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Proteolysis-targeting chimaera (PROTAC) has received extensive attention in industry. However, there are still some limitations that hinder its further development. In a previous study, our group first demonstrated that the HSP90 degrader BP3 synthesised by the principle of PROTACs showed therapeutic potential for cancer. However, its application was hindered by its high molecular weight and water insolubility. Herein, we aimed to improve these properties of HSP90-PROTAC BP3 by encapsulating it into human serum albumin nanoparticles (BP3@HSA NPs). The results demonstrated that BP3@HSA NPs showed a uniform spherical shape with a size of 141.01 ± 1.07 nm and polydispersity index < 0.2; moreover, BP3@HSA NPs were more readily taken up by breast cancer cells and had a stronger inhibitory effect in vitro than free BP3. BP3@HSA NPs also demonstrated the ability to degrade HSP90. Mechanistically, the improved inhibitory effect of BP3@HSA NPs on breast cancer cells was related to its stronger ability to induce cell cycle arrest and apoptosis. Furthermore, BP3@HSA NPs improved PK properties and showed stronger tumour suppression in mice. Taken together, this study demonstrated that hydrophobic HSP90-PROTAC BP3 nanoparticles encapsulated by human serum albumin could improve the safety and antitumour efficacy of BP3. [ABSTRACT FROM AUTHOR]

Heat shock protein 90 (HSP90) is involved in the stabilization and activation of oncoproteins, rendering it essential for oncogenic transformation. However, the HSP90 inhibitors evaluated to date have not led to the expected effects in cancer therapy. Herein, we systematically described the design, synthesis, and evaluation of HSP90 degraders based upon the proteolysis-targeting chimera (PROTAC) strategy. The results showed that the candidate compound 16b (BP3) potently degraded HSP90 and effectively inhibited the growth of human breast cancer cells. When used as a single agent, BP3 led to effective tumor suppression in mice. These findings demonstrate that our HSP90-targeting PROTAC strategy has potential novel applications in breast cancer therapy. [Display omitted] • A series of PROTACs targeting HSP90 were designed for the first time and subsequently synthesized. • BP3 had a certain degradation effect on HSP90 protein in MCF-7 cells. • BP3 had a significant inhibition of breast cancer cells in vitro or in vivo compared with control. [ABSTRACT FROM AUTHOR]