Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia.
J Pharm Sci. 2021 Jan;110(1):489-499. doi: 10.1016/j.xphs.2020.10.021. Epub 2020 Oct 15.
Drug delivery to the lymphatic system is gaining increasing attention, particularly in fields such as immunotherapy where drug access to lymphocytes is central to activity. We have previously described a prodrug strategy that facilitates the lymphatic delivery of a model immunomodulator, mycophenolic acid (MPA) via incorporation into intestinal triglyceride transport pathways. The current study explored a series of structurally related glyceride and phospholipid mimetic prodrugs of MPA in an attempt to enhance lymph targeting and to better elucidate the design criteria for lipid mimetic prodrugs. MPA was conjugated to a glyceride or phospholipid backbone at various positions using different spacers employing ester, ether, carbonate and amide bonds. Patterns of prodrug hydrolysis were evaluated in rat digestive fluid, and lymphatic transport and plasma pharmacokinetics were assessed in lymph duct cannulated rats. Prodrugs with different spacers between MPA and the glyceride backbone resulted in up to 70-fold differences in gastrointestinal stability. MPA conjugation at the 2 position of the glyceride backbone and via an ester bond were most effective in promoting lymphatic transport. Phospholipid prodrug derivatives, or glyceride derivatives with MPA attached at the 1 position or when linked via ether, carbonate or amide bonds were poorly incorporated into lymphatic transport pathways.
药物递送至淋巴系统受到越来越多的关注，特别是在免疫疗法等领域，药物到达淋巴细胞对于其活性至关重要。我们之前描述了一种前药策略，通过将模型免疫调节剂霉酚酸（MPA）整合到肠甘油三酯转运途径中，促进 MPA 经淋巴递送至体内。本研究探索了一系列结构相关的甘油酯和磷脂类似物前药，旨在增强淋巴靶向性，并更好地阐明脂质类似物前药的设计标准。MPA 通过酯、醚、碳酸酯和酰胺键连接到不同位置的甘油酯或磷脂骨架上。在大鼠消化液中评估了前药的水解模式，并在淋巴导管插管大鼠中评估了淋巴转运和血浆药代动力学。MPA 与甘油酯主链之间不同间隔物的前药在胃肠道稳定性方面存在高达 70 倍的差异。MPA 与甘油酯主链 2 位的连接以及通过酯键的连接最有效地促进了淋巴转运。磷脂前药衍生物，或 MPA 连接在甘油酯主链 1 位或通过醚、碳酸酯或酰胺键连接的甘油酯衍生物，很少被纳入淋巴转运途径。
