Preparation and Evaluation of Redox-Sensitive Cabazitaxel Cross-Linked Prodrug Micelles

By grafting lipoic acid (LA) onto the C-2 position of cabazitaxel (CTX), a modified cross-linked cabazitaxel (CTX-LA) has been successfully synthesized. Disulfide core-crosslinked CTX prodrug micelles (CTX-loaded CCMs) were prepared by a solid dispersion-thin film hydration method using a telodendrimer methoxy-poly(ethylene glycol)-poly(D,L-lactic acid)-end-capped with lipoic acid(mPEG-PLA-(LA)₄) as the carrier. The particle size distribution, encapsulation efficiency, drug loading and stability of the drug-loaded micelles were investigated by nano particle size analyzer, ultraviolet-visible spectrophotometer, transmission electron microscope (TEM), Fourier transform infrared (FT-IR), nuclear magnetic resonance hydrogen spectrum (¹H-NMR) and X-ray diffraction (XRD). The normal physiological environment was simulated to induce drug release in vitro. The acute toxicity was investigated with BALB/c Nude mice as a model, and the cytotoxicity and anti-tumor activity were investigated with A549 lung adenocarcinoma cells as a cell model. Results showed that the mean particle size of the prepared micelles was (26.09 ± 0.18) nm, the encapsulation rate was (97.43 ± 2.34)%, and the drug loading capacity was 8.94%. Meanwhile, the micelles had excellent colloidal stability, and had obvious sustained release effect and reduction responsiveness. In addition, the micelles significantly reduced the acute toxicity of CTX without significant cytotoxicity, and the drug tolerance dose was more than 2 times higher than that of the commercial available cabazitaxel formulation (Jevtana). The anti-tumor efficacy was significantly improved with a tumor growth inhibition rate of 99.06% in an A549 lung cancer xenograft model.