Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
Small. 2019 Mar;15(12):e1804452. doi: 10.1002/smll.201804452. Epub 2019 Feb 13.
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.
小分子化学疗法面临的主要挑战是循环时间短和脱靶毒性。为了克服这些缺点，开发了一种化学疗法的白蛋白结合肽缀合物，它特异性地与内源性白蛋白结合，并利用其有利的药代动力学和药效学将药物递送到肿瘤。通过 pH 敏感的接头将源自蛋白 G 的白蛋白结合域 (ABD) 与阿霉素 (Dox) 缀合。ABD 与 Dox 之间不损失水溶解度地缀合一到两个 Dox 分子。白蛋白结合 ABD-Dox 缀合物对人源和鼠源白蛋白具有纳摩尔亲和力，并且在小鼠中给药后，其血浆半衰期为 29.4 h，接近于鼠源白蛋白。此外，给药后 2 h，ABD-Dox 在肿瘤中的浓度比游离 Dox 高约 4 倍。游离 Dox 从肿瘤中迅速清除，而 ABD-Dox 在肿瘤中保持稳定的浓度至少 72 h，因此其在 72 h 的相对积累比游离 Dox 高约 120 倍。ABD-Dox 的改善的药代动力学和生物分布导致与游离 Dox 和 aldoxorubicin（目前正在临床开发中的白蛋白反应性 Dox 前药）相比，在同源 C26 结肠癌细胞和 MIA PaCa-2 胰腺肿瘤异种移植物中增强了治疗效果。
