Bromo and extraterminal domain (BET) inhibitors-PROteolysis TArgeting Chimera (BETi-PROTAC) is a new family of compounds that induce proteasomal degradation through the ubiquitination of the tagged to BET inhibitors Bromodomain proteins, BRD2 and BRD. The encapsulation and controlled release of BET-PROTACs through their vectorization with antibodies, like trastuzumab, could facilitate their pharmacokinetic and efficacy profile. Antibody conjugated nanoparticles (ACNPs) using PROTACs have not been designed and evaluated. In this pioneer approach, the commercial MZ1 PROTAC was encapsulated into the FDA-approved polymeric nanoparticles. The nanoparticles were conjugated with trastuzumab to guide the delivery of MZ1 to breast tumoral cells that overexpress HER2. These ACNPs were characterized by means of size, polydispersity index, and Z-potential. Morphology of the nanoparticles, along with stability and release studies, completed the characterization. MZ1-loaded ACNPs showed a significant cytotoxic effect maintaining its mechanism of action and improving its therapeutic properties.

中文翻译：

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BET-PROTAC的控制传递：乳腺癌中MZ1负载的聚合物抗体偶联纳米粒子的体外评估

溴和末端外域（BET）抑制剂-蛋白水解嵌合体（BETi-PROTAC）是一种新的化合物家族，通过标记的BET抑制剂Bromodomain蛋白，BRD2和BRD的泛素化诱导蛋白酶体降解。通过用抗体（如曲妥珠单抗）将其进行载体化，BET-PROTAC的包封和控制释放可以促进其药代动力学和功效谱。尚未设计和评估使用PROTAC的抗体偶联纳米颗粒（ACNP）。在这种开创性方法中，将商业MZ1 PROTAC封装在FDA批准的聚合物纳米颗粒中。将纳米颗粒与曲妥珠单抗缀合以指导将MZ1递送至过表达HER2的乳腺肿瘤细胞。这些ACNP通过尺寸，多分散指数和Z电位来表征。纳米颗粒的形态以及稳定性和释放性研究完成了表征。加载MZ1的ACNPs表现出显着的细胞毒性作用，维持其作用机理并改善其治疗性能。