Abstract：
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.
摘要：
蛋白水解靶向嵌合体(PROTAC)在工业上受到广泛关注。然而,仍有一些限制阻碍其进一步发展。在之前的研究中,我们的研究小组首先证明了通过PROTACs原理合成的HSP90降解剂BP3对癌症具有治疗潜力.然而,它的高分子量和水不溶性阻碍了它的应用。在这里，我们旨在通过将HSP90-PROTACBP3封装到人血清白蛋白纳米颗粒（BP3@HSANP）中来改善HSP90-PROTACBP3的这些特性。结果表明，BP3@HSA纳米粒子呈均匀的球形，尺寸为141.01±1.07nm，多分散指数<0.2；BP3@HSANP更容易被乳腺癌细胞吸收，并且在体外比游离BP3具有更强的抑制作用。BP3@HSANP也证明了降解HSP90的能力。机械上,BP3@HSANPs对乳腺癌细胞抑制作用的改善与其诱导细胞周期阻滞和凋亡的能力更强有关。此外，BP3@HSANP改善了PK特性，并在小鼠中显示出更强的肿瘤抑制作用。一起来看,这项研究表明，人血清白蛋白包裹的疏水性HSP90-PROTACBP3纳米颗粒可以提高BP3的安全性和抗肿瘤功效。
