Crosslinked triblock copolymeric micelle for redox-responsive drug delivery

In this paper, novel biodegradable amphiphilic triblock copolymer based on methoxy poly(ethylene glycol)-b-poly(ɛ-caprolactone)-b-poly(2-(2-oxo-1,3,2-dioxaphospholoyloxy)ethyl methacrylate) (mPEG-b-PCL-b-PPEMA) was successfully synthesized. After Michael-addition reactions between amine groups of cystamine and carbon-carbon double bonds of PPEMA segments, the crosslinked reduction-sensitive copolymer mPEG-b-PCL-b-PPEMA-SS- was obtained for efficient delivery and controlled release of doxorubicin (DOX) to cancer cells. Both the uncrosslinked and crosslinked copolymers could self-assemble to form nano-sized micelles in aqueous solution, while transmission electron microscopy (TEM) observation showed that the micelles dispersed in spherical shape with nano-size before and after DOX loading. Meanwhile, (1)H NMR spectra in D2O indicated the formation of a lower mobility core by crosslinking method and a solid-like rigid core via further DOX-loaded. As compared to the uncrosslinked copolymer, the core crosslinking structure in mPEG-b-PCL-b-PPEMA-SS- could improve the micellar stability and enhance the drug loading capacity and entrapment efficiency. The in vitro release studies showed more sustained drug release behavior of crosslinked mPEG-b-PCL-b-PPEMA-SS- which could be accelerated quantitatively in response to the reductive condition similar to intracellular environment. Furthermore, confocal laser scanning microscopy (CLSM) indicated much more efficient cellular uptake of DOX delivered by mPEG-b-PCL-b-PPEMA-SS-, while MTT assays also demonstrated potent cytotoxic activity against HeLa cells.