Study On The Anti-atherosclerotic Effects Of Hydroxypropyl-beta-Cyclodextrin Inclusion Complex

Cardiovascular diseases(CVDs)are chronic diseases with a relative high morbidity and mortality among which atherosclerotic CVD(ASCVD)is well known.During the development of atherosclerosis,multiple factors/steps mediate the thickening of aortic intima,the formation of atherosclerotic lesions,the thrombosis,and eventually the shortage of blood supply in specific organs/tissues and the onset of the ASCVD.Our previous studies showed that hydroxypropyl-β-cyclodextrin(HPβCD)treatment during the early stage of atherosclerosis can reduce blood lipids and atherosclerotic plaques and effectively delay the occurrence of atherosclerosis in mice.Moreover,the lipid-loaded HPβCD still has the anti-atherosclerotic efficacy.Therefore,we speculate that the drug-loaded HPβCD inclusion complexes may also have anti-atherosclerotic effect.To verify this hypothesis,this study recruited Levofloxacin(or Lev,a broad-spectrum antibacterial drug but without reported anti-atherosclerotic efficacy)as a drug to be loaded in the HPβCD inclusion complex.In this study,the HPβCD inclusion complex loaded with levofloxacin was prepared in vitro and characterized by X-ray diffractometer(XRD),Fourier transform infrared spectroscopy(FT-IR),and proton nuclear magnetic resonance spectroscopy(H1 NMR).The data showed that the preparation of the inclusion complex was successful.Moreover,the encapsulation efficiency and the drug loading efficiency of levofloxacin were determined by high performance liquid chromatography(HPLC).In animal experiments,ApoE-/-C57BL/6 mice were randomly divided into five groups including the control group,the model group,the HPβCD alone group,the HPβCD-Lev inclusion complex group,and the levofloxacin alone group.The drugs were intravenously administered every two days via tail vein of mice fed a high fat diet.Three months later,blood lipids were measured,atherosclerotic plaques in aortic full length,aortic arch,and aortic root were observed and compared,as well as the liver,the spleen,the lung,and the kidney.The pharmacokinetic experiment and the drug tissue distribution experiment also were performed.According to the animal experimental data,the following results/conclusions are obtained:(1)The HPβCD-levofloxacin inclusion complex has a significant effect on delaying atherosclerosis;(2)levofloxacin per se has a significantly inhibitory effect on atherosclerosis;(3)the levofloxacin loading of HPβCD helps to sustain the release of levofloxacin and to reduce the side effects of levofloxacin.Surprisingly but interestingly,for the first time,this study reveals the potential anti-atherosclerotic effect of levofloxacin which needs to be further studied in the future.