开发了一种将共晶与纳米技术相结合的综合策略，以优化海洋抗肿瘤药物阿糖胞苷（ARA）的体外/体内性能，并进一步获得共晶合金纳米制剂开发的创新见解。其中，ARA的性质优化和协同作用主要依靠与尿嘧啶（U）和抗肿瘤药物5-氟尿嘧啶（FU）通过共晶技术组装成同一晶体，而长期疗效主要通过发挥优势来维持纳米技术。沿着这条路线，成功获得了第一个ARA共晶合金，即ARA-FU-U（0.6：0.4），然后将其转化为纳米晶。单晶X射线衍射分析表明，该共晶合金由两种ARA同构共晶组成，即ARA-FU和ARA-U，比例为0.6:0.4。 ARA的胞嘧啶片段与U或FU形成的R22(8)氢键环状体系可以保护和稳定ARA上的胺基，为调控其性质奠定基础。通过理论和实验手段研究了共晶合金及其纳米晶的体外/体内性能。结果表明，合金和纳米晶都可以改善理化性质并促进药物吸收，从而带来优化的药代动力学行为。纳米晶体比合金具有更好的效果，有助于延长治疗时间和作用。特别是，相对于相应的二元共晶，共晶合金中ARA和FU的协同抗肿瘤活性明显增强。 U可能有助于减少FU的降解，特别是增加其在肿瘤中的浓度，从而增强FU和ARA的协同作用。这些研究结果为共晶合金在海洋药物领域的应用提供了新思路，为共晶合金制剂优化药物性能开辟了新的天地。

An integrated strategy by combining cocrystallization with nanotechnology is developed to optimize in vitro/vivo performances of marine antitumor drug cytarabine (ARA) and further obtain innovative insights into the exploitation of cocrystal alloy nanoformulation. Therein, the optimization of properties and synergistic effects of ARA mainly depends on assembling with uracil (U) and antitumor drug 5-fluorouracil (FU) into the same crystal by cocrystallization technology, while the long-term efficacy is primarily maintained by playing the superiority of nanotechnology. Along this line, the first cocrystal alloy of ARA, viz., ARA-FU-U (0.6:0.4), is successfully obtained and then transformed into a nanocrystal. Single-crystal X-ray diffraction analysis demonstrates that this cocrystal alloy consists of two isomorphic cocrystals of ARA, namely, ARA-FU and ARA-U, in 0.6:0.4 ratio. An R22(8) hydrogen-bonding cyclic system formed by a cytosine fragment of ARA with U or FU can protect and stabilize the amine group on ARA, laying the foundation for regulating its properties. The in vitro/in vivo properties of the cocrystal alloy and its nanocrystals are investigated by theoretical and experimental means. It reveals that both the alloy and nanocrystal can improve physicochemical properties and promote drug absorption, thus bringing to optimized pharmacokinetic behaviors. The nanocrystal produces superior effects than the alloy that helps to extend therapeutic time and action. Particularly, relative to the corresponding binary cocrystal, the synergistic antitumor activity of ARA and FU in the cocrystal alloy is heightened obviously. It may be that U contributes to reducing the degradation of FU, specifically increasing its concentration in tumors to enhance the synergistic effects of FU and ARA. These findings provide new thoughts for the application of cocrystal alloys in the marine drug field and break fresh ground for cocrystal alloy formulations to optimize drug properties.