Abstract

Aiming to address the insufficient endocytosis ability of traditional albumin drug conjugates, this paper reports elegant guanidine modification to improve efficacy for the first time. A series of modified albumin drug conjugates were designed and synthesized with different structures, including guanidine (GA), biguanides (BGA) and phenyl (BA), and different quantities of modifications. Then, the endocytosis ability and in vitro/vivo potency of albumin drug conjugates were systematically studied. Finally, a preferred conjugate A4 was screened, which contained 15 BGA modifications. Conjugate A4 maintains spatial stability similar to that of the unmodified conjugate AVM and could significantly enhance endocytosis ability (p*** = 0.0009) compared with the unmodified conjugate AVM. Additionally, the in vitro potency of conjugate A4 (EC₅₀ = 71.78 nmol in SKOV3 cells) was greatly enhanced (approximately 4 times) compared with that of the unmodified conjugate AVM (EC₅₀ = 286.00 nmol in SKOV3 cells). The in vivo efficacy of conjugate A4 completely eliminated 50% of tumors at 33 mg/kg, which was significantly better than the efficacy of conjugate AVM at the same dose (P** = 0.0026). In addition, theranostic albumin drug conjugate A8 was designed to intuitively realize drug release and maintain antitumor activity similar to conjugate A4. In summary, the guanidine modification strategy could provide new ideas for the development of new generational albumin drug conjugates.

摘要

针对传统白蛋白药物缀合物内吞能力不足的问题，本文首次报道了优雅的胍修饰以提高疗效。设计并合成了一系列不同结构的修饰白蛋白药物缀合物，包括胍（GA）、双胍（BGA）和苯基（BA），以及不同修饰量。然后，系统研究了白蛋白药物缀合物的内吞能力和体外/体内效力。最后，筛选出优选的缀合物A4，其含有15个BGA修饰。缀合物 A4 保持与未修饰缀合物 AVM 类似的空间稳定性，并且可以显着增强内吞能力（p*** = 0.0009) 与未修饰的缀合物 AVM 相比。此外，与未修饰的缀合物AVM（SKOV3细胞中EC _{50 = 286.00 nmol）相比，缀合物A4（SKOV3细胞中EC 50 = 71.78 nmol）的}体外效力大大增强（约4倍） 。结合物 A4 33 mg/kg 的体内功效完全消除了 50% 的肿瘤，明显优于相同剂量结合物 AVM 的功效（P** = 0.0026)。此外，治疗诊断白蛋白药物缀合物A8旨在直观地实现药物释放并保持与缀合物A4类似的抗肿瘤活性。综上所述，胍修饰策略可为新一代白蛋白药物偶联物的开发提供新思路。