Redox/NIR dual-responsive PEG-betulinic acid/pluronic-cypate prodrug micelles for chemophotothermal therapy

Abstract

Betulinic acid (BA) is a new class of anticancer drug, but its relatively short half-life and poor water solubility limit its therapeutic effect and clinical application. Herein, to tackle the dilemma, BA prodrugs were prepared by conjugating BA onto the polyethylene glycol (PEG) polymer via cleavable disulfide bonds. The prodrugs exhibited high water solubility (270-fold of free BA) and a relatively high drug-loading efficiency of 14.2 %. To further endow the BA prodrugs with a photothermal therapeutic effect, the near-infrared (NIR) agent Cypate was grafted on the Pluronic triblock copolymer. The different PEG polymers and different Pluronic polymers were chosen to obtain the optimal drug loading efficiency and the photothermal generation effect. The P-SS-BA/F68-Cy prodrug micelles integrate the redox-responsive BA prodrugs and the NIR-responsive amphiphilic triblock polymer into one single nanocomposite. The release of BA was less than 20 % in pH 7.4 PBS in the absence of glutathione (GSH), whereas the release of BA was obviously accelerated in pH 5.0 PBS with 10 mM GSH. In addition, the release of BA was further accelerated under the NIR irradiation. The P-SS-BA/F68-Cy micelles showed an excellent photothermal heating effect under NIR irradiation. The prepared P-SS-BA/F68-Cy micelles showed the synergistic thermochemotherapeutic effect on tumors both in vitro and in vivo. Therefore, the present study shows the great potential of dual-triggered drug delivery and thermochemotherapy for combination therapy.