Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry of Education and Key Laboratory of Polymeric Materials & Application Technology of Hunan Province, Xiangtan University, Xiangtan 411105, China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
Biomater Sci. 2023 Jul 25;11(15):5195-5204. doi: 10.1039/d3bm00664f.
Tumor-active-targeting drugs such as antibody-drug conjugates have emerged as promising accurate therapeutic agents. However, their complex preparations risk compromising the targeting ability of the fragment antigen binding (Fab) region and promote aggregation over long-term storage. Here, we propose a tumor-active-targeting nanomedicine, aPDL1-PLG-MMAE, that effectively targets programmed death-ligand 1 (PDL1) high-expressing tumors and delivers monomethyl auristatin E (MMAE). aPDL1-PLG-MMAE consists of an anti-PDL1 monoclonal antibody (aPDL1) and poly(L-glutamic acid) (PLG) grafted Fc-III-4C peptide/Val-Cit-PAB-MMAE (Fc-PLG-MMAE). Fc-PLG-MMAE was obtained by conjugating the Fc-III-4C peptide and Val-Cit-PAB-MMAE to PLG amide condensation. The strong affinity between the fragment crystallizable (Fc) region of aPDL1 and the Fc-III-4C peptide enabled aPDL1 and Fc-PLG-MMAE to self-assemble into aPDL1-PLG-MMAE after four hours of coincubation in PBS. As this nanomedicine can be quickly prepared for immediate use, the required antibodies can be stored separately from the Fc-PLG-MMAE portion for extended periods, which also facilitates transport. Moreover, aPDL1-PLG-MMAE demonstrated robust tumor recognition and targeting effects on MC38 colon cancer cells, resulting in potent therapeutic efficacy without significant toxicities.
肿瘤激活靶向药物，如抗体药物偶联物，已经成为很有前途的精准治疗药物。然而，它们复杂的制备方法有可能损害片段抗原结合 (Fab) 区域的靶向能力，并在长期储存过程中促进聚集。在这里，我们提出了一种肿瘤激活靶向纳米药物，即 aPDL1-PLG-MMAE，它能够有效地靶向程序性死亡配体 1 (PDL1) 高表达肿瘤，并递送单甲基奥瑞他汀 E (MMAE)。aPDL1-PLG-MMAE 由抗 PD-L1 单克隆抗体 (aPDL1) 和聚 L-谷氨酸 (PLG) 接枝 Fc-III-4C 肽/缬氨酸-瓜氨酸-PAB-MMAE (Fc-PLG-MMAE) 组成。Fc-PLG-MMAE 通过将 Fc-III-4C 肽和缬氨酸-瓜氨酸-PAB-MMAE 与 PLG 酰胺缩合而获得。aPDL1 的 Fc 区与 Fc-III-4C 肽之间的强亲和力使得 aPDL1 和 Fc-PLG-MMAE 在 PBS 中共孵育四小时后能够自组装成 aPDL1-PLG-MMAE。由于这种纳米药物可以快速制备以供立即使用，因此所需的抗体可以与 Fc-PLG-MMAE 部分分开储存较长时间，这也便于运输。此外，aPDL1-PLG-MMAE 对 MC38 结肠癌细胞表现出强大的肿瘤识别和靶向作用，具有强大的治疗效果，而没有明显的毒性。
