2,2′-Dithiodisuccinic acid-stabilized polyion complex micelles for pH and reduction dual-responsive drug delivery

Abstract

In this work, a new kind of polyion complex (PIC) micelles with pH and reduction dual responsiveness was developed for effective intracellular drug delivery. The PIC micelles can be readily prepared by mixing a polycationic block polymer, methoxy poly(ethylene glycol)-b-poly(l-lysine) (mPEG-PLL), with a small molecule polyacid, 2, 2′-dithiodisuccinic acid (DTS) in aqueous media. The resultant PIC micelles are of uniform spherical shapes with hydrodynamic radii ranging from 65 to 75 nm based on different feeding ratios of mPEG-PLL and DTS. Interestingly, by using the small molecule polyacid DTS, the obtained PIC micelles show distinct pH-responsive disintegration in acid solution. Meanwhile, the PIC micelles were also assessed to be reduction-responsive due to the presence of disulfide bond in DTS. In view of these stimuli-responsive properties, the potential use of this PIC micelle as smart drug carrier was then investigated. Doxorubicin (DOX), a cationic anticancer drug, was loaded into the PIC micelles with high efficiency. In vitro drug release studies revealed that release of DOX from the PIC micelles was suppressed in neutral solutions due to the stable electrostatic interactions between PIC micelles and DOX, but could be accelerated in acidic solutions or under high GSH condition. Furthermore, flow cytometry and confocal laser scanning microscopy (CLSM) studies indicated that the DOX-loaded PIC micelles could be effectively internalized by MCF-7 human breast cancer cells and release the loaded DOX in intracellular environment. Consequently, the DOX-loaded PIC micelles were capable of inhibiting the proliferation of C26 murine colon cancer and MCF-7 human breast cancer cells in high efficiency, showing similar IC50 values as free DOX. Thus, this biocompatible PIC micelle may be promising for intracellular drug delivery.