Department of Chemistry & Biochemistry , University of California San Diego , La Jolla , California 92093 , United States.
Departments of Chemistry, Materials Science & Engineering, Biomedical Engineering, Chemistry of Life Processes Institute, International Institute for Nanotechnology, Simpson Querrey Institute , Northwestern University , Evanston , Illinois 60208 , United States.
J Am Chem Soc. 2019 Jul 31;141(30):11765-11769. doi: 10.1021/jacs.9b04272. Epub 2019 Jul 18.
We describe the design, synthesis, and antitumor activity of an 18 carbon α,ω-dicarboxylic acid monoconjugated via an ester linkage to paclitaxel (PTX). This 1,18-octadecanedioic acid-PTX () prodrug readily forms a noncovalent complex with human serum albumin (HSA). Preservation of the terminal carboxylic acid moiety on enables binding to HSA in the same manner as native long-chain fatty acids (LCFAs), within hydrophobic pockets, maintaining favorable electrostatic contacts between the ω-carboxylate of and positively charged amino acid residues of the protein. This carrier strategy for small molecule drugs is based on naturally evolved interactions between LCFAs and HSA, demonstrated here for PTX. shows differentiated pharmacokinetics, higher maximum tolerated doses and increased efficacy in multiple subcutaneous murine xenograft models of human cancer, as compared to two FDA-approved clinical formulations, Cremophor EL-formulated paclitaxel (crPTX) and Abraxane (nanoparticle albumin-bound (nab)-paclitaxel).
我们描述了一种通过酯键连接到紫杉醇（PTX）的 18 个碳原子的α，ω-二羧酸的设计、合成和抗肿瘤活性。这种 1,18-十八烷二酸-PTX（）前药很容易与人血清白蛋白（HSA）形成非共价复合物。在 上保留末端羧酸部分，使其能够以与天然长链脂肪酸（LCFAs）相同的方式与 HSA 结合，位于疏水性口袋内，保持 ω-羧酸与蛋白质带正电荷的氨基酸残基之间的有利静电接触。这种小分子药物的载体策略基于 LCFAs 和 HSA 之间自然进化的相互作用，在这里针对 PTX 进行了证明。与两种已获 FDA 批准的临床制剂，即聚氧乙基代蓖麻油制剂的紫杉醇（crPTX）和纳米白蛋白结合紫杉醇（nab-PTX）相比， 显示出不同的药代动力学特征，更高的最大耐受剂量和在多种人源癌症的皮下异种移植模型中的疗效增强。
