Research Status of Quercetin's Cardiovascular Protective Effects and Its Novel Dosage Forms

With the development and utilization of traditional Chinese medicine, quercetin and its derivatives have been discovered in various Chinese medicinal materials and foods, such as rutin, forsythia, onions, cranberries, and apples. Quercetin is one of the most extensively studied flavonoids, and its potent antioxidant and anti-inflammatory activities have been well-established, demonstrating strong biological activities and a wide range of pharmacological effects. Quercetin has therapeutic effects on cardiovascular diseases; however, due to its extremely low water solubility, poor oral absorption, and low bioavailability, research into the application of quercetin in novel dosage forms for cardiovascular diseases has garnered increasing attention.

1. Improving heart function and reducing myocardial hypertrophy

Studies have shown that quercetin can inhibit myocardial hypertrophy induced by abdominal aortic constriction and improve cardiac diastolic function. In primary cardiomyocytes, quercetin significantly reduces the surface area of angiotensin II-induced cardiomyocyte hypertrophy and atrial natriuretic factor (ANF) mRNA levels. Additionally, quercetin increases the activity of the proteasome GSK3. In spontaneously hypertensive rats, quercetin reduces hypertension and significantly decreases the ratio of left ventricular weight to body weight. In vitro experiments have found that quercetin inhibits leucine incorporation into H9C2 cells in a concentration-dependent manner and reduces the surface area of hypertrophied cells, indicating that quercetin can effectively inhibit angiotensin II-induced hypertrophy of H9C2 cells. Furthermore, inhibiting myocardial hypertrophy can effectively reduce mortality from cardiovascular diseases. In rats three weeks after abdominal aortic constriction surgery compared to sham-operated rats, the heart-to-body weight ratio increases, while myocardial hypertrophy is completely inhibited in the quercetin-treated surgical group, with a significant reduction in related malondialdehyde products. In the model group, the activities of ERK1/2, p38 MAPK, Akt, and GSK-3β significantly increase with the increase in pressure load. After treatment with quercetin, the activities of these proteins are inhibited, suggesting that quercetin can inhibit the development of pressure-induced myocardial hypertrophy and exert protective effects by reducing oxidative stress and inhibiting the activities of ERK1/2, p38 MAPK, Akt, and GSK-3β.

2.Antiplatelet and Antithrombotic Effects

Diabetes is associated with an increased risk of cardiovascular diseases. In a study using type 1 diabetic model mice, researchers explored the effects of quercetin on platelet function and the formation of carotid artery thrombosis induced by ferric chloride. The study found that diabetic model mice administered with quercetin maintained significantly higher blood flow velocities compared to those in the untreated control group. Furthermore, the quercetin-treated group significantly reduced diabetes-induced platelet hyperaggregability, indicating that quercetin can effectively inhibit thrombosis in diabetes and has potential as an antiplatelet agent in diabetes treatment. Additionally, quercetin inhibits platelet aggregation induced by collagen, adenosine diphosphate (ADP), and arachidonic acid, as well as agonist-induced GPIIb/IIIa activation. Quercetin also inhibits the extracellular secretion of platelet granules. It completely inhibits PI3K and Src kinases, moderately inhibits Akt1/2, and slightly inhibits p38 and ERK1/2. Combining quercetin with ADP and thromboxane A2 inhibitors can effectively inhibit platelet spreading. The antiplatelet aggregation effects of quercetin are also related to the inhibition of Fyn kinase activity and the tyrosine phosphorylation of Syk and PLCγ2.

3.Vasodilatory and Antihypertensive Effects

Clinical trials have shown that intake of quercetin at a dosage greater than 500 mg/day for over 8 weeks can effectively reduce both systolic and diastolic blood pressure. In animal studies, researchers observed that quercetin directly influences aortic pressure in renal artery hypertensive rats. Specifically, quercetin at concentrations of 5 to 10 mol/L was found to rapidly alleviate vascular pressure in acetylcholine-induced hypertensive rats, suggesting that quercetin lowers blood pressure by reducing vascular tone. The antihypertensive effects of quercetin have also been observed in spontaneously hypertensive rats.

4.Improvement of Coronary Blood Circulation

Researchers have studied the impact of quercetin on central hemodynamics and myocardial ischemia parameters in patients with stable coronary heart disease (CHD). Based on 24-hour Holter monitoring, the number of premature ventricular contractions (PVCs) significantly decreased under the influence of quercetin treatment, demonstrating quercetin's cardioprotective properties in CHD conditions. Studies investigating the effects of quercetin and its metabolites on U46619-induced contractions, using porcine coronary artery segments prepared for isometric tension recording or cGMP content measurements, have shown that quercetin selectively modulates cGMP-dependent relaxation and related tolerance in isolated porcine coronary arteries. By inhibiting receptor-mediated contractions of isolated porcine coronary arteries through an endothelium-dependent mechanism, quercetin can be beneficial in the treatment of angina pectoris patients.

Quercetin exhibits certain therapeutic effects in cardiovascular diseases; however, its low water solubility limits its bioavailability, thereby affecting its therapeutic efficacy. Although combining quercetin with other drugs can improve its poor oral absorption, its oral bioavailability remains low. To enhance the bioavailability and efficacy of quercetin, scholars worldwide have conducted numerous experiments to formulate it into various dosage forms, including nanoparticles, liposomes, self-microemulsions, solid dispersions, micelles, and inclusion complexes. These formulations not only improve the bioavailability of quercetin but also lay the foundation for its clinical application.

1. Nanoparticle Formulations

Quercetin nanoparticles based on polylactic-co-glycolic acid (PLGA) polymer were developed using the single-emulsion solvent evaporation technique and evaluated in vitro. The results showed that compared to pure quercetin, these nanoparticles exhibited better diuretic activity in vivo, suggesting that PLGA polymer-based nanoparticles could be a potential option for quercetin delivery. Oral administration of quercetin nanocrystals suspension significantly altered the pharmacokinetic profile of the drug in rats, enhancing its absorption and effectively improving oral bioavailability. Researchers developed double emulsions (DE) incorporating olive oil, linseed oil, and fish oil as the oil phase, with quercetin encapsulated in an oil-in-water (O/W) nanoemulsion (QN), allowing for free dispersion in the aqueous phase. This significantly improved the oxidative stability of DE/QN, and encapsulating quercetin within it enhanced the drug's stability. Additionally, comparative studies using in situ intestinal perfusion and relative bioavailability experiments in rats were conducted to investigate the in vitro and in vivo biological properties of quercetin suspension, phospholipid complexes, and nanostructured lipid carriers (NLCs). The results showed that quercetin NLCs improved the oral bioavailability of quercetin by enhancing its lipid and water solubility, thereby increasing passive permeation. Quercetin-loaded nanostructured lipid carriers (QT-NLCs) prepared using a low-temperature emulsification-evaporation-solidification method were found to promote quercetin penetration, increase its retention in the epidermis and dermis, and enhance its therapeutic efficacy.

2.Self-Microemulsifying Drug Delivery Systems (SMEDDS)

A quercetin-based SMEDDS formulation was optimized using a central composite design-response surface methodology. When the ratio of oleic acid, polyethylene glycol, glyceryl monooleate-polyoxyethylene (35) castor oil-diethylene glycol monoethyl ether was 27.0:55.6:17.4 (w:w:w), rapid emulsification was achieved with a solubility of 67.87 mg·g-1. Upon 50-fold dilution with water, the average particle size was 25.26 nm, and the Zeta potential was -6.73 mV. The prepared quercetin SMEDDS showed stable quality and a simple preparation process, providing a basis for the development of new quercetin formulations for use in the cardiovascular system.

Researchers have also developed a curcumin-quercetin SMEDDS (CUR-QUE-SMEDDS) delivery system using Capryol 90 as the oil phase, Cremophor RH40 as the surfactant, and Transcutol HP as the cosurfactant. The resulting CUR-QUE-SMEDDS was a clear liquid with good fluidity and stability, which could spontaneously form an oil-in-water (O/W) microemulsion upon contact with water. This formulation enhanced the solubility of the hydrophobic drugs curcumin and quercetin, improved the distribution of curcumin on the inflamed surface, promoted absorption, and leveraged their synergistic effects, thereby enhancing therapeutic efficacy.

3.Dispersions

Researchers introduced an innovative fluorescent cubosome dispersion based on a monooleate-based system, where dansyl groups were conjugated to the hydrophilic termini of the PEO-PPO-PEO block copolymer PF108. This novel fluorescently labeled block copolymer mixture effectively stabilized the cubic phase formulation in aqueous solutions and encapsulated quercetin without disrupting its morphology and structure. This new cubosome formulation has potential applications in molecular nanomedicine.

A quercetin solid dispersion was prepared using a combination of polyvinylpyrrolidone (PVP) and precipitated calcium carbonate (PCC) as the carrier. The solid dispersion of quercetin prepared with PVP and PCC as a mixed carrier exhibited rapid release properties, significantly improving the dissolution behavior of quercetin and demonstrating good stability.

4.Micelles

Mixed polymeric micelles (MPM) containing quercetin were prepared using the thin-film hydration method. In vitro release experiments demonstrated that MPM exhibited sustained release of quercetin compared to free quercetin. MPM was also highly stable in aqueous media and significantly improved the solubility of quercetin compared to pure quercetin.

A novel micellar carrier material, N-(4-imidazolylmethyl)-hydroxyethyl chitosan (MHC), was synthesized through chitosan derivatization. In vitro and in vivo release experiments of quercetin-MHC showed distinct sustained-release characteristics. Compared to quercetin solution, quercetin-MHC micelles significantly improved the drug retention time in vivo, with a marked increase in AUC, thereby enhancing its pharmacological efficacy.

Quercetin possesses a wide range of pharmacological activities, particularly in cardiovascular medicine. It not only has the effects of lowering blood pressure and blood lipids but also exhibits anti-thrombotic and myocardial hypertrophy inhibitory properties, suggesting great potential for clinical applications. However, the absorption of quercetin remains an issue that needs to be addressed, and further research and exploration are required to enhance its absorption rate. Additionally, the majority of quercetin research has focused on cellular and animal experiments, with human and clinical trial data still lacking in abundance. It is hoped that future progress in the clinical application of quercetin will be significant, fully realizing its potential in the treatment of cardiovascular diseases.

References:

[1] Chen Zhenhua, Hu Xiaoyan, Zhao Teng, Xu Quan, Wang Jing, Xiong Yinhua, Zhou Bin. Research Progress on the Effects of Quercetin on Cardiovascular Diseases and Its Novel Dosage Forms [J]. Lishizhen Medicine and Materia Medica Research, 2019, 30(02): 440-443.

[2] Liang Yanling, Jiang Wei. Research Progress on the Cardioprotective Effects of Quercetin [J]. Journal of Anatomical Sciences, 2018, 40(05): 444-448.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.