Drug–Drug\nCocrystal Alloy and Nanoformulation\nof Cytarabine: Optimized Biopharmaceutical Property and Synergistic\nAntitumor Efficacy

An integrated strategy by combining cocrystallization\nwith nanotechnology\nis developed to optimize in vitro/vivo performances of marine antitumor\ndrug cytarabine (ARA) and further obtain innovative insights into\nthe exploitation of cocrystal alloy nanoformulation. Therein, the\noptimization of properties and synergistic effects of ARA mainly depends\non assembling with uracil (U) and antitumor drug 5-fluorouracil (FU)\ninto the same crystal by cocrystallization technology, while the long-term\nefficacy is primarily maintained by playing the superiority of nanotechnology.\nAlong this line, the first cocrystal alloy of ARA, <i>viz.</i>, ARA-FU-U (0.6:0.4), is successfully obtained and then transformed\ninto a nanocrystal. Single-crystal X-ray diffraction analysis demonstrates\nthat this cocrystal alloy consists of two isomorphic cocrystals of\nARA, namely, ARA-FU and ARA-U, in 0.6:0.4 ratio. An <i>R</i><sub>2</sub><sup>2</sup>(8) hydrogen-bonding cyclic system formed\nby a cytosine fragment of ARA with U or FU can protect and stabilize\nthe amine group on ARA, laying the foundation for regulating its properties.\nThe <i>in vitro</i>/<i>in vivo</i> properties\nof the cocrystal alloy and its nanocrystals are investigated by theoretical\nand experimental means. It reveals that both the alloy and nanocrystal\ncan improve physicochemical properties and promote drug absorption,\nthus bringing to optimized pharmacokinetic behaviors. The nanocrystal\nproduces superior effects than the alloy that helps to extend therapeutic\ntime and action. Particularly, relative to the corresponding binary\ncocrystal, the synergistic antitumor activity of ARA and FU in the\ncocrystal alloy is heightened obviously. It may be that U contributes\nto reducing the degradation of FU, specifically increasing its concentration\nin tumors to enhance the synergistic effects of FU and ARA. These\nfindings provide new thoughts for the application of cocrystal alloys\nin the marine drug field and break fresh ground for cocrystal alloy\nformulations to optimize drug properties.