Polylactic acid based biodegradable hybrid block copolymeric nanoparticle mediated co-delivery of salinomycin and doxorubicin for cancer therapy

Abstract

Existence of cancer stem cells (CSCs) are primarily responsible for chemoresistance, cancer reoccurrence and treatment failure in cancer patients. Eliminating CSCs along with bulk tumor is a necessity to achieve complete cancer inhibition. Salinomycin (SAL) has potential to specifically target and kill CSCs through blocking their multiple pathways simultaneously. SAL has also been reported to improve anti-cancer efficacy of numerous chemo-based drugs when used in combination therapy. However, clinical use of SAL is restricted due to its high off targeted toxicity. Herein, we have developed a PLA based hybrid block copolymer for concomitant delivery of SAL and doxorubicin (DOX) with an aim to reduce their adverse side effects and enhance the therapeutic efficacy of the treatment. Designed PLA based nanoplatform showed high encapsulation and sustained release profile for both the drugs. Cytotoxicity evaluation on cancer cell lines confirmed the synergistic effect of SAL:DOX co-loaded NPs. Additionally, prepared SAL NPs were also found to be highly effective against chemo-resistant cancer cells and CSCs derived from cancer patient. Most importantly, encapsulation of SAL in PLA NPs improved its pharmacokinetics and biodistribution profile. Consequently, undesired toxicity with SAL NPs was significantly reduced which in-turn increased the dose tolerability in mice as compared to free SAL. Treatment of EAC tumor bearing mice with SAL:DOX co-loaded NPs resulted in excellent tumor regression and complete inhibition of cancer reoccurrence. These results conclude that concomitant delivery of SAL and DOX using PLA based block copolymeric nano-carrier have a strong potential for cancer therapy.

Keywords: Block copolymer; Cancer stem cells; Doxorubicin; Nanoparticles; Polylactic acid; Salinomycin.