Chiral 5-fluorouracil-arginine cocrystals screened by wet powder grinding method: Leading to synergistic anti-tumor and alleviate cardiotoxicity

Arginine (ARG) is a precursor for producing NO, which can relax vascular smooth muscle. We herein report cocrystals screened by powder grinding using chiral ARG to improve the bioavailability of 5-fluorouracil (5-FU) and alleviate 5-FU induced cardiotoxicity. The results of powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) inferred the formation of new solid phases. Hydrogen bonding interactions between C=O group and N-H were supported by Fourier transform infrared (FTIR) spectroscopy. The spectra intensity of circular dichroism (CD) of cocrystals were higher than that of ARG after combined with non-optically active 5-FU. The bioavailability and cytotoxicity of 5-FU were enhanced by cocrystallization. Notably, L-cocrystal prepared using biologically active L-ARG released lower dose NO in human umbilical vein endothelial cells (HUVEC) cells than that of D-cocrystal. D-cocrystal performed higher NO release ability by non-enzymatic pathway, indicating a greater potential to alleviate cardiotoxicity. 5-FU-induced cardiotoxicity in rats was effectively alleviated, proved by the least increased LDH, cTnI and CK-MB level induced by D-cocrystal.