Cellular uptake of pH/reduction responsive phosphorylcholine micelles

Abstract

Phosphorylcholine micelles based on pH/reduction responsive copolymers, poly(ε-caprolactone)-ss-b-poly((N,N-diethylaminoethyl methacrylate)-r-poly(2-methacryloyloxyethyl phosphorylcholine)) (PCL-ss-PDEAPMPC) were developed for the intracellular delivery of doxorubicin. The micelles were spherical (less than 90 nm in diameter) and demonstrated pH/reduction sensitivity. The DOX loaded micelles presented the fastest drug release under simultaneously acidic and reductive conditions. Although PCL₂₀-ss-PDEA₅PMPC₁₀ had lower pH sensitivity than PCL₂₀-ss-PDEA₁₅PMPC₁₀, the DOX loaded micelles of the former released the drug faster than the latter at pH 5.0 and in the presence of a reductant. The cytotoxicities of the blank micelles and the drug-loaded micelles were investigated using the human cervical cancer cell line (HeLa). The IC₅₀ (half maximal inhibitory concentration) of PCL₂₀-ss-PDEA₅PMPC₁₀ micelles was the lowest among PCL-ss-PDEAPMPC micelles. The results of CLSM and flow cytometry showed that the micelles effectively delivered the drug cargo into cancer cells. The cellular uptake pathways of PCL-ss-PDEAPMPC micelles were mainly clathrin-mediated endocytosis, and accompanied by a certain degree of giant pinocytosis.