Redox and pH Dual-Responsive Polypeptide Micelles for Doxorubicin Delivery with Enhanced Anticancer Efficacy
Hanlei Xing, Yanhao Zhang, Ji Wang, Chao Liu, Wenhui Zha, Yang Wang, Shuo Dong, Xinsong Li
Abstract
Herein, redox and pH dual-responsive poly(glutamic acid) micelle-encapsulated doxorubicin (DOX) was developed in this report. First, methoxy poly(ethylene glycol)- block -poly(glutamic acid) (PEG-SS-PG) linked by a disulfide bond was synthesized through ring-opening polymerization of l -glutamic acid γ-benzyl ester carboxyanhydride using terminal aminosylated poly(ethylene glycol) (PEG-SS-NH 2 ) as an initiator. After that, PEG-SS-PG was assembled with doxorubicin (DOX) by a simple mixing to form tight PEG-SS-PG/DOX micelles by virtue of the electrostatic interaction between carboxylic acid groups of PEG-SS-PG and amine groups of DOX. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) characterization indicated that the micelles have a spherical structure with an average particle size of about 70 nm. The drug loading efficiency (DLE) was measured to be 92.3 wt %. The release behavior of PEG-SS-PG/DOX was checked in the presence of glutathione (GSH) and different pH. The results showed that about 90% DOX was released within 36 h under the combined action of high GSH concentration and low pH, while less than 25% DOX was released at pH 7.4 in the absence of GSH. These data confirmed the glutathione and pH dual-responsiveness of PEG-SS-PG/DOX micelles. The micelles could be internalized by cancer cells, as revealed by confocal laser scanning microscopy (CLSM) and flow cytometry (FCM). The pharmacokinetics and biodistribution of the PEG-SS-PG/DOX micelles were further investigated in detail. Compared with free DOX, PEG-SS-PG/DOX micelles improved the biodistribution of DOX and prolonged blood circulation time. Finally, in vivo antitumor efficacy was studied using 4T1 breast tumor-bearing BALB/c mice. It was found that the tumor inhibition rate of PEG-SS-PG/DOX was up to 86.32%, indicating greatly effective antitumor performance. Taken together, PEG-SS-PG micelles can encapsulate DOX via electrostatic interaction to form tight micelles and possess redox and pH dual-responsive release of DOX and highly effective inhibition of tumor growth, which have potential application for the treatment of tumors.