ROS-activated prodrug nano-assemblies based on cinnamaldehyde-modified paclitaxel for treating breast cancer

Purpose One of the hallmarks of cancer cells is their elevated levels of reactive oxygen species (ROS) compared with normal cells. Capitalizing on this, a novel paclitaxel (PTX, a first-line chemotherapeutic agent) prodrug was designed and synthesized by attaching a cinnamaldehyde (CA) molecule to PTX via a ROS-responsive thioacetal group. Methods The paclitaxel prodrug (PTX-S-CA) prodrug was synthesized and characterized, followed by self-assembly into nanoparticles (NPs) using DSPE-PEG 2K as a stabilizer, forming PTX-S-CA/DSPE-PEG 2K NPs. The physicochemical properties of the NPs were evaluated, which included drug-loading capacity, encapsulation efficiency, and plasma stability. In vitro cytotoxicity assays were conducted on cancer cells, and in vivo anti-tumor efficacy was assessed in a murine tumor model. The pharmacokinetics of the NPs were also studied in rats. Results In the tumor microenvironment, the ROS-sensitive thioacetal group in PTX-S-CA was degraded due to high ROS levels, leading to the release of both PTX and CA. The released CA synergistically enhanced the anti-tumor effects of PTX by inducing additional ROS production within the mitochondria. The NPs demonstrated a high loading capacity and encapsulation efficiency for PTX-S-CA, high cytotoxicity against cancer cells, excellent anti-tumor effects on mice, and high plasma stability in rats. Conclusion The use of the NP drug delivery platform served as a potentially effective therapeutic strategy for treating tumors, especially breast cancer.