Modified chitosan nanogel-polymersomes for oral co-delivery of oxaliplatin and rapamycin for synergistic chemotherapy

Oxaliplatin (OXA) and rapamycin (RAPA) combination therapy have shown the advantages of synergistically inhibiting the growth of cancer cells by enhancing apoptosis in cancerous cell lines. However, drug resistance and the lack of an orally administered formulation which exhibited the best clinical dosing compliance limited the clinical application of this regimen. Here, we report a nanogel-polymersomes drug delivery system (i.e.TMOR-CDAN) based on modified chitosan, chitosan diacetate (CDA), methoxy-poly-(ethylene glycol)-b-poly (lactide) (MPP), and D-alpha-tocopheryl polyethylene glycol succinate (TPGS) with permeation-glycoprotein (P-gp) inhibition capability for enhancing the oral chemotherapy efficacy of erroneously soluble RAPA and its synergistic chemotherapy with OXA. Hydrophilic OXA and hydrophobic RAPA were co-loaded using MPP and TPGS-based polymer capsules (i.e. TMOR), which were further coated by chitosan-modified gel to form TMOR-CDAN. The TMOR-CDAN displayed higher stability in both acidic and basic pH than free OXA and RAPA and could withstand the harsh gastric environmental conditions, preventing the burst drugs release while releasing the co-loaded drugs in a sustained and controlled manner. The dual-drug-loaded TMOR-CDAN provides a bifunctional platform for synergistic tumor therapy. Compared with the single drug OXA, RAPA, or the OXA and RAPA mixtures (OR), the TMOR-CDAN showed more outstanding in vitro cytotoxicity and in vivo antitumor chemotherapeutic efficacy, endowing the TMOR-CDAN with a prodigious potential for futuristic cancer chemotherapy .