A water-soluble nucleolin aptamer-paclitaxel conjugate for tumor-specific targeting in ovarian cancer.

Abstract

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.

• Authors: Fangfei Li, Jun Lu, Jin Liu, Chao Liang, Maolin Wang, Luyao Wang, Defang Li, Houzong Yao, Qiulong Zhang, Jia Wen, Zong-Kang Zhang, Jie Li, Quanxia Lv, Xiaojuan He, Baosheng Guo, Daogang Guan, Yuanyuan Yu, Lei Dang, Xiaohao Wu, Yongshu Li, Guofen Chen, Feng Jiang, Shiguo Sun, Bao-Ting Zhang, Aiping Lu, Ge Zhang
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 1390 (11 09 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29123088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Aptamers, Peptide
• Drug Carriers
• Phosphoproteins
• RNA-Binding Proteins
• Cathepsin B
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Aptamers, Peptide (chemistry, pharmacology)
• Cathepsin B (metabolism)
• Cell Line, Tumor
• Drug Carriers (chemical synthesis, chemistry, pharmacology)
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Ovarian Neoplasms (drug therapy, pathology)
• Paclitaxel (chemistry, pharmacology)
• Phosphoproteins (chemistry, pharmacology)
• RNA-Binding Proteins (chemistry, pharmacology)
• Xenograft Model Antitumor Assays
• Nucleolin