Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE, 68198, United States; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE, 68198, United States.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE, 68198, United States; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE, 68198, United States; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198, United States; Eppley Cancer Center, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE, 68198, United States.
Eur J Med Chem. 2019 Sep 1;177:386-400. doi: 10.1016/j.ejmech.2019.05.068. Epub 2019 May 25.
We explored the approach of using an analog of E-64, a well-known and hydrophilic cysteine cathepsin (CC) inhibitor, as a potent cysteine cathepsin-trapping agent (CCTA) to improve the tumor retention of low-molecular-weight, receptor-targeted radiopharmaceuticals. The synthesized hydrophilic CCTA-incorporated, NTSR1-targeted agents demonstrated a substantial increase in cellular retention upon uptake into the NTRS1-positive HT-29 human colon cancer cell line. Similarly, biodistribution studies using HT-29 xenograft mice revealed a significant and substantial increase in tumor retention for the CCTA-incorporated, NTSR1-targeted agent. The intracellular trapping mechanism of the CCTA-incorporated agents by macromolecular adduct formation was confirmed using multiple in vitro and in vivo techniques. Furthermore, utilization of the more hydrophilic CCTA greatly increased the hydrophilicity of the resulting NTSR1-targeted constructs leading to substantial decreases in most non-target tissues in contrast to our previously reported dipeptidyl acyloxymethyl ketone (AOMK) constructs. This work further confirms that the CCTA trapping approach can make significant improvements in the clinical potential of NTSR1-and other receptor-targeted radiopharmaceuticals.
我们探讨了使用 E-64 的类似物作为有效的半胱氨酸组织蛋白酶（CC）捕获剂（CCTA）来提高低分子量受体靶向放射性药物在肿瘤中的保留的方法。合成的亲水性 CCTA 结合的、NTSR1 靶向的试剂在摄取到 NTRS1 阳性 HT-29 人结肠癌细胞系时表现出细胞内保留的显著增加。同样，使用 HT-29 异种移植小鼠的生物分布研究表明，CCTA 结合的、NTSR1 靶向的试剂在肿瘤保留方面有显著增加。通过多种体外和体内技术证实了 CCTA 结合的试剂通过大分子加合物形成的细胞内捕获机制。此外，与我们之前报道的二肽酰氧基甲基酮（AOMK）构建体相比，使用更亲水性的 CCTA 大大增加了所得 NTSR1 靶向构建体的亲水性，导致大多数非靶组织的含量显著降低。这项工作进一步证实，CCTA 捕获方法可以显著提高 NTSR1 和其他受体靶向放射性药物的临床潜力。
