Polymersome-stabilized doxorubicin-lipiodol emulsions for high-efficacy chemoembolization therapy.

Abstract

Transarterial chemoembolization (TACE) with free doxorubicin-lipiodol emulsions (free DOX/L) is a favored clinical treatment for advanced hepatocellular carcinoma (HCC) patients ineligible for radical therapies; however, its inferior colloidal stability not only greatly reduces its tumor retention but also hastens drug release into blood circulation, leading to suboptimal clinical outcomes. Here, we find that disulfide-crosslinked polymersomes carrying doxorubicin (Ps-DOX) form super-stable and homogenous water-in-oil microemulsions with lipiodol (Ps-DOX/L). Ps-DOX/L microemulsions had tunable sizes ranging from 14 to 44 μm depending on the amount of Ps-DOX, were stable over 2 months storage as well as centrifugation, and exhibited nearly zero-order DOX release within 15 days. Of note, Ps-DOX induced 2.3-13.4 fold better inhibitory activity in all tested rat, murine and human liver tumor cells than free DOX likely due to its efficient redox-triggered intracellular drug release. Interestingly, transarterial administration of Ps-DOX/L microemulsions in orthotopic rat N1S1 syngeneic HCC model showed minimal systemic DOX exposure, high and long hepatic DOX retention, complete tumor elimination, effective inhibition of angiogenesis, and depleted adverse effects, significantly outperforming clinically used free DOX/L emulsions. This smart polymersome stabilization of doxorubicin-lipiodol microemulsions provides a novel TACE strategy for advanced tumors.