结合
白蛋白
药代动力学
阿霉素
前药
体内分布
化学
药理学
血清白蛋白
体内
人血清白蛋白
连接器
生物利用度
肽
生物化学
医学
体外
生物
化疗
内科学
数学分析
生物技术
数学
操作系统
计算机科学
作者
Parisa Yousefpour,Lucie Ahn,Joel Tewksbury,Soumen Saha,Simone A. Costa,Joseph J. Bellucci,Xinghai Li,Ashutosh Chilkoti
出处
期刊:Small
[Wiley]
日期:2019-02-13
卷期号:15 (12): e1804452-e1804452
被引量:59
标识
DOI:10.1002/smll.201804452
摘要
Short circulation time and off-target toxicity are the main challenges faced by small-molecule chemotherapeutics. To overcome these shortcomings, an albumin-binding peptide conjugate of chemotherapeutics is developed that binds specifically to endogenous albumin and harnesses its favorable pharmacokinetics and pharmacodynamics for drug delivery to tumors. A protein-G-derived albumin-binding domain (ABD) is conjugated with doxorubicin (Dox) via a pH-sensitive linker. One to two Dox molecules are conjugated to ABD without loss of aqueous solubility. The albumin-binding ABD-Dox conjugate exhibits nanomolar affinity for human and mouse albumin, and upon administration in mice, shows a plasma half-life of 29.4 h, which is close to that of mouse albumin. Additionally, 2 h after administration, ABD-Dox exhibits an approximately 4-fold higher concentration in the tumor than free Dox. Free Dox clears quickly from the tumor, while ABD-Dox maintains a steady concentration in the tumor for at least 72 h, so that its relative accumulation at 72 h is ≈120-fold greater than that of free Dox. The improved pharmacokinetics and biodistribution of ABD-Dox result in enhanced therapeutic efficacy in syngeneic C26 colon carcinoma and MIA PaCa-2 pancreatic tumor xenografts, compared with free Dox and aldoxorubicin, an albumin-reactive Dox prodrug currently in clinical development.
科研通智能强力驱动
Strongly Powered by AbleSci AI