Development and Evaluation of Liposomal Celastrol-PROTACs for Treating Triple-Negative Breast Cancer.

Background: Based on our previous study, Celastrol-based proteolysis-targeting chimeras (Celastrol-PROTACs) were shown to induce apoptosis in 4T1 cells by selectively degrading GRP94 and CDK1/4 through the endogenous ubiquitin-proteasome system. However, their clinical translation is limited by poor solubility, low targeting efficiency, and liver and kidney toxicity. Methods: To address these limitations, we developed a pegylated liposomal formulation of Celastrol-PROTACs (Lip-Celastrol-PROTACs) and evaluated its therapeutic efficacy and safety profile. Results: The tumor volume of the mice in the Celastrol-PROTACs solution group (286 ± 79 mm³) was significantly larger than that of those in the Lip-Celastrol-PROTACs group (229 ± 49 mm³) on day 18 after intravenous administration (p < 0.01). This difference between the two groups was statistically significant (p < 0.01). Notably, the Celastrol-PROTACs group exhibited significantly greater weight loss compared to the Lip-Celastrol-PROTACs group (p < 0.001). In vivo toxicity assessments revealed that the levels of AST and BUN in the Celastrol-PROTACs group were 27.93 ± 4.88 U/L and 12.36 ± 1.33 μmol/L, respectively, whereas those in the Lip-Celastrol-PROTACs group were found to be 7.92 ± 0.94 U/L and 8.19 ± 0.67 μmol/L, respectively. These findings indicate a statistically significant difference between the two formulations (p < 0.01). Conclusions: Our research demonstrated that pegylated liposomes could improve the targeting efficiency and minimize the toxicity of PROTACs, thereby improving overall therapeutic efficacy. These findings indicated that Lip-Celastrol-PROTACs represent a promising strategy for future clinical applications.