In vitro/vivo evaluation of novel mitochondrial targeting charge-reversal polysaccharide-based antitumor nanoparticle.

Mitochondrial targeting drug delivery systems have made unprecedented progress in tumor treatment. Nevertheless, the stability of systemic circulation and the effectiveness of tumor accumulation are the basis for achieving tumor subcellular targeting. This study aims to overcome the biological barrier while improving the mitochondria-targeted effect of nanoparticles based on natural polysaccharides. Novel polysaccharide-based nanoparticles, with tumor microenvironment-responsive charge-reversal and mitochondrial targeting abilities, were prepared in our study. Curcumin (Cur) was loaded into the core of a positively charged chitosan oligosaccharide (COS) derivative with mitochondrial targeting ability, and a negatively charged shell based on angelica sinensis polysaccharide (AS) derivative was wrapped in the surface of the core. At the same time, the pH-sensitive borate ester bond was formed between the shell and the core. In vitro experiments showed that mitochondrial-targeted core-shell nanoparticles achieved charge-reversal and release more Cur in the acidic tumor microenvironment. After entering into the tumor cells, the lysosomes escape was effectively realized, and more Cur was transmitted to the mitochondria. This process led to the enhancement of the cytotoxicity, the reduction of the mitochondrial membrane potential and the activation of the apoptotic pathway. The results of in vivo experiments showed that the core-shell nanoparticles efficiently delivered the drug to the tumor site and significantly prolonged the retention time of the drug in the tumor tissue. At the same time, it had excellent antitumor activity and in vivo safety for tumor-bearing nude mice.