Polyphosphazene vesicles for co-delivery of doxorubicin and chloroquine with enhanced anticancer efficacy by drug resistance reversal.

The conventional chemotherapeutic agent doxorubicin hydrochloride (DOX·HCl) is often accompanied by drug resistance which has severely hindered its clinical application. By taking advantage of the self-assembled behavior of amphiphilic polyphosphazenes, we constructed novel polymersomes loading DOX·HCl or desalted DOX with chloroquine phosphate (CQ) as a drug resistance-reversal agent at 1:1 or 2:1 weight ratios via a one-step common dialysis method. The cytotoxicity evaluation of this dual drug-loaded polymersome was performed on DOX-resistant MCF-7/Adr breast cancer and HL60/Adr leukemia cells. Simultaneously, to simulate in vivo cancerous tissue, 3D tumor spheroid was constructed for tissue penetration and anti-cancer effect evaluation. As a result, PEP-DHC-1 containing DOX·HCl and CQ at 1:1 weight ratio exhibited the strongest toxicity. Furthermore, the in vivo tumor inhibition study carried out on a zebrafish xenograft model also validated that PEP-DHC-1 made the outstanding contribution to improve the sensitivity of MCF-7/Adr breast cancer to chemotherapeutics. These findings suggest that this DOX·HCl and CQ co-delivery system based on PEP polymersomes might be promising for drug resistance reversal of cancer therapy and consequently enhanced anti-cancer efficacy.