Stabilization of Paclitaxel-Conjugated Micelles by Cross-Linking with Cystamine Compromises the Antitumor Effects against Two- and Three-Dimensional Tumor Cellular Models.

Paclitaxel (PTX)-conjugated micelles provide a promising tool for the treatment of prostate cancer. Core cross-linking by incorporating a disulfide bridge is a useful approach to improving the in vivo stability of polymeric micelles. This paper aims to investigate the effects of different degrees of cross-linking on the antitumor efficacy of micelles formed by poly(ethylene glycol methyl ether acrylate)-b-poly(carboxyethyl acrylate) (POEGMEA-b-PCEA-PTX) block copolymer. Both two-dimensional (2D) and three-dimensional (3D) in vitro prostate tumor cell models were used to evaluate the un-cross-linked and cross-linked micelles. The cytotoxicity decreased with an increase in the degree of cross-linking upon being tested with 2D cultured cells, and all micelles remained less cytotoxic than free PTX. In the 3D prostate MCTS model, however, there was no statistical difference between the performance of un-cross-linked micelles and free PTX, while increasing cross-linking densities led to significantly relevant decreases in the antitumor efficacy of micelles. These results are contradictory to our previous research using an irreversible cross-linker (1,8-diaminooctane) to stabilize POEGMEA-b-PCEA-PTX conjugate micelles where it was shown that cross-linking accelerates and improves the effects of the micelles when compared to those of un-cross-linked micelles. Further studies that aim to investigate the underlying mechanisms of disulfide bonds when micelles are internalized into cells are desired.