Complex targeting cardiovascular diseases

Abstract

The present invention provides a complex comprising: (a) a cardiovascular disease (CVD) -targeting ligand; (b) a hydrophilic polymer which is polyethylene glycol (PEG), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), or dextran; and (c) a flavonoid. The present invention also provides a micelle nanoparticle composition comprising: (a) an outer shell comprising the complex; optionally (b) an inner shell comprising oligomeric (-)-epigallocatechin gallate (OEGCG); and optionally (c) a CVD therapeutic molecule encapsulated in the inner shell. The present invention further provides a method for treating CVD by administering to a subject an effective amount of the nanoparticle composition. The CVD-targeting ligand targets heart tissue and delivers an active ingredient to the heart tissue to treat cardiovascular diseases or conditions.

Description

【Technical Field】 【0001】 Reference to a Sequence Listing, Table, or Computer Program This application includes a Sequence Listing compliant with ST.26, which was simultaneously submitted in xml format through the Patent Center and is hereby incorporated by reference in its entirety. The ".xml" copy was created on June 2, 2023, named SequenceListing 8006, and has a size of 23.6 KB. 【0002】 Field of the Invention The present invention relates to a complex comprising (a) a CVD (cardiovascular disease) targeting ligand; (b) a hydrophilic polymer which is polyethylene glycol (PEG), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), or dextran; and (c) a flavonoid, wherein the hydrophilic polymer is covalently bonded to the flavonoid and the CVD targeting ligand. The present invention relates to micelle nanoparticles comprising (a) an outer shell comprising a CVD targeting ligand-hydrophilic polymer-epigallocatechin gallate (EGCG) complex; optionally, (b) an inner shell comprising an oligomeric flavonoid; and optionally, (c) a CVD therapeutic agent encapsulated in the inner shell. 【Background Art】 【0003】 Cardiovascular disease (CVD) is a type of disease related to the heart or blood vessels. Examples of CVD include coronary artery disease (such as angina and myocardial infarction), stroke, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, cardiac arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysm, peripheral artery disease, thromboembolism, and venous thrombosis. Coronary artery disease (CAD) and stroke account for 80% of CVD deaths in men and 75% of CVD deaths in women. 【0004】 CVD includes hypertension, atherosclerosis, acute myocardial infarction (AMI), heart failure, aortic aneurysm, and restenosis. 【0005】 Hypertension is a global cause of high mortality due to CVD. Hypertension causes disease states in important organs in the body, such as the heart, brain, blood vessels, eyes, and kidneys. Hypertension is also associated with the development of various CVDs, such as ischemia, atherosclerosis, congestive heart failure, and cardiac arrest. 【0006】 Atherosclerosis is an important factor in stroke and other CVDs. The accumulation of lipoproteins in the subendothelial extracellular matrix induces the formation of atherosclerotic plaques. The rupture of plaques causes myocardial infarction and stroke. 【0007】 AMI and ischemic death of cardiomyocytes are one of the most severe types of atherosclerotic cardiovascular diseases. 【0008】 Heart failure is a complex pathophysiological syndrome that occurs when the heart's ability to fill with or eject blood is reduced. Heart failure has been associated with various clinical conditions involving myocardial injury, such as genetic factors, hypertension, hypertrophy, and coronary artery disease. 【0009】 Aortic aneurysm is dangerous if rupture or dissection occurs and can be fatal. The pathophysiology of aortic aneurysm includes the loss of smooth muscle cells in the aortic wall, chronic inflammation, and destructive remodeling of connective tissue. 【0010】 Restenosis occurs as a serious complication of vascular intervention procedures, resulting in abnormal narrowing of the blood vessels. This is because vascular intervention procedures tend to focus on restoring blood flow in occluded arteries. 【0011】 Cardiovascular disease (CVD) imposes a huge health and economic burden not only in the United States but also globally. According to data from the National Health and Nutrition Examination Survey in the United States, the number of CVD patients in 2016 was 121.5 million, and approximately half of adults suffered from CVD, with the prevalence increasing with age. In 2016, approximately 17.6 million people died from CVD worldwide, a 14.5% increase over 10 years. Cardiovascular disease is the leading cause of death among people around the world. It is estimated that 23.6 million people will die from CVD in 2030. All types of cardiovascular diseases develop heart failure (HF) in the late stage, but at that time, the therapeutic effect of heart failure is limited with conventional treatment methods. 【0012】 CVD is a progressive disease cascade that initially results from risk factors such as dyslipidemia, hypertension, diabetes, smoking, and obesity, causing atherosclerosis (blockage of blood flow in arteries) and left ventricular hypertrophy (LVH), and then leading to coronary artery disease (CAD), myocardial ischemia, coronary thrombosis, and myocardial infarction (AMI). At the stage of AMI, heart cells are severely damaged, arrhythmia and muscle loss occur, which may lead to sudden cardiac death. After initial AMI, the heart begins to remodel. CVD patients often develop ventricular dilation, which progresses to congestive heart failure (CHF) and ultimately end-stage heart disease. Without efforts to halt the progression of CVD or attempts to promote cardiovascular regeneration, CVD will become a life-threatening disease (Circulation. 2006;114:2850-2870). 【0013】 CAD is the leading CVD and the leading cause of death among all diseases. CAD is the result of atherosclerotic lesions in the coronary arteries. Atherosclerosis occurs when lipoproteins (low-density lipoprotein, LDL) accumulate in the intima of coronary vessels with impaired endothelial function. High concentrations of LDL have the ability to penetrate the damaged endothelium (vascular cells), undergo oxidation, and attract white blood cells (immune cells including T cells and B cells), which are scavenged by macrophages to form foamy cells. These foam cells replicate to form lesions and attract smooth muscle cells (SMCs). SMCs proliferate to produce an extracellular matrix of collagen and proteoglycans, forming fibrous plaques in the lesions. Atherosclerotic plaques in the coronary arteries reduce the supply of oxygen and nutrients to heart cells, resulting in the death of billions of myocardial cells (cardiomyocytes) and the vascular system (endothelial cells, pericytes). Eventually, the dead cardiovascular tissue is replaced by fibroblast-mediated scar formation and loses its functionality, resulting in pathological remodeling of the heart and dysfunction of conduction system cells (atrioventricular node, sinoatrial node, Purkinje fibers) and nervous system cells (glial cells, neurons). That is, starting from CAD / atherosclerosis, many dysfunctional cells, and environmental factors (LDL, MMP, etc.), the progression of CVD ultimately leads to heart failure (J Cell Physiol. 2019;1-12). 【0014】 Acute myocardial infarction (AMI) is an ischemic heart disease caused by coronary artery occlusion. Conventional clinical approaches to myocardial infarction rely on thrombolytic agents such as TPA, or surgical revascularization procedures such as coronary stent placement or coronary artery bypass grafting. AMI can cause significant damage to cardiomyocytes. New therapeutic methods using cells (especially stem cells), genes, exosomes, and growth factors have emerged and shown great research results in the repair of cardiomyocytes, but there are still many challenges in the clinical application of these technologies. 【0015】 The myocardium, like other parenchymal organs, contains endogenous stem cells that have the ability to proliferate and replace cardiomyocytes that have died by apoptosis or oncosis. However, the regenerative capacity of the adult heart is limited and is insufficient to overcome the massive loss (over 1 billion) of cardiomyocytes during acute injury or long-term remodeling. Cardiovascular regenerative medicine (CRM) can provide growth factors and cytokines that promote the regeneration of cardiovascular cells (Eur Heart J. 2017 Sep 1;38(33):2532-2546.). These CRMs can be used in acute myocardial infarction (AMI), chronic ischemic cardiomyopathy (CIC), dilated cardiomyopathy (DCM), other forms of non-ischemic heart disease (NIHD), and possibly other heart conditions (such as valvular heart disease, arrhythmias, and congenital myopathies). 【0016】 CRM products intended to be used for the regulation, enhancement, and activation of the endogenous regenerative response can be subdivided into three main groups: (1) cell transplantation; (2) injection of biological or synthetic factors that have active functions in the endogenous regenerative process; (3) genetic and epigenetic modifications that regulate the expression of genes and mRNAs involved in the endogenous regenerative capacity. 【Summary of the Invention】 【0017】 The challenges of clinical CRM are as follows: ·Combination therapy is required because it is necessary to demonstrate effectiveness in multiple cell types of the heart (cardiomyocytes, vascular endothelial cells, fibroblasts), the extracellular matrix environment, and the electromechanical coupling necessary to coordinately improve cardiac contractility. MINC is a platform that can deliver combination therapy to damaged cardiovascular lesions. ·An excellent delivery system is needed to provide a sufficient CRM dose of the therapeutic agent to the target area of the host tissue in order to achieve bioavailability and minimize off-target effects. 【0018】 With many therapeutic agents, only a small percentage of the drug reaches the tissue where it is intended to act. For example, in chemotherapy, approximately 99% of the administered drug does not reach the tumor site. Targeted drug delivery aims to concentrate the drug in the target tissue while reducing the relative concentration of the drug in other tissues. For example, by avoiding the host's defense mechanisms and suppressing non-specific distribution in the liver and spleen, the system can reach the target site of action at a higher concentration. Targeted delivery may improve efficacy while reducing side effects. The cardiac delivery system is designed to specifically deliver drugs / biomolecules to CVD lesions, enhance their accumulation, and improve overall efficacy and safety. 【Brief Description of the Drawings】 【0019】 【Figure 1】 Figure 1 shows a micelle composition of the present invention, in which drug molecules are encapsulated within the micelle, the micelle contains a ligand-PEG-EGCG complex in the outer shell, and oligomeric EGCG (OEGCG) in the inner shell. 【Figure 2】 Figure 2 shows a micelle composition of the present invention, in which drug molecules are encapsulated within the micelle, the micelle contains a ligand-PEG-EGCG complex and naked PEG-EGCG in the outer shell, and oligomeric EGCG (OEGCG) in the inner shell. 【Figure 3】 Figure 3 shows a chemical synthesis scheme of VS7-PEG-EGCG by linking the N-terminus of the VS7 peptide to HOOC-PEG-EGCG. 【Figure 4】 Figure 4 shows a chemical synthesis scheme of CST-PEG-EGCG by linking the N-terminus of the CST peptide to HOOC-PEG-EGCG. 【Figure 5】 Figure 5 shows a chemical synthesis scheme of CLI-PEG-EGCG by linking the N-terminus of the CLI peptide to HOOC-PEG-EGCG. 【Figure 6】 Figure 6 shows the successful formation of VS7-MINC-doxorubicin (A), CST-MINC-doxorubicin (B), and CLI-MINC-doxorubicin (C). 【Figure 7】 Figure 7 shows the uptake of CST-MINC-doxorubicin, CLI-MINC-doxorubicin, and VS7-MINC-doxorubicin into the cardiomyoblast cell line (H9C2) by measurement of the fluorescence signal. 【Figure 8】 Figure 8 shows the chemical synthesis scheme of VS7-PEG-EGCG by linking the C-terminus of the VS7 peptide to HO-PEG-EGCG. 【Figure 9】 Figure 9 shows the chemical synthesis scheme of CST-PEG-EGCG by linking the C-terminus of the CST peptide to HO-PEG-EGCG. 【Figure 10】 Figure 10 shows the chemical synthesis scheme of CLI-PEG-EGCG by linking the C-terminus of the CLI peptide to HO-PEG-EGCG. 【Figure 11】 Figure 11 shows the chemical synthesis scheme of VS7-PLA-EGCG by linking the N-terminus of the VS7 peptide to HOOC-PLA-EGCG. 【Figure 12】 Figure 12 shows the chemical synthesis scheme of VS7-PLGA-EGCG by linking the N-terminus of the VS7 peptide to HOOC-PLGA-EGCG. 【Figure 13】 Figure 13 shows the chemical synthesis scheme of VS7-dextran-EGCG by linking the C-terminus of the VS7 peptide to HO-dextran-EGCG. 【Modes for Carrying Out the Invention】 【0020】 Definitions The term "about" is defined as ±10%, preferably ±5% of the stated value. 【0021】 As used herein, the term "CVD-targeting ligand" refers to a molecule, such as a peptide or small molecule, having a molecular weight of less than 10,000 daltons, e.g., 300 - 3500 daltons, that binds to or targets receptors on the cardiovascular system, heart, or endothelial cell surface. 【0022】 The term "cytokine" refers to proteins (about 5 - 70 kDa) that are important for cell signaling. Cytokines have been shown to be involved in autocrine, paracrine, and endocrine signaling as immunomodulatory substances. 【0023】 The term "epigallocatechin gallate" refers to an ester of epigallocatechin and gallic acid and is used interchangeably with "epigallocatechin-3-gallate" or "EGCG". 【0024】 The term "oligomeric EGCG" (OEGCG) refers to a substance in which 2 - 50 or 3 - 20 monomers of EGCG are covalently bonded. OEGCG preferably contains 4 - 12 EGCG monomers. 【0025】 The term "nanoparticle" refers to particles having a diameter of less than 1 μm and between 1 - 999 nm. 【0026】 The term "polyethylene glycol - epigallocatechin gallate complex" or "PEG - EGCG" refers to a substance in which one or two molecules of EGCG are linked to polyethylene glycol (PEG). The term "PEG - EGCG" refers to both the PEG - mEGCG complex (monomeric EGCG) and the PEG - dEGCG (dimeric EGCG) complex. 【0027】 The term "MINC" (Multi - pathway Immune - modulating Nanocomplex Combination therapy) is one of the platform technologies. The MINC used in this application utilizes the biological activities of the PEG - flavonoid complex and oligomeric EGCG (OEGCG). An additional CVD therapeutic agent can be encapsulated in MINC to form MINC - drug. 【0028】 The term "MINC-agent" as used in this application is a micelle having a shell formed by a CVD-targeting ligand-PEG-flavonoid complex and optionally an oligomeric flavonoid such as OEGCG, and having an agent encapsulated therein. 【0029】 Flavonoid The flavonoid suitable for the present invention has the general structure of Formula I: 【Chemical formula】 and wherein R1 is H or phenyl; R2 is H, OH, gallate, or phenyl, and the phenyl is optionally substituted with one or more (for example, 2 to 3) hydroxyls; R3 is H, OH, or =O (oxo); or R1 and R2 together form a closed-loop ring structure; or R2 and R3 together form a closed-loop ring structure. 【0030】 The 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th position of Formula I can be linked to a group containing hydrocarbon, halogen, oxygen, nitrogen, sulfur, phosphorus, boron, or metal. 【0031】 Examples of the flavonoid of Formula I include the following: 【Chemical formula】 【0032】 Preferred flavonoid compounds of Formula I include the following: EGCG (CAS# 989-51-5), EC (CAS# 490-46-0), EGC (CAS# 970-74-1), or ECG (CAS# 1257-08-5) 【Chemical formula】 【0033】 Complex The present invention provides a complex comprising: (a) a CVD-targeting ligand; (b) a hydrophilic polymer which is polyethylene glycol (PEG), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), or dextran; and (c) a flavonoid of formula I, wherein said PEG is covalently bonded to said flavonoid and said CVD-targeting ligand. 【0034】 The complex targets CVD by means of the CVD-targeting ligand and delivers an active ingredient to cardiovascular tissue in order to treat CVD. 【0035】 The CVD-targeting ligand is covalently bonded to PEG, PLA, PLGA, or dextran via its -COOH group or its -NH2 group by standard chemical reactions known to those skilled in the art. The molecular weight of the hydrophilic polymer in the complex is generally from 1K to 100K, preferably from 3K to 80K, more preferably from 5K to 40K. 【0036】 The flavonoid in the complex has the general formula (I) and is preferably epigallocatechin gallate (EGCG), epicatechin (EC), epicatechin gallate (ECG), or epigallocatechin (EGC). In one embodiment, the flavonoid is epigallocatechin gallate (EGCG). 【0037】 In one embodiment, PEG contains an aldehyde group linked to the 5-position, 6-position, 7-position, or 8-position (preferably the 6-position or 8-position) of ring A of the flavonoid compound. 【0038】 In another embodiment, PEG contains a thiol group linked to R1 or R2 (when R1 or R2 is -OH) of ring B of the flavonoid. 【0039】 In one embodiment, the complex comprises PEG-EGCG in which one or two molecules of EGCG are linked to PEG, which can be prepared by linking aldehyde-terminated PEG and EGCG, and the linking is by the reaction of the free aldehyde group with the 5-, 6-, 7-, or 8-position (preferably the 6- or 8-position) of formula I to effect the attachment of PEG. See WO 2006 / 124000 pamphlet and WO 2009 / 054813 pamphlet. PEG-EGCG can also be prepared by linking thio-terminated PEG and EGCG, and the linking is by the reaction of the free thio group with R1 or R2 of formula I (wherein R1 or R2 is a phenyl group) to effect the attachment of PEG. See WO 2015 / 171079 pamphlet. 【0040】 In another embodiment, the complex comprises PEG-EC, PEG-EGC, or PEG-ECG, and the complex can be prepared by linking aldehyde-terminated PEG to EC, EGC, or ECG, and the linking is by the reaction of the free aldehyde group with the 5-, 6-, 7-, or 8-position (preferably the 6- or 8-position) of formula I to effect the attachment of PEG. 【0041】 HOOC-PEG-CHO and HO-PEG-CHO are generally available. In one embodiment, HOOC-PEG-CHO is linked to EGCG, EC, EGC, or ECG according to WO 2006 / 124000 pamphlet and WO 2009 / 054813 pamphlet. HOOC-PEG-flavonoid has a COOH group and reacts with the N-terminus of the CVD targeting peptide. Generally, the CVD targeting peptide is incubated in DMSO with HOOC-PEG-flavonoid, N,N'-dicyclohexylcarbodiimide (DCC), and N-hydroxysuccinimide (NHS). The reaction is carried out with stirring at room temperature under light shielding and nitrogen atmosphere. The reaction mixture is dialyzed against methanol and distilled water (membrane molecular weight cut-off = 2000 Da). Next, the solution is lyophilized to obtain a lyophilized powder. To avoid self-reaction of the peptide, the C-terminus of the CVD targeting peptide may be protected, for example, by resin during the reaction. Merrifield, hydroxymethylpolystyrene, PAM, and MBHA resins are generally used to prevent the ligation of unwanted peptides. After the reaction, the resin can be removed under acidic conditions. 【0042】 In another embodiment, HO-PEG-CHO is linked to EGCG, EC, EGC, or ECG according to WO 2006 / 124000 pamphlet and WO 2009 / 054813 pamphlet. The HO-PEG-flavonoid has an OH group and reacts with the C-terminus of the CVD targeting peptide. Generally, the peptide is incubated with HO-PEG-EGCG and N,N'-dicyclohexylcarbodiimide (DCC) in DMSO. The reaction is carried out with stirring at room temperature under light shielding and nitrogen atmosphere. The reaction mixture is dialyzed against methanol distilled water (membrane molecular weight cut-off = 2000 Da). Next, the solution is lyophilized to obtain a lyophilized powder. To avoid self-reaction of the peptide, the N-terminus of the CVD targeting peptide may be protected by, for example, a resin during the reaction. Merrifield, hydroxymethylpolystyrene, PAM, and MBHA resins are generally used to prevent the ligation of unwanted peptides. After the reaction, the resin can be removed under acidic conditions. In this reaction, the COOH group on the peptide selectively reacts with the OH group on PEG. This is because the primary OH group on PEG is more reactive than the tertiary OH of the aromatic ring of the flavonoid. 【0043】 HOOC-PLA-CHO, HOOC-PLGA-CHO, and HO-dextran-CHO are commercially available. 【0044】 In one embodiment, HOOC-PLA-CHO is linked to EGCG, EC, EGC, or ECG according to WO 2006 / 124000 pamphlet and WO 2009 / 054813 pamphlet. HOOC-PLA-flavonoid has a COOH group and reacts with the N-terminus of the CVD-targeting peptide. Generally, the CVD-targeting peptide is incubated in DMSO with HOOC-PLA-flavonoid, N,N'-dicyclohexylcarbodiimide (DCC), and N-hydroxysuccinimide (NHS). The reaction is carried out with stirring at room temperature under light shielding and nitrogen atmosphere. The reaction mixture is dialyzed against methanol and distilled water (membrane fractional molecular weight = 2000 Da). Next, the solution is lyophilized to obtain a lyophilized powder. To avoid self-reaction of the peptide, the C-terminus of the CVD-targeting peptide may be protected by, for example, a resin during the reaction. Merrifield, hydroxymethylpolystyrene, PAM, and MBHA resins are generally used to prevent the ligation of unwanted peptides. After the reaction, the resin can be removed under acidic conditions. 【0045】 In one embodiment, HOOC-PLGA-CHO is linked to EGCG, EC, EGC, or ECG according to WO 2006 / 124000 pamphlet and WO 2009 / 054813 pamphlet. HOOC-PLGA-flavonoid has a COOH group and reacts with the N-terminus of the CVD-targeting peptide. Generally, the CVD-targeting peptide is incubated in DMSO with HOOC-PLGA-flavonoid, N,N'-dicyclohexylcarbodiimide (DCC), and N-hydroxysuccinimide (NHS). The reaction is carried out with stirring at room temperature under light shielding and nitrogen atmosphere. The reaction mixture is dialyzed against methanol and distilled water (membrane fractional molecular weight = 2000 Da). Next, the solution is lyophilized to obtain a lyophilized powder. To avoid self-reaction of the peptide, the C-terminus of the CVD-targeting peptide may be protected by, for example, a resin during the reaction. Merrifield, hydroxymethylpolystyrene, PAM, and MBHA resins are generally used to prevent the ligation of unwanted peptides. After the reaction, the resin can be removed under acidic conditions. 【0046】 In one embodiment, HO-dextran-CHO is linked to EGCG, EC, EGC, or ECG according to WO 2006 / 124000 pamphlet and WO 2009 / 054813 pamphlet. HO-dextran-flavonoid has an OH group and reacts with the C-terminus of the CVD-targeting peptide. Generally, the peptide is incubated with HO-dextran-EGCG and N,N'-dicyclohexylcarbodiimide (DCC) in DMSO. The reaction is carried out with stirring at room temperature under light shielding and nitrogen atmosphere. The reaction mixture is dialyzed against methanol-distilled water (membrane fractionation molecular weight = 2000 Da). Next, the solution is lyophilized to obtain a lyophilized powder. To avoid self-reaction of the peptide, the N-terminus of the CVD-targeting peptide may be protected by, for example, a resin during the reaction. Merrifield, hydroxymethylpolystyrene, PAM, and MBHA resins are generally used to prevent the ligation of unwanted peptides. After the reaction, the resin can be removed under acidic conditions. In this reaction, the COOH group on the peptide selectively reacts with the OH of the CH2OH terminus of dextran. This is because this is the only primary OH group in dextran and is more reactive than other secondary OHs in dextran and the tertiary OHs of the aromatic ring of flavonoid. 【0047】 CVD-targeting ligand The CVD-targeting ligand in the present invention is a ligand selected to target receptors on the cardiovascular cell surface or in the surrounding cardiac environment, examples of which include, but are not limited to, cardiomyocytes, vascular system cells (endothelial cells, pericytes), fibroblasts, immune cells (macrophages, T cells, B cells, and mast cells), conduction system cells (atrioventricular node, sinoatrial node, Purkinje fibers), and nervous system cells (glial cells, neurons) in CVD lesions. 【0048】 Examples of receptors targeted by the CVD-targeted ligand include, but are not limited to, guanylate cyclase A (GC-A) receptor, angiotensin II receptor (AT1R), matrix metalloprotease (MMP), cysteine-rich protein 2 (CRIP2), TNF receptor (e.g., TNFR1, TNFR2), BDNF receptor, Toll-like receptor (TLR), protease-activated receptor (PAR), endothelin receptor (ETA / ETB receptor), TAM receptor, peroxisome proliferator-activated receptor (PPAR), ryanodine receptor (RyR), thromboxane receptor, chemokine receptor (CCR; e.g., CCR2), pattern recognition receptor (PRR), adrenergic receptor (e.g., Tβ-adrenergic receptor), cytokine receptor (CR; e.g., IL-1R, IL-2R, IL-4R), prostaglandin receptor (e.g., prostaglandin E2 receptor), serotonin receptor (e.g., 5-HT2 receptor), platelet fibrinogen receptor, corticosteroid receptor (e.g., glucocorticoid receptor), nucleotide-binding oligomerization domain-like receptor (NLR), class A1 scavenger receptor (SR-A1), scavenger receptor, adiponectin receptor, cell death receptor (e.g., DR4, DR5), purinergic receptor (e.g., P2X7), G protein-coupled receptor (GPCR), NOTCH receptor, epidermal growth factor receptor (EGFR), LDL receptor, platelet receptor, leptin receptor, estrogen receptor, vascular endothelial growth factor receptor (VEGFR), vascular cell adhesion protein (VCAM-1), intercellular adhesion molecule (ICAM-1), integrin (e.g., αvβ3), thrombin, stabilin-2, and the like. 【0049】 In one embodiment, the heart-targeted ligand is the VS7 peptide having the amino acid sequence VVLVTSS (SEQ ID NO: 1), which targets heart endothelium or the microenvironment in heart tissue. 【0050】 In one embodiment, the heart-targeted ligand is the CST peptide having the amino acid sequence CSTSMLKAC (SEQ ID NO: 2), which targets α-B crystallin in heart tissue. 【0051】 In one embodiment, the heart-targeting ligand is the CLI peptide having the amino acid sequence CLIDLHVMC (SEQ ID NO: 3), which targets heart cells or the microenvironment. 【0052】 In one embodiment, the heart-targeting ligand is the CTT peptide having the amino acid sequence CTTHWGFTLC (SEQ ID NO: 4), which targets MMP2 and MMP9 in heart tissue. 【0053】 In one embodiment, the heart-targeting ligand is the atrial natriuretic peptide (ANP) peptide having the amino acid sequence SLRRSSCFGGRMDRIGAQSGLGCNSFRY (SEQ ID NO: 5), which targets the guanylate cyclase A (GC-A) receptor in heart tissue. 【0054】 In one embodiment, the heart-targeting ligand is the CRS peptide having the amino acid sequence CRSWNKADNRSC (SEQ ID NO: 6), which targets heart endothelium or the microenvironment in heart tissue. 【0055】 In one embodiment, the heart-targeting ligand is the DF8 peptide having the amino acid sequence DRVYIHPF (SEQ ID NO: 7), which targets AT1R in heart tissue. 【0056】 In one embodiment, the heart-targeting ligand is the CRP peptide having the amino acid sequence CRPPR (SEQ ID NO: 8), which targets CRIP2 in heart tissue. 【0057】 In one embodiment, the heart-targeting ligand is the QV7 peptide having the amino acid sequence QAQGQLV (SEQ ID NO: 9), which targets the TNF-α receptor in heart tissue. 【0058】 In one embodiment, the heart-targeting ligand is the AV7 peptide having the amino acid sequence ARRGQAV (SEQ ID NO: 10), which targets the BDNF receptor in heart tissue. 【0059】 In one embodiment, the heart-targeting ligand is the GV7 peptide having the amino acid sequence GRRFIRV (SEQ ID NO: 11), which targets the BDNF receptor in heart tissue. 【0060】 In one embodiment, the heart-targeting ligand is the VR7 peptide having the amino acid sequence VHPKQHR (SEQ ID NO: 12), which targets VCAM-1 in heart tissue. 【0061】 In one embodiment, the heart-targeting ligand is the VK7 peptide having the amino acid sequence VHSPNKK (SEQ ID NO: 13), which targets VCAM-1 in heart tissue. 【0062】 In one embodiment, the heart-targeting ligand is the CC9 peptide having the amino acid sequence CNNSKSHTC (SEQ ID NO: 14), which targets VCAM-1 in heart tissue. 【0063】 In one embodiment, the heart-targeting ligand is the NA17 peptide having the amino acid sequence NNQKIVNLKEKVAQLEA (SEQ ID NO: 15), which targets ICAM-1 in heart tissue. 【0064】 In one embodiment, the heart-targeting ligand is the RGD peptide having the amino acid sequence RGD, which targets integrin in heart tissue. 【0065】 In one embodiment, the heart-targeting ligand is the GC11 peptide having the amino acid sequence GPXRSGGGGKC (SEQ ID NO: 16), which targets thrombin in heart tissue. 【0066】 In one embodiment, the heart-targeting ligand is the KL9 peptide having the amino acid sequence KKLVPRGSL (SEQ ID NO: 17), which targets thrombin in heart tissue. 【0067】 In one embodiment, the heart-targeting ligand is a CRK peptide having the amino acid sequence CRKRLDRNC (SEQ ID NO: 18), which targets the IL-4 receptor in heart tissue. 【0068】 In one embodiment, the heart-targeting ligand is a CRT peptide having the amino acid sequence CRTLTVRKC (SEQ ID NO: 19), which targets stabilin-2 in heart tissue. 【0069】 In one embodiment, the heart-targeting ligand is a CKR peptide having the amino acid sequence CKRAVR (SEQ ID NO: 20), which targets heart endothelium or the microenvironment in heart tissue. 【0070】 In one embodiment, the heart-targeting ligand is a CPK peptide having the amino acid sequence CPKTRRVPC (SEQ ID NO: 21), which targets heart endothelium or the microenvironment in heart tissue. 【0071】 In one embodiment, the heart-targeting ligand is a CAR peptide having the amino acid sequence CARPAR (SEQ ID NO: 22), which targets heart endothelium or the microenvironment in heart tissue. 【0072】 In one embodiment, the heart-targeting ligand is a CRS9 peptide having the amino acid sequence CRSTRANPC (SEQ ID NO: 23), which targets heart endothelium or the microenvironment in heart tissue. 【0073】 In one embodiment, the heart-targeting ligand is a GQ7 peptide having the amino acid sequence GGGVFWQ (SEQ ID NO: 24), which targets heart endothelium or the microenvironment in heart tissue. 【0074】 In one embodiment, the heart-targeting ligand is an HH7 peptide having the amino acid sequence HGRVRPH (SEQ ID NO: 25), which targets heart endothelium or the microenvironment in heart tissue. 【0075】 In one embodiment, the heart-targeting ligand is the CLH peptide having the amino acid sequence CLHRGNSC (SEQ ID NO: 26), which targets heart endothelium or the microenvironment in heart tissue. 【0076】 In one embodiment, the heart-targeting ligand is the CRS12 peptide having the amino acid sequence CRSWNKADNRSC (SEQ ID NO: 27), which targets heart endothelium or the microenvironment in heart tissue. 【0077】 Nanoparticle composition The term "MINC" (Multi-pathway Immune-modulating Nanocomplex Combination therapy) is one of the platform technologies. The present invention provides a nanoparticle micelle (MINC) composition. The micelle contains a CVD-targeting ligand-PEG-flavonoid complex in the outer shell and oligomeric EGCG (OEGCG) in the inner shell (see Figure 1). The CVD-targeting ligand enables the nanoparticle composition to specifically target cardiovascular tissue. 【0078】 In one embodiment, the micelle composition includes both the outer shell and the inner shell as described above; the composition optionally has a drug encapsulated within those shells. 【0079】 In one embodiment, the micelle composition includes the outer shell as described above and does not include the inner shell; the composition optionally has a drug encapsulated within the shell. 【0080】 In one embodiment, the micelle composition includes an outer shell of a CVD-targeting ligand-polymer-flavonoid complex and an inner shell of oligomeric flavonoid, where the flavonoid of the outer shell and the flavonoid of the inner shell are independently EGCG, EC, EGC, or ECG, and the polymer is PEG, PLA, PLGA, or dextran. A preferred polymer is PEG. A preferred flavonoid is EGCG. Figure 1 shows a preferred micelle composition. The CVD-targeting ligand enables the nanoparticle composition to specifically target CVD tissue. 【0081】 In one embodiment, the micelle outer shell further includes a naked PEG-flavonoid complex such as PEG-EGCG that does not have a CVD-targeting ligand linked to the PEG-flavonoid. Refer to Figure 2. In such a micelle outer shell, the ratio of ligand-PEG-EGCG to PEG-EGCG is generally more than 10%, or more than 20%, or more than 30%, or more than 50%, up to 100%. In one embodiment, the ratio of ligand-PEG-EGCG to PEG-EGCG is 10 - 90%, or 20 - 80%, or 40 - 60%. 【0082】 In one embodiment, the micelle shell includes two or more different ligand-polymer-flavonoid complexes, where different CVD-targeting ligands target different receptors of cardiovascular cells. 【0083】 The micelle optionally includes a CVD therapeutic molecule (drug) encapsulated within the micelle (MINC-drug). 【0084】 In one embodiment, the MINC-drug composition includes three active ingredients, which are complementary in terms of the function of addressing both the immune response and signal transduction pathways by the skeletal elements of the composition (PEG-flavonoid / OEGCG), and the function of addressing additional signal transduction pathways by selected drug molecules for treating CVD. Each nanoparticle is a fixed-dose combination drug formulated with those three active ingredients in a certain molar ratio. 【0085】 The present invention delivers the MINC-drug to target cardiovascular tissues by actively delivering micelles to the cardiovascular system having specific receptors via CVD-targeting ligands. 【0086】 In one embodiment, the nanocomposite shell of the present invention contains the first two active ingredients, OEGCG and PEG-flavonoid (e.g., PEG-EGCG), in the skeleton of the micelle composition. These are derivatives of EGCG and are potent immunomodulators that control a wide range of disease signal transduction pathways. EGCG controls both innate and adaptive immunity. However, the bioavailability of EGCG is low, and EGCG is not stable. The nanocomposite composition of the present invention overcomes the problem of the bioavailability of EGCG by forming a nanocarrier that transports EGCG to the target site for treatment, and also overcomes the problem of the stability of EGCG by forming the OEGCG and PEG-EGCG complex, thereby effectively making EGCG a highly effective therapeutic agent. 【0087】 The nanocomposite of the present invention optionally includes a third active ingredient, which is a drug molecule encapsulated in the nanoparticle for treating CVD. 【0088】 As used herein, the agent refers to a molecule having therapeutic activity (e.g., a drug for treating CVD). For example, the encapsulated agent can be various chemical substances such as small molecule chemicals, peptides, proteins, monoclonal antibodies, RNA / DNA, and vaccines. 【0089】 Examples of therapeutic agents effective in suppressing the progression of CVD and promoting cardiovascular regeneration include, but are not limited to, IGF-1, TGF-β1, MCP-1, TIMP-1, VEGF, β-FGF, endothelin-1, urocortin, VEGF, HGF, FGF, PDGF, TGF-β, neuregulin, NO synthase, Evasin-3, Evasin-4, IL-1 trap, IL-1RA, anti-IL-1β, anti-IL-8, anti-TNF-α, anti-CCL-5, anti-MCP-1, anti-CXCR2, anti-IL-6R, IL-19, anti-IL-12, anti-IL-23, anti-MMP9, anti-IL-1β, anti-TNF-α, anti-IL-1β, anti-IL-6, anti-IL-7, anti-IL-12 or anti-IL-23, sacubitril, valsartan, aliskiren, enoxaparin, clopidogrel, abciximab, eptifibatide, bivalirudin, morphine, cyclosporine A, furosemide, staphylokinase, dapagliflozin, anakinra, canakinumab, rimonabant, losmapimod, darapladib, SERCA2a gene, or IONIS-AGT-LRx siRNA, etc. 【0090】 In one embodiment, the MINC-agent comprises a CVD-targeting ligand such as CTT, CST, CRS, DF8, CRP, CKR, CPK, CAR, CRS9, CLI, GQ7, HH7, VS7, CLH, CRS12, QV7, AV7, or GV7 and a drug such as anti-CD3, anti-CD3, anti-CD39, anti-CD73, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, anti-GZM A, anti-GZM B, IGF-1, or anti-TNF-α; such agents are suitable for promoting the survival of cardiomyocytes for treating myocardial infarction, heart failure, and other heart-related diseases. 【0091】 In one embodiment, the MINC-agent comprises a CVD-targeting ligand such as CTT, CST, CRS, DF8, CRP, CKR, CPK, CAR, CRS9, CLI, GQ7, HH7, VS7, CLH, CRS12, QV7, AV7, or GV7 and the SERCA2a gene or IONIS-AGT-LRx antisense RNA, which is a drug for treating heart failure. 【0092】 In one embodiment, the MINC-agent comprises a CVD-targeting ligand such as CTT, CST, CRS, DF8, CRP, CKR, CPK, CAR, CRS9, CLI, GQ7, HH7, VS7, CLH, CRS12, QV7, AV7, or GV7 and a drug such as Evasin-3, Evasin-4, IL-1 trap, IL-1RA, anti-CD3, anti-CD3, anti-CD39, anti-CD73, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, anti-GZM A, anti-GZM B, anti-IL-1β, TGF-β1, MCP-1, anti-IL-8, anti-IL-6, anti-IL-10, anti-MCP-1, anti-CXCR2, TIMP-1, VEGF, β-FGF, or anti-TNF-α; such MINC-agents are suitable for reducing inflammation for treating myocardial infarction, heart failure, and other heart-related diseases. 【0093】 In one embodiment, the MINC-agent comprises a CVD-targeting ligand such as CTT, CST, CRS, DF8, CRP, CKR, CPK, CAR, CRS9, CLI, GQ7, HH7, VS7, CLH, CRS12, QV7, AV7, or GV7, and an agent such as endothelin-1, urocortin, VEGF, HGF, FGF, PDGF, TGF-β, neuregulin, NO synthase, FGF, or IGF-1; such a MINC-agent is suitable for promoting the proliferation of cardiac cells and angiogenesis for treating myocardial infarction, heart failure, and other heart-related diseases. 【0094】 In one embodiment, the MINC-agent comprises a CVD-targeting ligand such as CTT, CST, CRS, DF8, CRP, CKR, CPK, CAR, CRS9, CLI, GQ7, HH7, VS7, CLH, CRS12, QV7, AV7, or GV7, and an agent such as sacubitril, valsartan, aliskiren, enoxaparin, clopidogrel, abciximab, eptifibatide, ivabradine, morphine, cyclosporin A, furosemide, staphylokinase, dapagliflozin, anakinra, canakinumab, rimonabant, rosmapimod, or darapladib; such a MINC-agent is suitable for the treatment of myocardial infarction, heart failure, and other heart-related diseases. 【0095】 In one embodiment, the MINC-agent comprises VR7, VK7, CC9, RGD, GC11, KL9, CRK, or CRT, and an agent such as anti-CD3, anti-CD3, anti-CD39, anti-CD73, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, anti-GZM A, anti-GZM B, anti-PCSK9, anti-endothelial lipase, anti-IL-1, anti-IL-4, anti-IL5, anti-IL-6, anti-IL-10, anti-IL-13, anti-IIL-17, anti-IL-19, anti-TNF-α, anti-TNF-β, anti-TNF-γ, anti-IFN-γ, or anti-TGFβ; such a MINC-agent is suitable for the treatment of atherosclerosis and the prevention of the progression of CVD. 【0096】 In one embodiment, the MINC-agent includes RGD and an agent such as anti-elastin, anti-TNF-α, anti-IL-8, anti-IL-1β, anti-IL-6, anti-IL-17, or anti-MCP-1; such a MINC-agent is suitable for the treatment of aneurysms. 【0097】 The nanoparticle composition of the present invention is stable in a hydrophilic environment such as blood circulation and dissociates in a hydrophobic environment such as heart tissue. When the nanoparticle complex enters a hydrophobic tissue, it dissociates, and its active ingredient OEGCG, PEG-flavonoids such as PEG-EGCG, and drug molecules in the nanocomplex are released. The released active ingredients regain their biological activity in the suppression of CVD. 【0098】 Method for preparing the nanoparticle composition The nanoparticle composition of the present invention can be prepared by a process comprising the following steps: (a) mixing a drug molecule with a flavonoid oligomer (e.g., OEGCG) and the CVD-targeting ligand complex of the present invention in an aqueous solution; and (b) filtering the mixture through a membrane with a molecular weight cut-off of 8000 to 300,000 Daltons to remove low molecular weight molecules and retain high molecular weight molecules. 【0099】 In a preferred embodiment, this process further includes step (c) of filtering the high molecular weight molecules through a 0.2 - 0.3 μm membrane and collecting the filtrate. 【0100】 This process optionally further includes a lyophilization step (d) after step (c). Step (d): The filtrate is lyophilized by freezing it stepwise at (i) about 0 - 5 °C, (ii) about -20 - 30 °C, and (iii) about -60 - 100 °C, and then drying it. 【0101】 In step (a), the drug molecule is dissolved in an aqueous solvent such as phosphate buffered saline, saline, water, bicarbonate buffer, oxyhemoglobin buffer, bis-tris alkane, Tris-HCl, HEPES, histidine buffer, NP-40, RIPA (radioimmunoprecipitation assay buffer), tricine, TES, TAPS, TAPSO, bicine, MOPS, PIPES, cacodylate, or MES. Preferred solvents are phosphate buffered saline, saline, or water. The protein drug concentration is generally from 0.01 to 50 mg / ml, preferably from 0.05 to 10 mg / ml, more preferably from 0.1 to 5 mg / ml. 【0102】 The flavonoid oligomer and CVD targeting ligand complex are dissolved in ketone, acetonitrile, alcohol, aldehyde, ether, acetate, sulfoxide, benzene, organic acid, amide, aqueous buffer, and any combination thereof. Preferred solvents are alcohol, acetonitrile, sulfoxide, amide, and any combination thereof. The OEGCG / EGCG and PEG-EGCG concentrations are generally, independently, from 0.001 to 10 mg / ml, preferably from 0.005 to 1 mg / ml, or from 0.1 to 5 mg / ml. 【0103】 It is important that OEGCG is in molar excess relative to the drug agent. Generally, the molar ratio of EGCG in OEGCG to the drug molecule is between 1 to 1 - 500, 1 to 2 - 500, 1 to 3 - 500, or 1 to 5 - 500, preferably 1 to 3 - 100, 1 to 5 - 100, or 1 to 10 - 50. The molar ratio is calculated by the number of moles of monomeric EGCG in OEGCG relative to the number of moles of the drug molecule. By having EGCG in molar excess, it is ensured that most or all of the drug agent is encapsulated by the OEGCG molecules. Unencapsulated drug agent may not be selectively distributed to the target tissue and may cause a decrease in efficacy and safety issues. This is avoided in this process by controlling the molar ratio of OEGCG to the protein. 【0104】 In step (b), the mixture is filtered through a membrane with a molecular weight cut-off of 8,000 to 300,000 Daltons, preferably 8,000 to 200,000 Daltons, 8,000 to 150,000 Daltons, or 8,000 to 12,000 Daltons to remove low molecular weight molecules and retain high molecular weight molecules. The ultrafiltration membrane material is selected from the group consisting of cellulose (and its derivatives), polyethersulfone (PES), polytetrafluoroethylene (PTFE), nylon, polyvinylidene fluoride or polyvinylidene difluoride (PVDF), and polypropylene (PP); preferably, cellulose (and its derivatives), PTFE, and PVDF; 【0105】 This mixture is optionally diluted with an aqueous solvent as described above in step (a) prior to ultrafiltration. 【0106】 In the ultrafiltration step (b), unwanted low molecular weight impurities such as unreacted OEGCG or EGCG, or reaction by-products are removed. These impurities may reduce the medicinal efficacy and safety. Also, if the unreacted OEGCG or EGCG becomes excessive, individual nanoparticles may aggregate into particles of about 1000 nm in size, which may reduce the effectiveness and cause toxicity. 【0107】 In step (c), the retained high molecular weight molecules are filtered through a membrane having a pore size of about 0.2 to 0.3 μm, for example 0.22 μm, and the filtrate is collected. This is to remove unwanted impurities of high molecular size such as mega-aggregates. Due to their large size, these aggregates may be excreted from the entry tissue. These aggregates reduce the overall effectiveness / safety and are likely to induce immunogenicity in patients. Also, large-sized nanoparticles are easily taken up by the RES in undesirable organs such as the liver and lungs. 【0108】 The membrane material for step (c) is selected from the group consisting of cellulose (and its derivatives), PES, PTFE, nylon, PVDF, and PP; preferably, cellulose (and its derivatives), PES, and PP. 【0109】 In one embodiment, before step (d), steps (b) and (c) are repeated at least once, for example, 1, 2, 3, or 4 times, thereby effectively removing unnecessary low-molecular impurities and large aggregates. 【0110】 After step (c), the filtrate is stored at 2 - 8°C. 【0111】 Optionally, this process further includes a lyophilization step (d) after step (c) to provide long-term stability of the nanoparticle composition. 【0112】 Pharmaceutical composition The present invention provides a pharmaceutical composition comprising the nanoparticle composition of the present invention and optionally one or more pharmaceutically acceptable carriers. Generally, in the case of tablets, powders, or parenteral preparations, the formulation of the nanoparticles in the pharmaceutical composition is about 1 - 90%, preferably 20 - 90%, or 30 - 80%. Generally, in the case of capsule preparations, the formulation of the nanoparticles in the pharmaceutical composition is 1 - 100%, preferably 20 - 100%, 50 - 100%, or 70 - 100%. Generally, in the case of suspension preparations, the formulation of the nanoparticles in the pharmaceutical composition is 1 - 50%, 5 - 50%, or 10 - 40%. 【0113】 In one embodiment, the pharmaceutical composition can be in the form of tablets, capsules, granules, fine granules, powders, suspensions, patches, parenterals, injections, or the like. The above pharmaceutical composition can be prepared by conventional methods. 【0114】 Pharmaceutically acceptable carriers that are inert ingredients can be selected by those skilled in the art using conventional criteria. Pharmaceutically acceptable carriers include, but are not limited to, physiological saline and aqueous electrolyte solutions; ionic and non-ionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and dextrose; pH adjusters and buffers such as salts of hydroxides, phosphoric acid, citric acid, acetic acid, boric acid, and trolamine; antioxidants such as bisulfites, sulfites, metabisulfites, thiosulfites, ascorbic acid, acetylcysteine, cysteine, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, and salts, acids, and / or bases of ascorbyl palmitate; surfactants such as lecithin and phospholipids including, but not limited to, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol; poloxamers and poloxamines; polysorbates such as polysorbate 80, polysorbate 60, and polysorbate 20; polyethers such as polyethylene glycol and polypropylene glycol; polyvinyls such as polyvinyl alcohol and polyvinylpyrrolidone (PVP, povidone); cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose, and their salts; petroleum derivatives such as mineral oil and white petrolatum; fats such as lanolin, peanut oil, palm oil, and soybean oil; mono-, di-, and triglycerides; polysaccharides such as dextran; and glycosaminoglycans such as sodium hyaluronate; and the like. Such pharmaceutically acceptable carriers may be preserved against bacterial contamination using well-known preservatives such as benzalkonium chloride, ethylenediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenyl ethyl alcohol, among others, or formulated as non-preserved formulations for single or multiple uses. 【0115】 For example, tablets, capsules, or parenteral formulations of the active compound may contain other excipients that are biologically inactive and do not react with the active compound. Excipients for tablets or capsules include fillers, binders, lubricants and glidants, disintegrants, wetting agents, and release rate regulators, among others. Examples of excipients for tablets or capsules include, but are not limited to, carboxymethyl cellulose, cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, karaya gum, starch, tragacanth gum, gelatin, magnesium stearate, titanium dioxide, poly(acrylic acid), and polyvinyl pyrrolidone. 【0116】 For example, tablet formulations may contain inactive ingredients such as colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide. Capsules may contain inactive ingredients such as gelatin, magnesium stearate, and titanium dioxide. Powder oral formulations may contain inactive ingredients such as silica gel, sodium benzoate, sodium citrate, sucrose, and xanthan gum. 【0117】 Method of treatment The present invention is directed to a method of treating CVD diseases, comprising the step of administering an effective amount of the nanoparticle composition of the present invention to a subject in need thereof. CVDs suitable for treatment according to the present invention include, but are not limited to, coronary artery disease, myocardial infarction, heart failure, aortic aneurysm, and atherosclerosis. 【0118】 As used in this application, "effective amount" means an amount effective to treat a disease by alleviating the medical condition or reducing the symptoms of the disease. 【0119】 The dosage of the injectable ligand-polymer-flavonoid, for example, ligand-polymer-EGGC, is generally 0.01 - 100 mg / kg (total weight of polymer-flavonoid / body weight of subject), or 0.01 - 1000 mg / kg. 【0120】 In one embodiment, the method includes administering to a subject in need thereof an effective amount of MINC having a shell, wherein the shell is formed by one or more ligand-hydrophilic polymer-flavonoid complexes and optionally naked polymer-flavonoid complexes, which may or may not contain flavonoid oligomers, and optionally has a drug encapsulated therein. 【0121】 In one embodiment, the shell is formed of ligand-PEG-EGCG and optionally PEG-EGCG. 【0122】 In one embodiment, the shell is formed of ligand-PEG-EGCG and OEGCG, and optionally PEG-EGCG. 【0123】 The dosage of the MINC-drug is based on the known dosage of the drug for treating a specific disease and the condition of the subject. The dosage may be the dosage approved by the Food and Drug Administration (FDA) or the dosage used in clinical trials. 【0124】 In the MINC-drug, the total weight of ligand-PEG-EGCG and PEG-EGCG (if present) is close to that of the encapsulated drug substance. The weight of OEGCG (if present) varies. Generally, the dosage when ligand-PEG-EGCG and PEG-EGCG (if present) are combined with OEGCG is 0.01 - 1000 mg / kg. 【0125】 The concentration of the encapsulated drug substance can be as low as 0.01 mg / kg (such as a cytokine drug) or as high as 100 mg / kg (such as an antibody drug). 【0126】 For the treatment of myocardial infarction, anti-IL-6 is intravenously administered at 0.01 - 100 mg / kg or 0.01 - 1000 mg / kg, 1 - 3 times a week. An effective amount of AT-MINC-IL-6 in a similar dosage range can be used for the treatment of myocardial infarction. 【0127】 For the treatment of heart failure or coronary artery disease, anti-IL-1β is intravenously administered at 0.01 to 100 mg / kg or 0.01 to 1000 mg / kg, once to three times a week. An effective amount of AT-MINC-anti-IL-1 within the same dosage range can be used for the treatment of heart failure, coronary artery disease, or aortic aneurysm. 【0128】 For the treatment of atherosclerosis, anti-EL (anti-endothelial lipase) is intravenously administered at 0.01 to 100 mg / kg or 0.01 to 1000 mg / kg, once every 1 to 3 months. An effective amount of MINC-anti-EL within the same dosage range can be used for the treatment of atherosclerosis. 【0129】 The present invention is useful for the treatment of humans and non-human animals. For example, the present invention is useful for treating mammalian subjects such as humans, horses, pigs, cats, and dogs. 【0130】 The following examples further illustrate the present invention. These examples are merely intended to illustrate the present invention and should not be construed in a limiting sense. 【Example】 【0131】 Example 1: Ligation of VS7 Peptide to HOOC-PEG-EGCG Materials The VS7 peptide was purchased from Hangzhou Xinbosi Biomedical Co., Ltd. HOOC-PEG-CHO was purchased from NBC chemical Co., Ltd. 【0132】 Methods HOOC-PEG-CHO was ligated to EGCG according to WO 2006 / 124000 pamphlet and WO 2009 / 054813 pamphlet; the VS7 peptide was ligated to HOOC-PEG-EGCG via the ligation between the COOH group on PEG and the NH2 group on VS7 to form VS7-PEG-EGCG (N'-ligation) (Figure 3). 【0133】 Specifically, the PEGylation of 1 - 1000 mg of VS7 was carried out by incubating it with 1 - 1000 mg of HOOC - PEG - EGCG, 1 - 1000 mg of N,N'-dicyclohexylcarbodiimide (DCC), and 1 - 1000 mg of N - hydroxysuccinimide (NHS) in DMSO. The reaction was carried out with stirring at room temperature for 24 hours under light shielding and nitrogen atmosphere. The reaction mixture was dialyzed against methanol and distilled water for 3 days (membrane fractional molecular weight = 2000 Da). Next, the solution was lyophilized to obtain a lyophilized powder. 【0134】 Results The formulation of VS7 - PEG - EGCG was confirmed using HPLC. HPLC was carried out under the following conditions: Column: C18, 4.6×150 mm, 4 μm; Eluent: A = 0.1% TFA in H2O, B = 0.1% TFA in ACN; Oven temperature: 40 °C; Flow rate: 1 ml / min; Autosampler temperature: 15 °C; Measurement: UV280. 【0135】 The retention time of HOOC - PEG - EGCG was 6.04 minutes, but after the ligation with VS7, a new peak with a retention time of 7.08 minutes was present. The HPLC results indicate that the ligation of VS7 - PEG - EGCG was successful. 【0136】 Example 2: Ligation of CST peptide to HOOC - PEG - EGCG Materials The CST peptide was purchased from Hangzhou Xinbosi Biomedical Co., Ltd. HOOC - PEG - CHO was purchased from NBC chemical Co., Ltd. 【0137】 Methods HOOC - PEG - CHO was ligated to EGCG according to WO 2006 / 124000 pamphlet and WO 2009 / 054813 pamphlet; the CST peptide was ligated to HOOC - PEG - EGCG via the ligation between the COOH group on PEG and the NH2 group on CST to form CST - PEG - EGCG (N'-ligation) (Figure 4). 【0138】 Specifically, the PEGylation of 1 - 1000 mg of CST was carried out by incubating it with 1 - 1000 mg of HOOC - PEG - EGCG, 1 - 1000 mg of N,N'-dicyclohexylcarbodiimide (DCC), and 1 - 1000 mg of N-hydroxysuccinimide (NHS) in DMSO. The reaction was carried out with stirring at room temperature for 24 hours under light shielding and nitrogen atmosphere. The reaction mixture was dialyzed against methanol and distilled water for 3 days (membrane fractionation molecular weight = 2000 Da). Next, the solution was lyophilized to obtain a lyophilized powder. 【0139】 Results The formulation of CST - PEG - EGCG was confirmed using HPLC. HPLC was carried out under the following conditions: Column: C18, 4.6×150 mm, 4 μm; Eluent: A = 0.1% TFA in H2O, B = 0.1% TFA in ACN; Oven temperature: 40 °C; Flow rate: 1 ml / min; Autosampler temperature: 15 °C; Measurement: UV280. 【0140】 The retention time of HOOC - PEG - EGCG was 6.04 minutes, but after the ligation with CST, a new peak with a retention time of 7.06 minutes was present. The HPLC results indicate that the ligation of CST - PEG - EGCG was successful. 【0141】 Example 3: Ligation of CLI peptide to HOOC - PEG - EGCG Materials The CLI peptide was purchased from Hangzhou Xinbosi Biomedical Co., Ltd. HOOC - PEG - CHO was purchased from NBC chemical Co., Ltd. 【0142】 Methods HOOC - PEG - CHO was ligated to EGCG according to WO 2006 / 124000 pamphlet and WO 2009 / 054813 pamphlet; the CLI peptide was ligated to HOOC - PEG - EGCG through the ligation between the COOH group on PEG and the NH2 group on CLI to form CLI - PEG - EGCG (N'-ligation) (Figure 5). 【0143】 Specifically, the PEGylation of 1 - 1000 mg of CLI was carried out by incubating it with 1 - 1000 mg of HOOC - PEG - EGCG, 1 - 1000 mg of N,N'-dicyclohexylcarbodiimide (DCC), and 1 - 1000 mg of N - hydroxysuccinimide (NHS) in DMSO. The reaction was carried out with stirring at room temperature for 24 hours under light shielding and nitrogen atmosphere. The reaction mixture was dialyzed against methanol and distilled water for 3 days (membrane fractionation molecular weight = 2000 Da). Next, the solution was lyophilized to obtain a lyophilized powder. 【0144】 Results The formulation of CLI - PEG - EGCG was confirmed using HPLC. HPLC was carried out under the following conditions: Column: C18, 4.6×150 mm, 4 μm; Eluent: A = 0.1% TFA in H2O, B = 0.1% TFA in ACN; Oven temperature: 40 °C; Flow rate: 1 ml / min; Autosampler temperature: 15 °C; Measurement: UV280. 【0145】 The retention time of HOOC - PEG - EGCG was 6.04 minutes, but after the conjugation with CLI, a new peak with a retention time of 7.20 minutes was present. The HPLC results indicate that the conjugation of CLI - PEG - EGCG was successful. 【0146】 Example 4: Preparation of VS7 - MINC - doxorubicin, CST - MINC - doxorubicin, and CLI - MINC - doxorubicin Materials VS7 - PEG - EGCG was prepared according to Example 1. CST - PEG - EGCG was prepared according to Example 2. CLI - PEG - EGCG was prepared according to Example 3. Doxorubicin was purchased from Sigma - Aldrich. 【0147】 Method VS7-MINC-doxorubicin nanoparticles, CST-MINC-doxorubicin nanoparticles, and CLI-MINC-doxorubicin nanoparticles were prepared according to the following protocol: 1. Incubate 5 - 500 μg of doxorubicin in 1 mL of DMSO for 15 minutes to 1 hour. 2. Add 1 - 100 μg of OEGCG and 1 - 10,000 μg of VS7-PEG-EGCG, CST-PEG-EGCG, or CLI-PEG-EGCG. Incubate the mixture at 25°C for 3 hours. 3. Filter the liquid through a 10K MWCO filter unit. Wash the filter three times with 0.9% NaCl. 4. Lyophilize to obtain a dry powder. 【0148】 Results The nanoparticle size was measured by DLS (Anton Paar, Litesizer 500). Figure 6 shows the successful formulation of (A) VS7-MINC-doxorubicin, (B) CST-MINC-doxorubicin, and (C) CLI-MINC-doxorubicin. 【0149】 Example 5: Various ligand-conjugated MINC-doxorubicin in drug delivery to cardiomyocytes Materials VS7-MINC-doxorubicin, CST-MINC-doxorubicin, and CLI-MINC-doxorubicin were formulated according to Example 4. 【0150】 Methods The cardiomyoblast cell line H9C2 was seeded in a 96-well plate at 8×103 cells / well and incubated overnight. On the second day, the cells were treated with 2.5 μM of MINC-doxorubicin, VS7-MINC-doxorubicin, CST-MINC-doxorubicin, or CLI-MINC-doxorubicin for 2 hours (n = 2). After treatment, the delivery efficiency was evaluated by measuring the fluorescence intensity using a Molecular Devices Gemini XPS fluorescence microplate reader. The data are shown as mean ± SD and were statistically analyzed using GraphPad Prism 7. Statistical significance was calculated by one-way ANOVA, * : p < 0.05, ** : p < 0.01, *** : p < 0.001, **** : and a significant difference was considered at p < 0.0001. 【0151】 Results Doxorubicin is a red fluorescent compound, and its delivery into cells was observed using a fluorescence microplate reader. The higher the fluorescence intensity, the more doxorubicin was delivered into the cells. In Figure 7, compared with MINC-doxorubicin, the fluorescence signals of VS7-MINC-doxorubicin and CLI-MINC-doxorubicin were significantly stronger in H9C2 cells. Also, a tendency for a higher fluorescence signal was observed in CST-MINC-doxorubicin-treated cells. These results indicate that the heart-targeting peptide increased the specific drug delivery to cardiomyoblasts. 【0152】 Example 6: Ligation of the VS7 Peptide to HO-PEG-EGCG (Predictive Example) Objective This experiment aims to illustrate the ligation of the VS7 peptide to HO-PEG-EGCG. Using HPLC, the formation of a new product (VS7-PEG-EGCG) with a retention time different from that of HO-PEG-EGCG was detected. The structure can be confirmed using NMR. 【0153】 Materials Purchase the VS7 peptide from Hangzhou Xinbosi Biomedical Co., Ltd. Purchase HO-PEG-CHO from Huanteng pharma Co., Ltd. 【0154】 Method Prepare HO-PEG-EGCG by linking HO-PEG-CHO to EGCG according to the pamphlets of International Publication No. WO2006 / 124000 and International Publication No. WO2009 / 054813. 【0155】 Link the VS7 peptide to HO-PEG-EGCG via a linkage between the OH group on PEG and the COOH group on VS7 to form VS7-PEG-EGCG (C' linkage). Refer to Figure 8. 【0156】 Specifically, the PEGylation of 1 - 1000 mg of VS7 is carried out by incubating it with 1 - 1000 mg of HO-PEG-EGCG and 1 - 1000 mg of N,N'-dicyclohexylcarbodiimide (DCC) in DMSO. The reaction is carried out with stirring at room temperature for 24 hours under light shielding and nitrogen atmosphere. The reaction mixture is dialyzed against methanol and distilled water for 3 days (membrane molecular weight cut-off = 2000 Da). Then, the solution is lyophilized to obtain a lyophilized powder. 【0157】 Example 7: Linkage of CST peptide to HO-PEG-EGCG (predicted example) Objective The purpose of this experiment is to illustrate the linkage of the CST peptide to HO-PEG-EGCG. Detect the formation of a new product (CST-PEG-EGCG) with a retention time different from that of HO-PEG-EGCG using HPLC. The structure can be confirmed using NMR. 【0158】 Materials Purchase the CST peptide from Hangzhou Xinbosi Biomedical Co., Ltd. Purchase HO-PEG-CHO from Huanteng pharma Co., Ltd. 【0159】 Method HO-PEG-EGCG is prepared by linking HO-PEG-CHO to EGCG according to the pamphlets of International Publication No. WO 2006 / 124000 and International Publication No. WO 2009 / 054813. 【0160】 The CST peptide is linked to HO-PEG-EGCG via a linkage between the OH group on PEG and the COOH group on CST to form CST-PEG-EGCG (C'-linkage). Refer to Figure 9. 【0161】 Specifically, the PEGylation of 1 to 1000 mg of CST is carried out by incubating with 1 to 1000 mg of HO-PEG-EGCG and 1 to 1000 mg of N,N'-dicyclohexylcarbodiimide (DCC) in DMSO. The reaction is carried out by stirring at room temperature for 24 hours under light shielding and nitrogen atmosphere. The reaction mixture is dialyzed against methanol and distilled water for 3 days (membrane molecular weight cut-off = 2000 Da). Next, the solution is lyophilized to obtain a lyophilized powder. 【0162】 Example 8: Linkage of CLI Peptide to HO-PEG-EGCG (Predictive Example) Objective This experiment aims to illustrate the linkage of the CLI peptide to HO-PEG-EGCG. HPLC is used to detect the formation of a new product (CLI-PEG-EGCG) having a retention time different from that of HO-PEG-EGCG. The structure can be confirmed using NMR. 【0163】 Materials The CLI peptide is purchased from Hangzhou Xinbosi Biomedical Co., Ltd. HO-PEG-CHO is purchased from Huanteng pharma Co., Ltd. 【0164】 Method HO-PEG-CHO is linked to EGCG according to the pamphlets of International Publication No. WO2006 / 124000 and International Publication No. WO2009 / 054813 to prepare HO-PEG-EGCG. 【0165】 The CLI peptide is linked to HO-PEG-EGCG via a linkage between the OH group on PEG and the COOH group on CLI to form CLI-PEG-EGCG (C' linkage). Refer to Figure 10. 【0166】 Specifically, the PEGylation of 1 - 1000 mg of CLI is carried out by incubating with 1 - 1000 mg of HO-PEG-EGCG and 1 - 1000 mg of N,N'-dicyclohexylcarbodiimide (DCC) in DMSO. The reaction is carried out with stirring at room temperature for 24 hours under light-shielding and nitrogen atmosphere. The reaction mixture is dialyzed against methanol and distilled water for 3 days (membrane molecular weight cut-off = 2000 Da). Next, the solution is lyophilized to obtain a lyophilized powder. 【0167】 Example 9: Linkage of VS7 Peptide to HOOC-PLA-EGCG (Predictive Example) Objective This experiment aims to illustrate the linkage of the VS7 peptide to HOOC-PLA-EGCG. Using HPLC, the formation of a new product (VS7-PLA-EGCG) with a retention time different from that of HOOC-PLA-EGCG is detected. The structure can be confirmed using NMR. 【0168】 Materials The VS7 peptide is purchased from Hangzhou Xinbosi Biomedical. HOOC-PLA-CHO is purchased from Merck (Sigma-Aldrich). 【0169】 Method Link HOOC-PLA-CHO to EGCG according to WO 2006 / 124000 pamphlet and WO 2009 / 054813 pamphlet; link the VS7 peptide to HOOC-PLA-EGCG via a linkage between the COOH group on PLA and the NH2 group on VS7 to form VS7-PLA-EGCG (N'-linked). Refer to Figure 11. 【0170】 Specifically, incubate 1 - 1000 mg of VS7 with 1 - 1000 mg of HOOC-PLA-EGCG, 1 - 1000 mg of N,N'-dicyclohexylcarbodiimide (DCC), and 1 - 1000 mg of N-hydroxysuccinimide (NHS) in DMSO. The reaction is carried out with stirring at room temperature for 24 hours under light shielding and a nitrogen atmosphere. Dialyze the reaction mixture against methanol and distilled water for 3 days (membrane molecular weight cut-off = 2000 Da). Then, lyophilize the solution to obtain a lyophilized powder. 【0171】 Example 10: Linkage of VS7 Peptide to HOOC-PLGA-EGCG (Predictive Example) Objective This experiment aims to illustrate the linkage of the VS7 peptide to HOOC-PLGA-EGCG. Detect the formation of a new product (VS7-PLGA-EGCG) with a retention time different from that of HOOC-PLGA-EGCG using HPLC. The structure can be confirmed using NMR. 【0172】 Materials Purchase the VS7 peptide from Hangzhou Xinbosi Biomedical. Purchase HOOC-PLGA-CHO from Merck (Sigma-Aldrich). 【0173】 Methods Link HOOC-PLGA-CHO to EGCG according to WO 2006 / 124000 and WO 2009 / 054813; link the VS7 peptide to HOOC-PLGA-EGCG via a linkage between the COOH group on PLGA and the NH2 group on VS7 to form VS7-PLGA-EGCG (N'-linked). Refer to Figure 12. 【0174】 Specifically, 1 to 1000 mg of VS7 is incubated in DMSO with 1 to 1000 mg of HOOC-PLGA-EGCG, 1 to 1000 mg of N,N'-dicyclohexylcarbodiimide (DCC), and 1 to 1000 mg of N-hydroxysuccinimide (NHS). The reaction is carried out with stirring at room temperature for 24 hours under light shielding and a nitrogen atmosphere. The reaction mixture is dialyzed against methanol and distilled water for 3 days (membrane molecular weight cut-off = 2000 Da). Next, the solution is lyophilized to obtain a lyophilized powder. 【0175】 Example 11: Linkage of the VS7 Peptide to HO-Dextran-EGCG (Predictive Example) Objective This experiment aims to illustrate the linkage of VS7 to HO-dextran-EGCG. Using HPLC, the formation of a new product (VS7-dextran-EGCG) with a retention time different from that of HO-dextran-EGCG is detected. The structure can be confirmed using NMR. 【0176】 Materials Purchase the VS7 peptide from Hangzhou Xinbosi Biomedical. Purchase HO-dextran-CHO from Merck (Sigma-Aldrich). 【0177】 Method Prepare HO-dextran-EGCG by linking HO-dextran-CHO to EGCG according to WO 2006 / 124000 and WO 2009 / 054813. 【0178】 VS7 is linked to HO-dextran-EGCG via a linkage between the OH group on dextran and the COOH group on VSP7 to form VS7-dextran-EGCG (C’ linkage). Refer to Figure 13. 【0179】 Specifically, 1 to 1000 mg of VS7 is incubated in DMSO together with 1 to 1000 mg of HO-dextran-EGCG and 1 to 1000 mg of N,N'-dicyclohexylcarbodiimide (DCC). The reaction is carried out by stirring at room temperature for 24 hours under light-shielding and nitrogen atmosphere. The reaction mixture is dialyzed against methanol and distilled water for 3 days (membrane molecular weight cut-off = 2000 Da). Next, the solution is lyophilized to obtain a lyophilized powder. 【0180】 Example 12: Efficacy study (predictive example) of MINC-anti-CD3, VS7-MINC-anti-CD3, CST-MINC-anti-CD3, or CLI-MINC-anti-CD3 in a mouse model of acute myocardial infarction. Objective This experiment aims to illustrate the improvement of the therapeutic effect of MINC-anti-CD3 in comparison with MINC-anti-CD3. The therapeutic utility of heart-targeted peptide-conjugated MINC-anti-CD3 is evaluated using histological analysis of survival rate and myocardial infarction size. 【0181】 Materials Male C57BL / 6 mice are purchased from BioLasco. AT-MINC-anti-CD3 is formulated according to Example 4. Anti-CD3 antibody is purchased from Biolegend. MINC-anti-CD3 is prepared according to Example 4. 【0182】 Methods Male C57BL / 6 mice (10 - 12 weeks old) are induced to have myocardial infarction (MI). Briefly, on the first day, after anesthesia with isoflurane, the mice are intubated and connected to a small animal volume control ventilator. After exposing the heart by sternotomy, the left anterior descending branch (LAD) is permanently occluded with a suture. The sternotomy incision is closed and the mice are allowed to recover. On the 3rd to 7th day after MI, on the first and second days, the mice are grouped and administered anti-CD3, MINC-anti-CD3, VS7-MINC-anti-CD3, CST-MINC-anti-CD3, or CLI-MINC-anti-CD3 at 5 - 125 μg / mouse by tail vein injection. The survival rate is evaluated until the 14th day after the surgery. On the 14th day, after anesthetizing the mice, Evans blue dye (0.1 g / ml) is injected into the abdominal aorta (1 ml). The heart is quickly excised, weighed, and fixed with 4% paraformaldehyde. The infarcted area is pale white, while the non-infarcted area is red. Each slice is photographed and analyzed. The ratio of the myocardial infarction size is calculated using computerized area measurement (Image J). The ratio of the infarct size for each slice is calculated and the average is determined between the slices. 【0183】 Abbreviation Table 【Table 1】 【0184】 The present invention, as well as its modes and processes of manufacture and use, are described herein in full, clear, concise, and exact terms so that any person skilled in the art to which they pertain can make and use them. It is to be understood that the above describes preferred embodiments of the invention and that changes may be made thereto without departing from the scope of the invention as set forth in the claims. The specification is concluded by the following claims for the purpose of particularly pointing out and distinctly claiming the subject matter regarded as the invention.

Claims

[Claim 1] (a) Cardiovascular disease (CVD) targeted ligand; (b) Hydrophilic polymer which is polyethylene glycol (PEG), polylactic acid (PLA), polylactic acid-co-glycolic acid (PLGA), or dextran; and (c) Structure as shown below: 【Chemistry 1】 A complex comprising a flavonoid, which is EGCG, EC, EGC, or ECG, The hydrophilic polymer is covalently bonded to the flavonoid and the CNS-targeting ligand. The CVD-targeted ligand is VS7 peptide having amino acid sequence VVLVTSS (SEQ ID NO: 1), CST peptide having amino acid sequence CSTSMLKAC (SEQ ID NO: 2), CLI peptide having the amino acid sequence CLIDLHVMC (SEQ ID NO: 3), CTT peptide having amino acid sequence CTTHWGFTLC (SEQ ID NO: 4), Atrial natriuretic peptide (ANP) peptide having the amino acid sequence SLRRSSCFGGRMDRIGAQSGLGCNSFRY (SEQ ID NO: 5), CRS peptide having the amino acid sequence CRSWNKADNRSC (SEQ ID NO: 6), DF8 peptide having amino acid sequence DRVYIHPF (SEQ ID NO: 7), CRP peptide having the amino acid sequence CRPPR (SEQ ID NO: 8), CRP peptide having the amino acid sequence CRPPR (SEQ ID NO: 8), QV7 peptide having amino acid sequence QAQGQLV (SEQ ID NO: 9), AV7 peptide having the amino acid sequence ARRGQAV (SEQ ID NO: 10), GV7 peptide having the amino acid sequence GRRFIRV (SEQ ID NO: 11), VR7 peptide having amino acid sequence VHPKQHR (SEQ ID NO: 12), VK7 peptide having amino acid sequence VHSPNKK (SEQ ID NO: 13), CC9 peptide having amino acid sequence CNNSKSHTC (SEQ ID NO: 14), NA17 peptide having amino acid sequence NNQKIVNLKEKVAQLEA (SEQ ID NO: 15), RGD peptide having the amino acid sequence RGD, GC11 peptide having the amino acid sequence GPXRSGGGGKC (SEQ ID NO: 16), KL9 peptide having amino acid sequence KKLVPRGSL (SEQ ID NO: 17), CRK peptide having the amino acid sequence CRKRLDRNC (SEQ ID NO: 18), CRT peptide having the amino acid sequence CRTLTVRKC (SEQ ID NO: 19), CKR peptide having amino acid sequence CKRAVR (SEQ ID NO: 20), CPK peptide having the amino acid sequence CPKTRRVPC (SEQ ID NO: 21), CAR peptide having the amino acid sequence CARPAR (SEQ ID NO: 22), CRS9 peptide having the amino acid sequence CRSTRANPC (SEQ ID NO: 23), GQ7 peptide having the amino acid sequence GGGVFWQ (SEQ ID NO: 24), HH7 peptide having the amino acid sequence HGRVRPH (SEQ ID NO: 25), CLH peptide having the amino acid sequence CLHRGNSC (SEQ ID NO: 26), and CRS12 peptide having the amino acid sequence CRSWNKADNRSC (SEQ ID NO: 27) Selected from the group consisting of, A complex. [Claim 2] The complex according to claim 1, wherein the flavonoid is EGCG. [Claim 3] The composite according to claim 1, wherein the hydrophilic polymer is PEG. [Claim 4] A nanoparticle composition comprising nanoparticles having (a) an outer shell containing a complex according to any one of claims 1 to 3; optionally, (b) an inner shell containing one or more flavonoid oligomers; and optionally, (c) a drug encapsulated within the shell, wherein the flavonoid is EGCG, EC, EGC, or ECG, and the drug is effective in treating CNS diseases. [Claim 5] The encapsulated drugs are IGF-1, TGF-β1, MCP-1, TIMP-1, VEGF, β-FGF, endothelin-1, urocortin, VEGF, HGF, FGF, PDGF, TGF-β, neuregulin, NO synthase, evasin-3, evasin-4, IL-1 trap, IL-1RA, anti-CD3, anti-CD39, anti-CD73, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, anti-GZM A, and anti-GZM B, anti-IL-1β, anti-IL-8, anti-TNF-α, anti-CCL-5, anti-MCP-1, anti-CXCR2, anti-IL-6R, IL-19, anti-IL-12, anti-IL-23, anti-MMP9, anti-IL-1β, anti-TNF-α, anti-IL-1β, anti-IL-6, anti-IL-7, anti-IL-12 or anti-IL-23, sacubitril, valsartan, aliskiren, enoxaparin, clopidogrel, abciximab, eptifivatide The nanoparticle composition according to claim 4, wherein the nanoparticles are tifibate, bivalirudin, morphine, cyclosporine A, furosemide, staphylokinase, dapagliflozin, anakinra, canakinumab, rimonabant, rosmapimod, or darapladib. [Claim 6] The nanoparticle composition according to claim 4, further comprising a bare hydrophilic polymer-flavonoid complex in which the outer shell is not covalently bonded to the CVD-targeted ligand. [Claim 7] A pharmaceutical composition for use in a method for treating CVD disease, comprising the nanoparticle composition described in claim 4. [Claim 8] The pharmaceutical composition according to claim 7, wherein the CVD disease is coronary artery disease, myocardial infarction, heart failure, atherosclerosis, aneurysm, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, heart rhythm abnormality, congenital heart disease, valvular heart disease, carditis, aortic aneurysm, peripheral artery disease, thromboembolism, or venous thrombosis.

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