Abstract
In this study, a multifunctional and pH-responsive polymeric complex vesicle as an anticancer drug and MRI contrast agent carrier has been developed for cancer theranostics. The superparamagnetic iron oxide (SPIO)-loaded polymeric vesicles (ca. 110 nm) were formed by self-assembly of the poly(acrylic acid-co-disterin acrylate) (P(AAc-co-DSA)) in the SPIO aqueous solution (pH 5.0) via sonication technique while the SPIO was simultaneously encapulated into the interior aqueous compartment of the vesicles. The anticancer drug, doxorubicin (DOX), was then loaded within ionized AAc-rich regions of the membrane of polymer vesicle via electrostatic interaction between the ionized AAc units and postively charged DOX molecules. To improve the stability of the resulting polymer vesicles, chitosan and folate-polyethylene glycol-grafted poly(glutamic acid) (PGA-g-PEG(FA)) were sequentially deposited on the outermost surfaces of the DOX/SPIO-loaded polymer vesicles. The loading efficiency of DOX was ca. 70 %. The in vitro drug release behavior of SPIO/DOX-loaded complex vesicles shows a significant increased drug release at pH 4.7 (70%) and a severely retarded drug release at pH 7.4 (20%). This indicates that the loaded DOX molecules can be effectivitly released in the acid environment of tumor (e.g. endosomes or lysosomes). Compared to commercial MRI contrast agent, Resovist, the relaxivity r2 value of SPIO/DOX-loaded polymeric complex vesicles was much higher than Resovist. Results from flow cytometry and confocal laser scanning microscopy (CLSM) analysis showed that folate-conjugated vesicles exhibited higher than folat-free vesicles which also led to higher cytotoxicity. Thus, these DOX/SPIO-loaded folate-conjugated polymer complex vesicles can provide pH-controlled drug release, as well as enhanced MRI contrast, thereby mtargeted cancer therapy and diagnosis possible.