Institute of Molecular Medicine (IMM), State Key Laboratory of Oncogenes and Related Genes Renji Hospital, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering , Shanghai Jiao Tong University , Shanghai 200240 , China.
Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province , Hunan University , Changsha , Hunan 410082 , China.
Anal Chem. 2019 Nov 5;91(21):13818-13823. doi: 10.1021/acs.analchem.9b03281. Epub 2019 Oct 24.
Aptamer-drug conjugates (ApDCs) are emerging as targeted therapeutic drugs that can effectively broaden the chemotherapeutic window with higher efficacy and less toxicity. They show promising targeted tumor-killing effects both and . However, the mechanisms underlying the cellular internalization and transport of ApDCs remain unclear, and no systematic study on this topic has been reported. Therefore, we herein investigated the endocytic internalization and subsequent transport of ApDCs in mammalian cells through single-particle tracking. We found that ApDC enters the cells mainly by caveolin-mediated endocytosis and that it exhibits cytoskeleton-dependent transport, along microfilaments and microtubules, to acidic endosomes near the cell nucleus in cytoplasm. We also found that the cellular uptake pathways of ApDCs are identical to those of the aptamer itself, confirming that aptamers play a prominent role in the internalization of ApDCs. This study extends our understanding of the internalization and transport process of ApDCs such that the results could serve as the theoretical foundation for designing new ApDCs and, in turn, promoting cancer-targeted therapy.
适体-药物偶联物（ApDCs）作为靶向治疗药物正在兴起，它们可以通过提高疗效和降低毒性来有效拓宽化疗窗口。它们在体内和体外都表现出有前途的靶向肿瘤杀伤作用。然而，ApDC 进入细胞的细胞内化和运输机制仍不清楚，也没有对此主题的系统研究。因此，我们通过单颗粒示踪法研究了 ApDC 在哺乳动物细胞中的内吞作用和随后的运输。我们发现 ApDC 主要通过网格蛋白介导的内吞作用进入细胞，并且沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管沿着微丝和微管进入细胞。我们还发现，ApDC 的细胞摄取途径与适体本身的摄取途径相同，这证实了适体在 ApDC 的内化中起重要作用。这项研究扩展了我们对 ApDC 内化和运输过程的理解，为设计新型 ApDC 提供了理论基础，并进而促进了癌症靶向治疗。
