NPs were improved compared with Adriamycin