Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science, Qingdao, Shandong 266234, PR China.
School of Medicine, Linyi University, Linyi, Shandong 276000, PR China.
Mol Pharm. 2024 Nov 4;21(11):5716-5727. doi: 10.1021/acs.molpharmaceut.4c00733. Epub 2024 Oct 11.
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, , 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 (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 / 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.
一种通过将共晶结晶与纳米技术相结合的综合策略被开发出来，以优化海洋抗肿瘤药物阿糖胞苷（ARA）的体外/体内性能，并进一步为共晶合金纳米制剂的开发提供新的见解。在此，通过共晶结晶技术将 ARA 与尿嘧啶（U）和抗肿瘤药物 5-氟尿嘧啶（FU）组装到同一晶体中，主要优化 ARA 的性质和协同作用，而长期疗效主要通过发挥纳米技术的优势来维持。沿着这条路线，成功获得了 ARA 的第一个共晶合金 ARA-FU-U（0.6:0.4），然后将其转化为纳米晶体。单晶 X 射线衍射分析表明，该共晶合金由 ARA 的两个同晶共晶组成，即 ARA-FU 和 ARA-U，比例为 0.6:0.4。由 ARA 的胞嘧啶片段与 U 或 FU 形成的（8）氢键环状系统可以保护和稳定 ARA 上的氨基，为调节其性质奠定基础。通过理论和实验手段研究了共晶合金及其纳米晶体的性质。结果表明，合金和纳米晶体都可以改善物理化学性质并促进药物吸收，从而优化药代动力学行为。纳米晶体产生优于合金的效果，有助于延长治疗时间和作用。特别是，与相应的二元共晶相比，共晶合金中 ARA 和 FU 的协同抗肿瘤活性明显提高。这可能是因为 U 有助于降低 FU 的降解，特别是增加其在肿瘤中的浓度，以增强 FU 和 ARA 的协同作用。这些发现为共晶合金在海洋药物领域的应用提供了新的思路，并为共晶合金制剂优化药物性质开辟了新天地。
