Biodegradable poly(ε-caprolactone)-g-poly(2-hydroxyethyl methacrylate) graft copolymer micelles as superior nano-carriers for "smart" doxorubicin release

Biodegradable micelles were prepared from poly(epsilon-caprolactone)-g-poly(2-hydroxyethyl methacrylate) (PCL-g-PHEMA) graft copolymers and investigated for controlled release of doxorubicin (DOX). PCL-g-PHEMA copolymers were readily obtained by controlled ring-opening copolymerization of acryloyl cyclic carbonate and epsilon-caprolactone, Michael-type conjugate addition reaction with cysteamine, coupling reaction with 4-cyanopentanoic acid dithionaphthalenoate (CPADN) via carbodiimide chemistry, and reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-hydroxyethyl methacrylate (HEMA). H-1 NMR analyses showed that M-n of PHEMA ranged from 8.7, 16.3 to 33.8 kg mol(-1), in proximity to the design as well as those determined by gel permeation chromatography (GPC). Differential scanning calorimetry (DSC) revealed that all three PCL-g-PHEMA graft copolymers had depressed melting temperatures (T-m = 31.3-32.5 degrees C) and low crystallinities (X-c = 3.05-5.66%). Dynamic light scattering (DLS) showed that PCL-g-PHEMA formed monodisperse micelles with low polydispersity indexes of 0.04-0.16 and average sizes ranging from 80.5 to 179.7 nm depending on PHEMA chain lengths. These graft copolymers displayed low critical micelle concentrations (CMCs) of 0.051-0.151 mu M. The micellar sizes decreased following loading with DOX while PDI remained low. Interestingly, in vitro drug release studies showed that DOX-loaded PCL-g-PHEMA micelles exhibited superior pH-responsive release behaviors, in which up to 94.5% of DOX was released in 3 d at pH 5.0 while DOX release was significantly slower at pH 7.4 (maximum 54.1% release in 3 d). MTT assays with HeLa cells demonstrated that DOX-loaded PCL-g-PHEMA micelles retained high anti-tumor activity with low IC50 (half inhibitory concentration) of 1.47-1.74 mu g DOX equiv. mL(-1) while PCL-g-PHEMA micelles were practically non-toxic up to a tested concentration of 80 mg mL(-1). These novel biodegradable PCL-g-PHEMA graft copolymer micelles with low CMC, small and tunable sizes, high drug loading, and pH-responsive drug release have emerged as superior nanocarriers for "smart" tumor-targeting drug delivery.