ABSTRACT
PUE@PEG-PLGA micelles has excellent characteristics such as small particle size, high drug loading and slow drug release. The results of TEM electron microscopy showed that PUE@PEG-PLGA micelles had obvious core-shell structure. The critical micelle concentration(CMC) of PEG-PLGA micelles determined by pyrene assay was about 4.8 mg·L~(-1). Laser confocal experiments showed that PEG-PLGA micelles can enhance the cellular uptake of coumarin-6 and aggregate around the mitochondria; quantitative results of extracellular drug residues also indirectly confirmed that PEG-PLGA micelles can promote cellular uptake of the drug. Acute ischemic myocardial model rats were prepared by coronary artery ligation, and then the model rats were randomly divided into six groups: Sham operation group, model group, puerarin(PUE) group, as well as low-, mid-, and high-dose PUE@PEG-PLGA micelles groups. Drugs were given by iv administration 5 min after the ligation. The ST segment changes in the electrocardiogram were monitored; serum creatine kinase(CK), lactate dehydrogenase(LDH), aspartate aminotransferase(AST), and malondialdehyde(MDA) levels were detected and myocardial infarct size was also measured. Both PUE and PUE@PEG-PLGA micelles can reduce the elevated ST segment, reduce serum CK, LDH, AST and MDA levels, and reduce myocardial infarct size. The efficacy of PUE@PEG-PLGA medium and high dose groups was significantly better than that in the PUE group, and the efficacy in PUE@PEG-PLGA low dose group was basically equivalent to that in the PUE group. PUE@PEG-PLGA micelles can greatly improve the cardiomyocytes uptake of PUE, enhance the anti-acute myocardial ischemia effect of drugs, and reduce its dosage.
Subject(s)
Animals , Rats , Isoflavones , Pharmacology , Micelles , Myocardial Ischemia , Drug Therapy , Polyesters , Polyethylene Glycols , Random AllocationABSTRACT
Objective: To study the spectrum-activity relationships between the anti-myocardial ischaemia activity and the HPLC fingerprints of the formula, consisting of Angelicae Sinensis Radix-Chuanxiong Rhizoma supercritical fluid extraction (AC-SFE) and Carthami Flos (CF) solvent-extracted extracts. Methods: The rat model of acute myocardial ischemia was established by applying left anterior descending coronary ligation, and bivariate correlation analysis (BCA) and multivariate regression analysis (MRA) were used to investigate the spectrum-activity relationship between fingerprints and anti-myocardial ischaemia activity. LC-MS was used for peak assignment. Results: Eight peaks of AC-SFE were negatively correlated with the infarct size ratio (ISR) and the serum lactate dehydrogenase (LDH), and four of them were significantly correlated. Peak 8 (quercetin-3-O-β-D-galactose glycosides-4'-O-β-D-pyranglucoside) from CF was positively correlated with the efficacy. Study by regression analysis showed four peaks were in regression equations. LC-MS showed 16 peaks, among which 12 were correlated peaks. Conclusion: Ferulic acid (peak 13), senkyunolide H (peak 15), 3-hydroxy butylphthalide (peak 16), senkyunolide A (peak 18), 3-butylphthalide (peak 19), ligustilide (peak 20), dibutyl phthalide (peak 21), and phthalide (peak 17) of AC-SFE and peak 1 (4-methoxy-6-[3, 4, 5-trihydroxy-6-[[3, 4, 5-trihydroxy-6 (hydroxymethyl) tetra-hydropyran-2-yl]oxymethyl] tetrahydropyran-2-yl]oxy-cyclohexane-1, 2, 3, 5-tetrol) and peak 2 (3-{[6-O-(D-Galactopyranosyl)-β-D- galacto-pyrano-syl]oxy}-1,2-propanediyl diacetate) of CF might be the material foundation for the anti-myocardial ischaemia activity. Peak 8 might not be able to relieve myocardial ischaemia.