Dual passively active tumor-targeting micelles for pH-triggered intracellular anticancer drug release

Abstract

Novel passive–active dual tumor-targeting micelles for pH-triggered intracellular nitrogen mustard release were developed based on hydrophobic cores conjugated with anticancer drugs and shells functionalized with folic acid ligands for tumor cell targeting. The amphiphilic triblock copolymer, 4-( bis(2-chloroethyl)amino)benzaldehyde, N-(2-hydroxypropyl)methacrylamide, and folic acid copolymer (poly(mustard-acetal)- b-PHPMA- b-PFA), was synthesized via reversible addition fragmentation chain transfer polymerization. The amphiphilic copolymer was subsequently self-assembled into nanosized micelles of 83 nm with the nitrogen mustard drug safely encapsulated in the core. The cleavage of anticancer drug within the cores of micelles was effectively actuated under biologically relevant conditions, mildly acidic microenvironments (endosomal/lysosomal pH in the cytosol). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and fluorescence microscopy image analysis revealed that folate-conjugated nanosized micelles exhibited at least ~2.2-fold higher cellular uptake than folate unconjugated micelles against KB cells overexpressing folate receptors on the surface. Thus, poly(mustard-acetal)- b-PHPMA- b-PFA micelles could potentially be used as a promising system for triggering the release of nitrogen mustard drug.