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−W₃. 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.

中文翻译：

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优化的5-氟尿苷前药，可与阿霉素共同负载于临床相关脂质体

基于脂质体的药物递送系统具有更好的药物耐受性和更长的循环时间，但是由于将不同化学特性的两种药物共囊封存在固有的困难，因此通常针对单一药物进行了优化。在这里，我们设计和测试基于5-氟尿嘧啶，5-氟尿嘧啶（5FUR）的核糖基化核苷形式的前药，其最终目的是与阿霉素（DOX）共包裹在脂质体中。为了提高5FUR的载量，我们开发了两种5FUR前药，它们涉及一个或三个色氨酸（W）部分的缀合，分别称为5FUR-W和5FUR-W ₃。5FUR-W与5FUR-W3相比具有更高的化学稳定性，并且色氨酸水解产生的副产物更少，从而提高了负载量。封装了5FUR-W：DOX的各种药物比率，用于在高度侵袭性的4T1鼠类乳腺癌模型中进行体内测试。在概念验证研究中证明脂质体摩尔比为2.5 5FUR-W：DOX与未治疗的对照组相比肿瘤大小减少62.6％，与临床阿霉素脂质体相比减少33％包囊的脂质体。我们相信，新的前药5FUR-W通过减少色氨酸水解产生的副产物的数量，同时还允许上样的灵活性，展示了具有临床可翻译性的前药设计。