Mixed micellar system for codelivery of doxorubicin and caffeic acid phenethyl ester: design and enhanced antitumor activity

Abstract

Multifunctional nanocarriers of two or more anticancer drugs with different pharmacological mechanisms are being developed for combination therapy, which aims at achieving synergistic effects in cancer treatment and overcoming the increasingly common problem of drug resistance. This contribution reports the fabrication of functional nanosized micellar carriers of doxorubicin (DOX) and caffeic acid phenethyl ester (CAPE) via coassembly of two well-defined amphiphilic ABA triblock copolymers comprising identical hydrophobic poly(e-caprolactone) (PCL) blocks and different hydrophilic segments – poly(ethylene oxide) (PEO) or poly(acrylic acid) (PAA). CAPE was embedded into the PCL core via hydrophobic interactions, while DOX was loaded within a mixed PAA/PEO corona layer through complexation. The main physico-chemical properties of blank and dual drug-loaded micelles were investigated using dynamic and electrophoretic light scattering and transmission electron microscopy. Loading of CAPE and DOX increased the size and size distribution of carriers to some extent. However, the mixed micellar system was characterized by good colloidal stability and sustained release of the two drugs. The cytotoxic effect of DOX/CAPE-loaded mixed micelles in drug-resistant lymphoma cells expressing the multidrug resistance (MDR1) gene (L5178Y MDR1) was assessed. Functional micellar nanocarriers for codelivery of doxorubicin (DOX) and caffeic acid phenethyl ester (CAPE) were successfully developed via coassembly of PEO113-b-PCL35-b-PEO113 and PAA13-b-PCL35-b-PAA13. CAPE was entrapped into the PCL core via hydrophobic interactions, while DOX was loaded in the middle layer through complexation between the amino and carboxylic groups of DOX and PAA. The dual drug-loaded micelles exhibited superior colloidal stability and sustained drug release profiles. The dual drug -loaded system suppressed the proliferation of mouse T-lymphoma L5178Y MDR1 cells more effectively than the single drug-loaded micelles, suggesting a synergistic effect.