Wu Debra, Vogus Douglas, Krishnan Vinu, Broto Marta, Pusuluri Anusha, Zhao Zongmin, Kapate Neha, Mitragotri Samir
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.
Wyss Institute of Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
Pharmaceutics. 2021 Jan 15;13(1):107. doi: 10.3390/pharmaceutics13010107.
Liposome-based drug delivery systems have allowed for better drug tolerability and longer circulation times but are often optimized for a single agent due to the inherent difficulty of co-encapsulating two drugs with differing chemical profiles. Here, we design and test a prodrug based on a ribosylated nucleoside form of 5-fluorouracil, 5-fluorouridine (5FUR), with the final purpose of co-encapsulation with doxorubicin (DOX) in liposomes. To improve the loading of 5FUR, we developed two 5FUR prodrugs that involved the conjugation of either one or three moieties of tryptophan (W) known respectively as, 5FUR-W and 5FUR-W. 5FUR-W demonstrated greater chemical stability than 5FUR-W3 and allowed for improved loading with fewer possible byproducts from tryptophan hydrolysis. Varied drug ratios of 5FUR-W: DOX were encapsulated for in vivo testing in the highly aggressive 4T1 murine breast cancer model. A liposomal molar ratio of 2.5 5FUR-W: DOX achieved a 62.6% reduction in tumor size compared to the untreated control group and a 33% reduction compared to clinical doxorubicin liposomes in a proof-of-concept study to demonstrate the viability of the co-encapsulated liposomes. We believe that the new prodrug 5FUR-W demonstrates a prodrug design with clinical translatability by reducing the number of byproducts produced by the hydrolysis of tryptophan, while also allowing for loading flexibility.
基于脂质体的药物递送系统能够实现更好的药物耐受性和更长的循环时间，但由于共包封两种化学性质不同的药物存在固有困难，通常仅针对单一药物进行优化。在此，我们设计并测试了一种基于5-氟尿嘧啶的核糖基化核苷形式5-氟尿苷（5FUR）的前药，最终目的是将其与阿霉素（DOX）共包封于脂质体中。为了提高5FUR的负载量，我们开发了两种5FUR前药，分别涉及一个或三个色氨酸（W）部分的缀合，分别称为5FUR-W和5FUR-W3。5FUR-W比5FUR-W3表现出更高的化学稳定性，并且在色氨酸水解产生较少可能副产物的情况下实现了更高的负载量。在高度侵袭性的4T1小鼠乳腺癌模型中，对不同药物比例的5FUR-W:DOX进行了体内测试。在一项概念验证研究中，脂质体摩尔比为2.5的5FUR-W:DOX与未治疗的对照组相比，肿瘤大小减少了62.6%，与临床阿霉素脂质体相比减少了33%，以证明共包封脂质体的可行性。我们认为，新的前药5FUR-W通过减少色氨酸水解产生的副产物数量，同时还允许负载灵活性，展示了一种具有临床可转化性的前药设计。
