Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China.
Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China.
Nat Commun. 2017 Nov 9;8(1):1390. doi: 10.1038/s41467-017-01565-6.
Paclitaxel (PTX) is among the most commonly used first-line drugs for cancer chemotherapy. However, its poor water solubility and indiscriminate distribution in normal tissues remain clinical challenges. Here we design and synthesize a highly water-soluble nucleolin aptamer-paclitaxel conjugate (NucA-PTX) that selectively delivers PTX to the tumor site. By connecting a tumor-targeting nucleolin aptamer (NucA) to the active hydroxyl group at 2' position of PTX via a cathepsin B sensitive dipeptide bond, NucA-PTX remains stable and inactive in the circulation. NucA facilitates the uptake of the conjugated PTX specifically in tumor cells. Once inside cells, the dipeptide bond linker of NucA-PTX is cleaved by cathepsin B and then the conjugated PTX is released for action. The NucA modification assists the selective accumulation of the conjugated PTX in ovarian tumor tissue rather than normal tissues, and subsequently resulting in notably improved antitumor activity and reduced toxicity.
紫杉醇（PTX）是癌症化疗中最常用的一线药物之一。然而，其较差的水溶性和在正常组织中无差别分布仍是临床面临的挑战。本研究设计并合成了一种高度水溶性的核仁素适体-紫杉醇偶联物（NucA-PTX），该偶联物能够选择性地将紫杉醇递送至肿瘤部位。通过将肿瘤靶向核仁素适体（NucA）与紫杉醇 2' 位的活性羟基通过组织蛋白酶 B 敏感的二肽键连接，NucA-PTX 在循环中保持稳定且无活性。NucA 促进偶联的 PTX 特异性摄取进入肿瘤细胞。一旦进入细胞，NucA-PTX 的二肽键连接物就会被组织蛋白酶 B 切割，然后释放出共轭的 PTX 发挥作用。NucA 修饰有助于共轭的 PTX 在卵巢肿瘤组织中的选择性积累，而不是在正常组织中，从而显著提高了抗肿瘤活性并降低了毒性。
