posted on 2024-10-11, 14:36authored byYue-Ming Yu, Xue-Jie Li, Fan-Zhi Bu, Zhi-Long Zhao, Zhi-Yong Wu, Yan-Tuan Li
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.