Dendrimer compositions for the treatment of atherosclerosis, obesity, and metabolic syndromes

Abstract

Dendrimer-drug compositions have been developed that not only target the reactive inflammatory cells / macrophages in the plaque, but also in the adipose tissue, delivering drugs in a targeted manner to simultaneously and independently address both atherosclerosis and obesity, and associated metabolic disorders.   The dendrimers are preferably glucose dendrimers, hydroxyl-terminated PAMAM dendrimers, or sugar-modified dendrimers, most preferably glucose dendrimers.   The drugs are preferably a PPAR-α agonist; a PPAR-γ agonist; a dual PPAR agonist (e.g., a PPAR- α / γ agonists); a GLP-1 receptor agonist (e.g., semaglutide); a metformin; an SGLT2 agonist, a GIP-1 receptor agonist or antagonist; a dual GLP-1 / GIP-1 receptor agonist (e.g., tirzepatide); a mitochondrial uncoupler (e.g., niclosamide); or a combination thereof. These compositions have the ability to overcome the side effects of current drugs for obesity and heart disease, and open new avenues in addressing these disorders through targeting of selective cells.

Description

DENDRIMER COMPOSITIONS FOR THE TREATMENT OFATHEROSCLEROSIS, OBESITY, AND METABOLIC SYNDROMESCROSS REFERENCE TO RELATED APPLICATIONSThe application claims the benefit of and priority to U.S. Provisional Application No. 63 / 611,586, filed December 18, 2023, which is hereby incorporated by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCHThis invention was made with government support under Grant Nos. AG063831 and NS113140 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTIONThe disclosed invention is generally in the field of therapeutic agents causing weight loss and specifically in the area of dendrimer conjugated compounds and methods of use thereof for treatment of obesity, atherosclerosis, and / or metabolic syndrome.BACKGROUND OF THE INVENTIONAtherosclerosis is a major contributor to catastrophic cardiovascular diseases and events including heart attack, stroke and limb ischemia leading to amputation, resulting in the number one cause of death globally. The mainstay of therapy remains mitigation of risk factors, cholesterol lowering and lifestyle changes including stopping smoking, diet and exercise to manage obesity and type 2 diabetes. While these approaches are effective in delaying atherosclerosis progression, patient compliance remains low and incidence of life / limb threatening sequelae remains high. Due to the lack of therapies to treat and regress plaque, surgical intervention is the only option, and patients often progress from angioplasty and stent placement to requiring by-pass surgery. In the lower extremity in particular, bypass grafts have a high failure rate, and the need for repeat-procedures further increases not only the risk of mortality but also the emotional, societal, and financial burden of this formidable global issue. Thus, there is a critical unmet need to develop therapies to regress plaque that can be rapidly translated to the bedside. Obesity is a common, serious, and costly chronic disease of adults and children that continues to increase in the United States. Obesity can lead to type 2 diabetes, heart disease, and some cancers. Weight that is higher than what is considered healthy for a given height is described as overweight or obesity. Body Mass Index (BMI) is a screening tool for overweight and obesity. If the BMI is 25.0 to <30, it falls within the overweight range. A BMI of 30.0 or higher, falls within the obesity range. Obesity is frequently subdivided into categories: Class 1: BMI of 30 to < 35; Class 2: BMI of 35 to < 40, and Class 3: BMI of 40 or higher. Class 3 obesity is sometimes categorized as “severe” obesity.Metabolic syndrome is a group of conditions that together raise your risk of coronary heart disease, diabetes, stroke, and other serious health problems. Metabolic syndrome is also called insulin resistance syndrome. Metabolic syndrome is common in the United States. About 1 in 3 adults have metabolic syndrome. Metabolic syndrome is often diagnosed if an individual has abdominal obesity or "having an apple shape." Extra fat in the stomach area is a bigger risk factor for heart disease than extra fat in other parts of the body. If the blood pressure rises and stays high for a long time, it can damage the heart and blood vessels. High blood pressure can also cause plaque to build up in your arteries. Plaque can cause heart and blood vessel diseases such as heart attack or stroke.High blood sugar levels also can damage blood vessels and raise the risk of blood clots. Blood clots can cause heart and blood vessel diseases. High blood levels of triglycerides can raise the levels of LDL cholesterol, which raises the risk of heart disease.HDL cholesterol can help remove LDL cholesterol from the blood vessels, decreasing the risk of plaque buildup in the blood vessels.Treatment options that are effective for treating all of these indications are limited. Atherosclerosis is a major contributor to catastrophic cardiovascular diseases and events including heart attack, stroke and limb ischemia leading to amputation, resulting in the number one cause of death globally. Due to the lack of therapies to treat and regress plaque, surgical intervention is the only option, and patients often progress from angioplasty and stent placement to requiring by-pass surgery. Therapeutic approaches that can penetrate the plaque and target specific cells and delivery drugs into them would present major opportunities to address unmet needs in this area.Macrophages are involved not only in plaque propagation but are also seen in the adipose tissue in obesity. In normal people, only 10% of cells in white adipose tissue are macrophages but this can increase to up to 50% of cells in obesity leading to a state of chronic low grade inflammation that is associated with co-morbidities of obesity such as insulin resistance, Type 2 diabetes, atherosclerosis, and associated cardiovascular disease. Inflammation resulting in increased cytokine production from adipose tissue macrophages can worsen metabolic syndromes such as Type 2 diabetes and obesity due to increased lipid deposition, glucose intolerance and increased insulin resistance. Liang, W., Qi, Y., Yi, H., Mao, C., Meng, Q., Wang, H., & Zheng, C. (2022). Frontiers in immunology, 13, 908749. https: / / doi.org / 10.3389 / fimmu.2022.908749Targeting inflammation in obesity by specifically targeting adipose macrophages provides a unique mechanism to treat both obesity and co-morbidities and metabolic syndromes associated with it. It is therefore an object of the present invention to provide safer and / or more effective compositions for treatment of atherosclerosis, obesity and other metabolic diseases.BRIEF SUMMARY OF THE INVENTIONAtherosclerosis is often associated with obesity. Atherosclerosis and obesity share something common in terms of the role of inflammatory cells. Targeting inflammation in obesity provides a unique mechanism to treat both obesity and co-morbidities and metabolic syndromes associated with it. Dendrimer-drug compositions have been developed that not only target the reactive inflammatory cells / macrophages in the plaque, but also in the adipose tissue, delivering drugs in a targeted manner to simultaneously and independently address both atherosclerosis and obesity, and associated metabolic disorders. The dendrimers are preferably glucose dendrimers, hydroxyl-terminated PAMAM dendrimers, or sugar-modified dendrimers, most preferably glucose dendrimers. Preferred glucose dendrimers include G1, G2, and G3 glucose dendrimers, while preferred PAMAM dendrimers include G3, G4, G5, and G6 hydroxyl-terminated PAMAM dendrimers. The density and loading of agent on the dendrimer, the means of attachment of the agents to the dendrimer, the size and chemical composition of the dendrimer as well as the size and composition of linker to the agent, if any, govern the rate, selectivity, and activity of the agent to the site of delivery where the agent binds to receptor. In a preferred embodiment, a cleavable linker binds the agent to the dendrimer. In the most preferred embodiment, the cleavable linker is an ester. In some forms, the linker contains a triazole moiety. In some forms, the agent (e.g., the drug) has a loading between about 2% and about 35% by weight of the composition. In some forms, the agent (e.g., the drug) has a loading between about 2% and about 35% by weight of the dendrimer-agent conjugate (e.g., dendrimer-drug conjugate)..Dendrimer-drug compositions of small molecule drugs include PPAR- α / γ agonists such as TESAGLITAZAR; Metformin; glucagon-like peptide-1 (GLP-1) receptor agonists such as Semaglutide (OZEMPIC®); sodium-glucose co-transporter 2 (SGLT2) agonists such as canagliflozin (INVOKANA®), a GIP-1 receptor agonist or antagonist; a dual GLP-1 / GIP-1 receptor agonist (e.g., tirzepatide); a mitochondrial uncoupler (e.g., niclosamide); or a combination thereof. Efficacy of an exemplary dendrimer conjugate, dendrimer-tesaglitazar, was validated in an ApoE- / - mouse model. Route of administration, typically oral, intranasal or applied to other mucosal surface, affects the rate and dosage of the dendrimer conjugate to the brain. The dendrimer increases the brain uptake, solubility, target engagement, PK, and helps confine the drug to the right compartment. In some embodiments, the dendrimer is used to retain the therapeutic agent in the peripheral circulation rather than the central circulation. BRIEF DESCRIPTION OF THE DRAWINGSFIG.1is the protocol for the High fat diet (“HFD”) feeding of the mice, FIG. 2A-2D are graphs of the % change in body weight (2A), grams body weight (2B), % fat mass (2C), and % lean mass (2D) for mice on a HFD treated with free Tesa compared to dendrimer conjugated Tesa (D-Tesa).FIG. 3A-3C showing D-Tesa ameliorates markers of atherosclerosis: PWV is ameliorated with D-Tesa treatment, but not free Tesaglitazar(3A) (n=8-10 male mice per group); ****p<0.0001 by 2-way ANOVA. Systolic blood pressure (3B) was unchanged throughout the experiment. Body weight (3C) showed an increase due to HFD administration but decreased after D-Tesa treatment (n=8-9 male mice per group). (3C) During treatment, untreated mice did not lose weight, but D-Tesa treated mice exhibited a steady decrease.FIG. 4 is a graph of the percent lesion area comparing treatment with D-Tesa and untreated mice on a HFD.FIG. 5A-5D are graphs of relaxation (% PE Max) versus dose of D-Tesa (5A. 5C) and log EC50 (5B, 5D) for Ach dose (5A, 5C) or SNP dose (5C, 5D). Relaxation of PE pre-constricted aorta from baseline, untreated, and D-Tesa treated induced by increasing concentrations of acetylcholine (Ai) and sodium nitroprousside (Bi). -LogEC50s for Ach (Aii) and SNP (Bii) are calculated from dose response curves. (n=4 per group; *p<0.05, **p<0.01 by 1-way ANOVA).FIG. 6A and 6B are graphs showing D-Tesa treatment results in increase of PPAR-α / γ. Aortic lysate extracts from D-Tesa treated apoE mice on HFD shows increase in both PPAR-α (6A) and PPAR-γ (6B) when compared to untreated ApoE mice on HFD.FIG. 7A-7F demonstrates efficacy of D-Tesa and that it does not show the side effects of free Tesa. VCO2(FIG. 7A) and VO2 (FIG. 7B) are increased in D-Tesa treated mice versus vehicle and free Tesa treated mice, leading to an increased energy expenditure (FIG. 7C). Despite greater food intake (FIG. 7D), body weight in D-Tesa treated mice is significantly lower than vehicle treated mice after 3 weeks (FIG. 7E). Edema measured by degree of paw edema, a common side effect of Tesaglitazar, is not seen in D-Tesa treated mice but is observed in free Tesaglitazar treated mice (FIG. 7F).FIGs. 8A-8I are representative data showing that D-Tesa upregulates ABCA1 through PPAR-α / γ in vitro.FIGs. 9A-9D are representative data showing that PO D-Cy5 administration localize into plaque and adipose tissue macrophages. FIGs. 10A-10Mare representative data showing that D-Tesa halts aortic plaque progression through improved cholesterol efflux.FIGs. 11A-11N are representative data showing that D-Tesa improves aortic vessel stiffness.FIGs. 12A-12L are representative data showing that D-Tesa halts endothelial dysfunction due to progression of atherosclerosis.FIGs. 13A-13N are representative data showing that D-Tesa delivery to WAT (white adipose tissue) results in reduced inflammation and browning of adipocytes.FIGs. 14A-14F are representative data showing that dendrimer conjugation of Tesaglitazar circumvents renal side effects of systemic activation. FIGs. 15A-15M are representative data showing that physiological benefit of D-Tesa therapy are recapitulated in LDLr- / - with intact apoE mediated cholesterol efflux. FIGs. 16A-16D are representative data showing that intraperitoneal (IP) D-Cy5 administration shows localization into plaque and adipose tissue macrophages.FIGs. 17A-17F are representative data showing that D-Tesa circumvents side effects of weight gain and impaired kidney function in female apoE- / - mice.FIGs. 18A-18L are representative data showing that D-ApoE- / - mice treated with D-Tesa show improved inflammatory profile.FIG. 19shows the structure of an exemplary glucose dendrimer (GD) GLP-1 agonist conjugate, GD-Semaglutide. FIG. 20is a collection of micrographs showing that glucose dendrimer (GD) targets mitochondria of adipose cells (differentiated 3T3L1 cells), while hydroxyl-terminated poly(amidoamine) (HD) exhibits lower uptake: (top) dendrimer mitochondrial uptake differences in 1 hr; (bottom) dendrimer mitochondrial uptake differences in 24 hrs.FIG. 21is a synthesis scheme for an exemplary esterase cleavable niclosamide clickable conjugate (Niclosamide- PEG-N3).FIG. 22A is a representative H- NMR trace of an exemplary glucose dendrimer conjugated to a mitochondrial uncoupler, GD-niclosamide. FIG. 22B is a representative HPLC trace showing the newly formed conjugate at 335 nm. FIG. 23is a synthesis scheme for an exemplary dendrimer-GIP1 conjugate, dendrimer-tirzepatide conjugate. DETAILED DESCRIPTION OF THE INVENTIONI. DefinitionsThe terms “active agent” or “biologically active agent” are used interchangeably to refer to a chemical or biological compound that induces a desired pharmacological and / or physiological effect, which may be prophylactic, therapeutic, or diagnostic. These may be a nucleic acid, a nucleic acid analog, a small molecule having a molecular weight less than 2 kD, more typically less than 1 kD, a peptidomimetic, a protein or peptide, carbohydrate or sugar, lipid, or a combination thereof. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of agents, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, and analogs. An analog is a chemically modified active compound derived from the parent. The term “therapeutic agent” refers to an agent that can be administered to treat one or more symptoms of a disease or disorder. The term “diagnostic agent” generally refers to an agent that can be administered to reveal, pinpoint, and define the localization of a pathological process. The diagnostic agents can label target cells that allow subsequent detection or imaging of these labeled target cells. The term “therapeutically effective amount” refers to an amount of the therapeutic agent that, when incorporated into and / or onto dendrimers, produces some desired effect at a reasonable benefit / risk ratio applicable to any medical treatment. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted construct being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation. In some embodiments, the term “effective amount” refers to an amount of a therapeutic agent or prophylactic agent to reduce or diminish the symptoms of one or more diseases. The terms “inhibit” or “reduce” in the context of inhibition, mean to reduce, or decrease in activity and quantity. This can be a complete inhibition or reduction in activity or quantity, or a partial inhibition or reduction. Inhibition or reduction can be compared to a control or to a standard level. Inhibition can be 5, 10, 25, 50, 75, 80, 85, 90, 95, 99, or 100%. For example, dendrimer compositions including one or more inhibitors may inhibit or reduce the activity and / or quantity of diseased neurons by about 10%, 20%, 30%, 40%, 50%, 75%, 85%, 90%, 95%, or 99% from the activity and / or quantity of the same cells in equivalent tissues of subjects that did not receive, or were not treated with the dendrimer compositions. In some embodiments, the inhibition and reduction are compared at levels of mRNAs, proteins, cells, tissues, and organs. For example, an inhibition and reduction in the rate of neural loss, in the rate of decrease of brain weight, or in the rate of decrease of hippocampal volume, as compared to an untreated control subject. The term “treating” or “preventing” mean to ameliorate, reduce or otherwise stop a disease, disorder or condition from occurring or progressing in an animal which may be predisposed to the disease, disorder and / or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating, or palliating the disease state, and remission or improved prognosis. For example, an individual is successfully “treated” if one or more symptoms associated with depression are mitigated or eliminated, including, but are not limited to, reducing the level of anxiety, agitation, or restlessness, improving feelings of sadness, tearfulness, emptiness or hopelessness, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease.The phrase “pharmaceutically acceptable” or “biocompatible” refers to compositions, polymers, and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The phrase “pharmaceutically acceptable carrier” refers to pharmaceutically acceptable materials, compositions, or vehicles, such as a liquid or solid filler, diluent, solvent, or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient.The term “biodegradable” generally refers to a material that will degrade or erode under physiologic conditions to smaller units or chemical species that are capable of being metabolized, eliminated, or excreted in vivo. The degradation time is a function of composition and morphology. The term “dendrimer” includes, but is not limited to, a molecular architecture with an interior core, interior layers, or “generations” of repeating units regularly attached to this initiator core, and an exterior surface of terminal groups attached to the outermost generation.The term “functionalize” means to modify a compound or molecule in a manner that results in the attachment of a functional group or moiety. For example, a molecule may be functionalized by the introduction of a molecule that makes the molecule a strong nucleophile or strong electrophile. The term “targeting moiety” refers to a moiety that localizes to or away from a specific location. The moiety may be, for example, a protein, nucleic acid, nucleic acid analog, carbohydrate, or small molecule. The location may be a tissue, a particular cell type, a subcellular compartment, or a molecule such as a receptor. The term “prolonged residence time” refers to an increase in the time required for an agent to be cleared from a patient's body, or organ or tissue of that patient. In certain embodiments, “prolonged residence time” refers to an agent that is cleared with a half-life that is 10%, 20%, 50% or 75% longer than a standard of comparison such as a comparable agent without conjugation to a delivery vehicle such as a dendrimer. In certain embodiments, “prolonged residence time” refers to an agent that is cleared with a half-life of 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, or 10000 times longer than a standard of comparison such as a comparable agent without a dendrimer that specifically target specific cell types.The terms “incorporated” and “encapsulated” refer to incorporating, formulating, or otherwise including an agent into and / or onto a composition that allows for release, such as sustained release, of such agent in the desired application. The agent or other material can be incorporated into a dendrimer, by binding to one or more surface functional groups of such dendrimer (by covalent, ionic, or other binding interaction), by physical admixture, by enveloping the agent within the dendritic structure, and / or by encapsulating the agent inside the dendritic structure.“Hydroxyl-terminated,” as relates to dendrimers, refers to dendrimers that have a hydroxyl group on their surface. These hydroxyl groups are not attached to the termini of the dendrimers via a sugar moiety (such as a saccharide moiety).“Sugar-terminated,” as relates to dendrimers, refers to dendrimers that contain a sugar moiety (such as a saccharide moiety)on their surface and not in their core.“Sugar-based,” as relates to dendrimers, refers to dendrimers that contain a sugar moiety (such as a saccharide moiety) in their core, or their core and on their surface.“Analog” as relates to a given compound, refers to another compound that is structurally similar, functionally similar, or both, to the specified compound. Structural similarity can be determined using any criterion known in the art, such as the Tanimoto coefficient that provides a quantitative measure of similarity between two compounds based on their molecular descriptors. Preferably, the molecular descriptors are 2D properties such as fingerprints, topological indices, and maximum common substructures, or 3D properties such as overall shape, and molecular fields. Tanimoto coefficients range between zero and one, inclusive, for dissimilar and identical pairs of molecules, respectively. A compound can be considered an analog of a specified compound, if it has a Tanimoto coefficient with the specified compound between 0.5 and 1.0, inclusive, preferably between 0.7 and 1.0, inclusive, most preferably between 0.85 and 1.0, inclusive. A compound is functionally similar to a specified compound, if it induces the same pharmacological effect, physiological effect, or both, as the specified compound. “Analog” can also refer to a modification including, but not limited to, hydrolysis, reduction, or oxidation products, of the compounds. Hydrolysis, reduction, and oxidation reactions are known in the art.Immune targeting in obesity and cross talk between obesity and atherosclerosisMacrophages play a critical role in plaque development in atherosclerosis and in the adipose tissue in obesity. Adipose tissue macrophages can comprise up to 40%-50% of all the cells in white adipose tissue and obesity leads to a state of low grade inflammation that is associated with multiple co-morbidities of obesity such as atherosclerosis, cardiovascular disease, Type2 diabetes. Inflammation in adipose tissue macrophages lead to increased cytokine production and signaling, that subsequently leads to metabolic syndromes such as lipid deposition, glucotoxicity / glucose intolerance and insulin resistance. Targeting inflammation in obesity provides a unique mechanism to treat both obesity and co-morbidities and metabolic syndromes associated with it. Prior research has conclusively established the major role of both innate and adaptive immunity in the development and progression of atherosclerosis. The innate immune response in atherosclerosis is initiated by chronic inflammation, a hallmark of atherosclerosis. Chronic inflammation, particularly in branch points and other areas with oscillatory shear, causes endothelial cell activation and expression of adhesion molecules E-selectin and VCAM-1, which attracts dendritic cells and monocytes and stimulates monocyte to macrophage differentiation via the local production of macrophage colony stimulating factor (mCSF). The ensuing cholesterol uptake by macrophages results in the formation of foam cells that are characteristic of atherosclerosis. Pro-inflammatory M1-Macrophages further contribute to an aggravation of local inflammation, leading to activation of ECs, promoting VSMC motility and proliferation, and driving a vicious cycle of inflammation and cellular derangements leading to plaque growth. Macrophages in the plaque and dendritic cells act as antigen presenting cells and activate adaptive immune response. Th1 or pro-inflammatory cytokines such as TNF-a and IFN-g promote atherogenic inflammation and increase plaque instability that can lead to co-morbidities such as heart attacks and stroke. Due to the key role played by both the innate and adaptive immune system in plaque formation and progression, targeting the inflammatory system is a promising strategy in treatment of atherosclerosis. Targeting the immune system in atherosclerosis: Previous therapies have focused on binding IL-b (CANTOS study using Canakinumab an IL1b antibody showed some improvement in cardiovascular events). IL1 receptor antagonist anakinra ( MRC-ILA-HEART study, showed short term benefit but not long term), treatment with antibodies targeting IL6 receptors or ligands (tocilizumab and ziltivekimab) showed decrease in inflammation (long term ZEUS study ongoing); use of TNF-a inhibitors seem to be associated with decreased CVD; small molecule anti-inflammatory agents such as colchicine showed an improvement in CV events; CXCL1 neutralizing antibody, MLN1202, a highly specific humanized monoclonal antibody that prevents CCL2 binding, CXCR4 antagonist Plerixafor; immune checkpoint inhibitors targeting CD28, CD80,86, CTLA-4 and PD-1, or CD70, CD 27, CD137 9TNF superfamily), examples of these include--abatacept, a CTLA4-Ig construct that blocks CD80 / CD86 from interacting with CD28 and activating T cells or TRAF-STOP therapy with either SMI 6860766 or 6877002. Other targets include IL2 administration (LILACS and IVORY studies), rituximab (anti-CD20 antibody) targeting B cells. Other small molecules that decrease MACE are: Statins, GLP1 agonists such as semaglutide and analogs (e.g. Ozembic®) , Lp-PLA2 inhibitors such as darapladib, sPLA2 inhibitors such as Verespladib, 5-LO inhibitor, VIA-2291 (atreleuton); methotrexate, PPAR- α / γ agonists such as Tesaglitazar, Metformin have all shown some efficacy. However, trials have either not shown adequate efficacy or drugs have had debilitating side effects that has prevented further progression. These debilitating side effects can be prevented by specific delivery of these drugs to macrophages and / or neurons using hydroxyl and glucose dendrimers. Immune targeting in obesity and cross talk between obesity and atherosclerosisMacrophages play a critical role in plaque development in atherosclerosis and in the adipose tissue in obesity. Adipose tissue macrophages can comprise up to 40%-50% of all the cells in white adipose tissue and obesity leads to a state of low grade inflammation that is associated with multiple co-morbidities of obesity such as atherosclerosis, cardiovascular disease, Type2 diabetes. Inflammation in adipose tissue macrophages lead to increased cytokine production and signaling, that subsequently leads to metabolic syndromes such as lipid deposition, glucotoxicity / glucose intolerance and insulin resistance. Targeting inflammation in obesity provides a unique mechanism to treat both obesity and co-morbidities and metabolic syndromes associated with it. II.CompositionsA.Dendrimers1 Dendrimers are three-dimensional, hyperbranched, monodispersed, globular and polyvalent macromolecules including surface end groups (Tomalia, D. A., et al., Biochemical Society Transactions, 35, 61 (2007); and Sharma, A., et al., ACS Macro Letters, 3, 1079 (2014)). 2 The term “dendrimer” includes, but is not limited to, a molecular architecture with an interior core (“G0”) and layers (or “generations”) of repeating units which are attached to and extend from this interior core, each layer having one or more branching points, and an exterior surface of terminal groups attached to the outermost generation. In some embodiments, dendrimers have regular dendrimeric molecular structures, in other cases they can be hyperbranched structures with irregular branch lengths.3 Generally, the dendrimers have a diameter between about 1 nm and about 60 nm, more preferably between about 1 nm and about 50 nm, between about 1 nm and about 40 nm, between about 1 nm and about 30 nm, between about 1 nm and about 20 nm, between about 1 nm and about 10 nm, or between about 1 nm and about 5 nm. In some embodiments, the diameter is between about 1 nm to about 2 nm. The preferred size of the dendrimers for crossing the blood brain barrier (“BBB”) is less than 5 nm, whereas those for not crossing the BBB and staying in the peripheral circulation are greater than 5nm. In some embodiments, the dendrimers have a diameter effective to penetrate the BBB and to be retained close to or within target neural and / or glial cells for delivery of the agents conjugated thereto. In some embodiments, the dendrimers have a diameter effective to penetrate a BBB and to be internalized into target neural and / or glial cells for delivery of the agents conjugated thereto, such as for example, neurons, oligodendrocytes, astrocytes, microglial, and neuroglial support cells. In some embodiments, the dendrimers have a diameter effective to penetrate a barrier interface, such as a blood nerve barrier (“BNB”), and to be internalized into neural and glial cells of the peripheral nervous system for delivery of the agents conjugated thereto such as for example, neurons, Schwann cells, satellite cells, and neuroglial support cells. In some embodiments, the dendrimers have a diameter effective to be retained in the peripheral circulation for delivery of the agents conjugated thereto to target cells of the peripheral nervous system. In some embodiments, dendrimers have a molecular weight between about 500 Daltons and about 100,000 Daltons inclusive, between about 500 Daltons and about 50,000 Daltons inclusive, or between about 1,000 Daltons and about 20,000 Daltons inclusive. Dendrimer sizes <30,000 Da are preferred for transport across the BBB, and sizes of >50,000 Da are preferred for confinement to the periphery.In some embodiments, the dendrimers have a hypercore (e.g., dipentaerythritol) and one or more monosaccharide branching units. In some embodiments, the monosaccharide branching units are conjugated to the core or the prior layer of monomers via linkers such as polyethylene glycol chains. In preferred embodiments, the hypercore is dipentaerythritol and the monosaccharide branching unit is glucose-based branching unit such as shown in Structures II-IV. In the most preferred embodiment, the dendrimers are made entirely of glucose building blocks. PAMAM dendrimers modified by sugar may also work, but dendrimers made of sugars, especially glucose, are most preferred. Particularly preferred glucose dendrimers are G1 to G3 glucose dendrimers, such as G1, G2, and / or G3 glucose dendrimers.Suitable dendrimers scaffolds for use in the conjugates include, but are not limited to, poly(amidoamine), also known as PAMAM, or STARBURST™ dendrimers; polypropylamine (POPAM), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), aromatic polyether dendrimers, dendrimer of a sugar (e.g., glucose, galactose, mannose, fructose, etc.), and copolymers thereof, such as a copolymer of a sugar and an alkylene glycol (e.g., a dendrimer formed by glucose and ethylene glycol building blocks). The dendrimers can have a plurality of surface functional groups, such as carboxylic, amine, hydroxyl, and / or acetamide. The terms “surface functional groups” and “terminal groups” are used interchangeably herein. In some embodiments, the dendrimers have surface hydroxyl groups. In some embodiments, one or more of these surface functional groups are further modified with other molecules, such as further modified with a sugar (e.g., glucose, galactose, mannose, fructose, etc.) and / or a polyalkylene glycol, for example, polyethylene glycol, and thus have sugar molecules and / or polyalkylene glycols as terminal moieties / molecules. Preferred PAMAM dendrimers include hydroxyl-terminated PAMAM dendrimers, particularly G3 to G6 hydroxyl-terminated PAMAM dendrimers, such as G3, G4, G5, and G6 hydroxyl-terminated PAMAM dendrimers. Dendrimers can be any generation including, but not limited to, generation 1, generation 2, generation 3, generation 4, generation 5, generation 6, generation 7, generation 8, generation 9, or generation 10. In some embodiments, the dendrimers are PAMAM dendrimers used as a platform and modified with functional groups for increased number of surface hydroxyl groups. In some embodiments, the dendrimer-active agent conjugates can be confined to the peripheral circulation and specifically target a particular tissue region and / or cell type, such as peripheral neural and macrophage cells, by using higher generation dendrimer (such as generation 4, 5, or 6 PAMAM dendrimer, generation 2, 3, or higher glucose-based dendrimers). Additionally, or alternatively, the dendrimer-active agent conjugates can be confined to the peripheral circulation by appropriate functionalization of the dendrimer (such as PEGylation). In some embodiments, the dendrimers can specifically target a particular tissue region and / or cell type of the central nervous system (CNS), the peripheral nervous system (PNS), and / or the eye, such as neurons and glia of the CNS, and / or PNS, by using dendrimers of a certain generation, such as PAMAM dendrimers and / or glucose dendrimers of generation 2 (G2), G3, G4, and G5. In the most preferred embodiment, the dendrimers are made entirely of glucose building blocks. PAMAM dendrimers modified by sugar may also work, but dendrimers made of sugars, especially glucose, are most preferred. Monosaccharide-based DendrimersIn some embodiments, the branching units include monosaccharides. In some embodiments, the monosaccharide branching units are conjugated to the core or the prior layer of monomers via linkers such as polyethylene glycol chains. In some embodiments, the monosaccharide branching units are glucose-based branching units. In some embodiments, the branching units can include PEG and / or alkyl chain linkers between different dendrimer generations. For example, the glucose layers are connected via PEG linkers and triazole rings. In some embodiments, the branching units are the same for each generation of dendrimers generated from the core. Therefore, for example, the branching units are glucose-based branching units for generating generation 1 dendrimers, for generating generation 2 dendrimers, and for generating generation 3 dendrimers.In some embodiments, the dendrimers have a hypercore (e.g., dipentaerythritol) and one or more monosaccharide branching units. In some embodiments, the hypercore is dipentaerythritol and the monosaccharide branching unit is glucose-based branching unit. In further embodiments, spacer molecules can also be alkyl (CH2)n–hydrocarbon-like units. In some embodiments, dendrimers synthesized using glucose building blocks, with a surface made predominantly of glucose moieties, allow specific targeting in cells including injured neurons, ganglion cells, and other neuronal cells in the brain, the eye, and / or in peripheral nervous system. In some embodiments, the glucose-based dendrimer selectively targets or is enriched inside target neural and / or glial cells. In some embodiments, the glucose-based dendrimer selectively targets or enriched on the surface of target neural and / or glial cells. In some embodiments, the glucose-based dendrimer selectively targets or enriched inside target neuronal cells and on the surface of the target neural and / or glial cells. In some embodiments, the glucose-based dendrimer selectively targets or enriched inside and / or on the surface of injured, diseased, and / or hyperactive neurons and / or glial cells. In some cases, the dendrimers include an effective number of sugar molecules and terminal groups, for example, glucose and / or hydroxyl groups, for targeting to one or more neurons and / or glia of the CNS, PNS, and / or the eye. The terminal hydroxyl groups of these dendrimers may be part of terminal glucose molecules or extra hydroxyl groups that are not part of the glucose molecules, or a combination thereof. In some embodiments, all the terminal hydroxyl groups are part of the terminal glucose molecules. In some embodiments, the number of sugar molecules on the termination of dendrimer is determined by the generation number. In some embodiments, dendrimers are made of glucose and oligoethylene glycol building blocks. Exemplary glucose dendrimers are shown in Structures V and VII. Some exemplary glucose dendrimers include a generation 1 glucose dendrimer having 24 hydroxyl (-OH) end groups, a generation 2 glucose dendrimer having 96 hydroxyl (-OH) end groups, a generation 3 glucose dendrimer having 396 hydroxyl (-OH) end groups, and generation 4 glucose dendrimer having 1584 hydroxyl (-OH) end groups. For example, the glucose dendrimer is a generation 2 glucose-based dendrimer that has 24 glucose molecules at the periphery and 6 embedded glucose molecules in the backbone held together by PEG segments.Dendrimer compositions that can selectively accumulate inside neurons, particularly in the nucleus of injured and / or hyperactive neurons, referred to as “glucose dendrimers” have been developed. These dendrimers can also accumulate at a high level inside activated microglia. However, compared to hydroxyl dendrimers which primarily accumulate in microglia, these dendrimers primarily go to neurons. Glucose dendrimer are described in U.S.S.N. 63 / 327,610 “Dendrimer Compositions for Targeted Delivery of Therapeutics to Neurons” by The Johns Hopkins University, inventors Kannan Rangaramanujam, Rishi Sharma, Anjali Sharma, Sujatha Kannan, Nirnath Sah, Mira Sachdeva, and Siva P. Kambhampati filed April 5, 2022.Glucose dendrimers include (a) a central core, (b) one or more branching units, wherein the branching units are monosaccharide glucose-based branching units, optionally with a linker conjugated thereto; and optionally (c) one or more therapeutic, prophylactic and / or diagnostic agents. Generally, the one or more branching units are conjugated to the central core, and the surface groups of the dendrimer are monosaccharide glucose molecules. In some embodiments, the central core is dipentaerythritol, or a hexa-propargylated derivative thereof. In some embodiments, the branching unit is conjugated to the central core via a linker such as a hydrocarbon or an oligoethylene glycol chain. In a preferred embodiment, the branching units are β-D-Glucopyranoside tetraethylene glycol azide having the following structure, or peracetylated derivatives thereof.In some embodiments, the glucose dendrimer is a generation 1, generation 2, generation 3, generation 4, generation 5, or generation 6 dendrimer. In one embodiment, the dendrimer is a generation 1 dendrimer having the following structure: In a preferred embodiment, the dendrimer is a generation 2 dendrimer having the following structure: In some embodiments, the one or more therapeutic agents, prophylactic agents, and / or diagnostic agents are encapsulated, associated, and / or conjugated in the dendrimer, at a concentration of between about 0.01% to about 30%, preferably about 1% to about 20%, more preferably about 5% to about 20% by weight. In some embodiments, the dendrimer is conjugated to a small molecule, an antibody or antigen-binding fragment thereof, a nucleic acid, or a polypeptide. In some embodiments, the therapeutic agents conjugated to the dendrimer are anti-inflammatory agents, antioxidant agents, or immune-modulating agents. In other embodiments, the dendrimers are conjugated to one or more diagnostic agents such as fluorescent dyes, near infra-red dyes, SPECT imaging agents, PET imaging agents, and radioisotopes.In some embodiments, the dendrimer and the therapeutic, prophylactic, or diagnostic agent(s) are conjugated via one or more linkers or coupling agents such as one or more hydrocarbon or oligoethylene glycol chains. Exemplary linkages are disulfide, ester, ether, thioester, and amide linkages. PAMAM dendrimerThe term “PAMAM dendrimer” refers to poly(amidoamine) dendrimer, which may contain different cores, with amidoamine building blocks, and can have carboxylic, amine, acetamide, and / or hydroxyl terminations of any generation including, but not limited to, generation 1 PAMAM dendrimers, generation 2 PAMAM dendrimers, generation 3 PAMAM dendrimers, generation 4 PAMAM dendrimers, generation 5 PAMAM dendrimers, generation 6 PAMAM dendrimers, generation 7 PAMAM dendrimers, generation 8 PAMAM dendrimers, generation 9 PAMAM dendrimers, or generation 10 PAMAM dendrimers. In some embodiment, the dendrimers are generation (“G”) 4, 5 or 6 dendrimers. In some embodiments, the PAMAM dendrimers have hydroxyl terminations.Generally, the complete architecture of dendrimers can be distinguished into the inner core moiety followed by radially attached branching units (i.e., generations) which are further decorated with chemical functional groups carrying desired terminal groups at the exterior surface of the dendrimers. In some embodiments, the dendrimers are in nanoparticle form and are described in detail in U.S. Published Application Nos. US 2011 / 0034422, US 2012 / 0003155, and US 2013 / 0136697. For example, the molecular weight of the dendrimers can be varied to prepare polymeric nanoparticles that form particles having properties, such as drug release rate, optimized for specific applications. In general, conjugation to the dendrimer may further improve safety and efficacy of these agents. For example, dendrimer conjugation may change specific receptor activity and / or modify biodistribution. For example, use of higher generation dendrimers and / or dendrimers with molecular weights greater than 24 kDa can confine these agents to the peripheral nervous system in order to preclude their psychoactive effects. In some embodiments, different variations of dendrimers may be used as a delivery vehicle to conjugate and deliver one or more active agents, including, but not limited to, dendrons and tectodendrimers. Dendrons are dendritic wedges that comprise one type of functionality at the core (functional groups, f=1) and another at the periphery (f=8, 16, 32, etc…). Tectodendrimers are generally composed of a central dendrimer with multiple dendrimers attached at its periphery. 1.Core In some embodiments, dendrimers are prepared using methods in which the dendrimer is assembled from a multifunctional core, which is extended outward by a series of reactions. A multifunctional core moiety allows stepwise addition of branching units (i.e., generations) around the core. Exemplary chemical structures suitable as core moieties include dipentaerythritol, pentaerythritol, 2-(aminomethyl)-2-(hydroxymethyl) propane-1,3-diol, 2-ethyl-2-(hydroxymethyl) propane-1,3-diol, 3,3',3'',3'''-silanetetrayltetrakis (propane-1-thiol), 3,3-divinylpenta-1,4-diene, 3,3',3''-nitrilotripropionic acid, 3,3',3''-nitrilotris(N-(2-aminoethyl)propanamide), 3,3',3'',3'''-(ethane-1,2-diylbis(azanetriyl)) tetrapropanamide, 3-(carboxymethyl)-3-hydroxypentanedioic acid, 2,2'-((2,2-bis((2-hydroxyethoxy)methyl) propane-1,3-diyl)bis(oxy))bis(ethan-1-ol), tetrakis(3-(trichlorosilyl) propyl)silane, 1-Thioglycerol, 2,2,4,4,6,6-hexachloro-1,3,5,2l5,4l5,6l5-triazatriphosphinine, 3-(hydroxymethyl)-5,5-dimethylhexane-2,4-diol, 4,4',4''-(ethane-1,1,1-triyl)triphenol, 2,4,6-trichloro-1,3,5-triazine,5-(hydroxymethyl) benzene-1,2,3-triol, 5-(hydroxymethyl)benzene-1,3-diol, 1,3,5-tris(dimethyl(vinyl)silyl)benzene, Carbosiloxane core, nitrilotrimethanol, ethylene diamine, propane-1,3-diamine, butane-1,4-diamine, 2,2',2''-nitrilotris(ethan-1-ol), alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, Cucurbituril, benzene-1,2,3,4,5,6-hexathiol, monosaccharide, disaccharides, trisaccharides, oligosaccharides, or azide-, alkyne-modified moieties thereof. In some embodiments, the core moiety is chitosan. Thus, azide-modified chitosan, or alkyne-modified chitosan are suitable for conjugating to branching units using click chemistry. In some embodiments, the core moiety is ethylenediamine, or tetra(ethylene oxide). In some embodiments, the core moiety is dipentaerythritol. Exemplary chemical structures suitable for use as core moieties are shown in Table 1 below.Table 1. Structural representation of various building blocks (cores, branching units, surface functional groups, monomers) for the synthesis of dendrimers. Building BlocksStructureDipentaerythritolPentaerythritol2-(aminomethyl)-2-(hydroxymethyl)propane-1,3-diol2-ethyl-2-(hydroxymethyl)propane-1,3-diol3,3',3'',3'''-silanetetrayltetrakis(propane-1-thiol)3,3-divinylpenta-1,4-diene3,3',3''-nitrilotripropionic acid3,3',3''-nitrilotris(N-(2-aminoethyl)propanamide)3,3',3'',3'''-(ethane-1,2-diylbis(azanetriyl))tetrapropanamide3-(carboxymethyl)-3-hydroxypentanedioic acid2,2'-((2,2-bis((2-hydroxyethoxy)methyl)propane-1,3-diyl)bis(oxy))bis(ethan-1-ol)tetrakis(3-(trichlorosilyl)propyl)silane1-ThioglycerolAll the sugar based scaffoldsincluding mono, di, tri, or oligomers2,2,4,4,6,6-hexachloro-1,3,5,2l5,4l5,6l5-triazatriphosphinine3-(hydroxymethyl)-5,5-dimethylhexane-2,4-diol4,4',4''-(ethane-1,1,1-triyl)triphenol2,4,6-trichloro-1,3,5-triazine5-(hydroxymethyl)benzene-1,2,3-triol5-(hydroxymethyl)benzene-1,3-diol1,3,5-tris(dimethyl(vinyl)silyl)benzeneCarbosiloxane corenitrilotrimethanolethylene diaminepropane-1,3-diaminebutane-1,4-diamine2,2',2''-nitrilotris(ethan-1-ol)   benzene-1,2,3,4,5,6-hexathiolalpha cyclodextrinbeta cyclodextrin gamma cyclodextrinCucurbituril  2.Branching Units Exemplary chemical structures suitable as branching units include monosaccharides. In some embodiments, the monosaccharide branching units are conjugated to the core or the prior layer of monomers via linkers such as polyethylene glycol chains. In preferred embodiments, the monosaccharide branching units are glucose-based branching units. Exemplary glucose-based branching units are shown in Structures II-IV. These are spacer molecules, so can also be alkyl (CH2)n – hydrocarbon-like units.The branching units are the PEG or alkyl chain linkers between different dendrimer generations, for example, the glucose layers are connected via PEG linkers and triazole rings. In preferred embodiments, the branching units are the same for each generation of dendrimers generated from the core. Therefore, in one embodiment, the branching units are glucose-based branching units for generating generation 1 dendrimers as shown in Structures V-VII. In some embodiments, the branching units are hyper-monomers i.e., ABn building blocks. Exemplary hyper-monomers include AB4, AB5, AB6, AB7, AB8 building blocks. Hyper-monomer strategy drastically increases the number of available end groups. An exemplary AB4 hypermonomer is peracetylated β-D-Glucopyranoside tetraethylene glycol azide as shown in Structure III. The chemical structures listed in Table 1, are also suitable as building blocks to form the branching units of the dendrimer. For example, the branching units of the dendrimers are formed by dipentaerythritol, pentaerythritol, 2-(aminomethyl)-2-(hydroxymethyl) propane-1,3-diol, 2-ethyl-2-(hydroxymethyl) propane-1,3-diol, 3,3',3'',3'''-silanetetrayltetrakis (propane-1-thiol), 3,3-divinylpenta-1,4-diene, 3,3',3''-nitrilotripropionic acid, 3,3',3''-nitrilotris(N-(2-aminoethyl)propanamide), 3,3',3'',3'''-(ethane-1,2-diylbis(azanetriyl)) tetrapropanamide, 3-(carboxymethyl)-3-hydroxypentanedioic acid, 2,2'-((2,2-bis((2-hydroxyethoxy)methyl) propane-1,3-diyl)bis(oxy))bis(ethan-1-ol), tetrakis(3-(trichlorosilyl) propyl)silane, 1-Thioglycerol, 2,2,4,4,6,6-hexachloro-1,3,5,2l5,4l5,6l5-triazatriphosphinine, 3-(hydroxymethyl)-5,5-dimethylhexane-2,4-diol, 4,4',4''-(ethane-1,1,1-triyl)triphenol, 2,4,6-trichloro-1,3,5-triazine, 5-(hydroxymethyl) benzene-1,2,3-triol, 5-(hydroxymethyl)benzene-1,3-diol, 1,3,5-tris(dimethyl(vinyl)silyl)benzene, Carbosiloxane core, nitrilotrimethanol, ethylene diamine, propane-1,3-diamine, butane-1,4-diamine, 2,2',2''-nitrilotris(ethan-1-ol), alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, Cucurbituril, benzene-1,2,3,4,5,6-hexathiol, monosaccharide, disaccharides, trisaccharides, oligosaccharides, or azide- , alkyne-modified moieties thereof, or a combination thereof. Other examples of chemical structures that are suitable for forming the branching units of the dendrimers disclosed herein include, but are not limited to, sugar moieties, such as glucose, galactose, mannose, and fructose, and alkylene glycol, such as ethylene glycol, and combinations thereof. In some embodiments, the branching unit is chitosan. Thus, azide- modified chitosan, or alkyne-modified chitosan are suitable for conjugating to the core moiety or additional same or different branching units using click chemistry. In some embodiments, the branching unit is methyl acrylate or ethylenediamine, or a combination thereof. In some embodiments, the branching unit is polyethylene glycerol linear or branched. In some embodiments, the branching unit is a copolymer of an alkylene glycol (such as ethylene glycol) and a sugar moiety, such as glucose, galactose, mannose, and / or fructose.3.Surface Functional Groups Surface functional groups / molecules of the dendrimers are not limited to a primary amine end group, a hydroxyl end group, a carboxylic acid end group, an acetamide end group, a sugar molecule, an oligo- or poly-alkylene glycol, and / or a thiol end group. In some embodiments, the desired terminal functional groups can be added via one of the conjugation methods for the core and branching unit.In some embodiments, the surface functional groups are hydroxyl groups, for example those of PAMAM dendrimers, of generation 2 PEG dendrimer as shown in Structure I, or of the terminal glucose of dendrimers prepared with glucose-based branching units as shown in Structures V and VII. In some embodiments, desired surface functional groups can be modified or added via one of the conjugation methods for the core and branching unit. Exemplary surface functional groups include hydroxyl end groups, amine end groups, carboxylic acid end groups, acetamide end group, and thiol end groups, and combinations thereof. 4 In some embodiments, the dendrimers can specifically target a particular tissue region and / or cell type, such as the cells and tissues of the central nervous system (CNS), the peripheral nervous system (PNS), and / or the eye. In some embodiments, the dendrimers specifically target neurons and / or glia of the CNS. In some embodiments, the dendrimers specifically target neurons and / or glia of the PNS. In some embodiments, the glucose dendrimers are those of generation 1 (G1), G2, G3, G4, and G5. In some embodiments, the dendrimers include an effective number of terminal glucose and / or hydroxyl groups for targeting to one or more neurons and / or glia of the CNS, the PNS, and / or the eye. Glucose dendrimers are preferred. In some embodiments, dendrimers are made of glucose and oligoethylene glycol building blocks. Exemplary generation 1 glucose dendrimer is shown in Structure VI, and generation 2 glucose dendrimers is shown in Structure VIII. In some embodiments, the dendrimers have a plurality of surface functional groups, such as hydroxyl (-OH) groups, amine groups, acetamide groups, and / or carboxyl groups on the periphery of the dendrimers (also referred to herein as surface functional groups or peripheral functional groups). In some embodiments, the surface density of such peripheral functional groups is at least 1 group / nm2 (number of the surface functional groups / surface area in nm2). For example, in some embodiments, the surface density of the surface functional groups, such as hydroxyl groups, is more than 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 OH groups / nm2such as at least 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50 OH group / nm2. In some embodiments, the volumetric density of surface functional groups, such as hydroxyl groups, is between about 1 and about 50 groups / nm3, between about 5 and about 30 groups / nm3, or between about 10 and about 20 groups / nm3. In further embodiments, the surface density of the surface functional groups, such as hydroxyl groups, is between about 1 and about 50, preferably 5-20 group / nm2 (number of surface functional groups / surface area in nm2) while each surface functional moiety has a molecular weight of between about 100 Da and about 10 kDa, preferably between about 100 Da and 1000 Da. In some embodiments, the amount of the surface functional groups, such as any one of those described above, e.g., hydroxyl groups, of the dendrimer is at least 40%, at least 50%, more than 40%, more than 50%, or in a range from more than 40% to 100%. In some embodiments, one or more of the surface functional groups, such as any one of those described above, on the periphery of the dendrimers are further modified by conjugating with one or more carbohydrate molecules and / or more or more polyalkylene glycols, such as polyethylene glycols. In these embodiments, the surface density of the terminal carbohydrate moieties / molecules and / or polyalkylene glycols can be in any of the ranges described above for hydroxyl groups. Hydroxyl-terminated PAMAM dendrimers, PAMAM dendrimer modified on the surface with sugar moieties (with >10% of surface groups modified by sugars, especially by glucose, and glucose dendrimers (where the dendrimers are made of glucose building blocks) are preferred. For delivery to the brain, constructs with a total molecular weight of <30,000 Da are preferred. For confinement primarily to the peripheral circulation, constructs with a total molecular weight of >50,000 Da are preferred. When dendrimers are formed of, or include sugar moieties / molecules at termination, for example, glucose, the terminal hydroxyl groups of these dendrimers may be part of the terminal sugar moieties / molecules or extra hydroxyl groups that are not part of the sugar moieties / molecules, or a combination thereof. In some embodiments, all of the terminal hydroxyl groups are part of the terminal sugar moieties / molecules. a.Hydroxyl-terminated Dendrimers5 In some embodiments, the dendrimers include a plurality of hydroxyl groups. Some exemplary high-density hydroxyl groups-containing dendrimers include commercially available polyester dendritic polymer such as hyperbranched 2,2-Bis(hydroxyl-methyl)propionic acid polyester polymer (for example, hyperbranched bis-MPA polyester-64-hydroxyl, generation 4), dendritic polyglycerols. In some embodiments, the hydroxyl terminated dendrimers include hydroxyl-terminated PAMAM dendrimers, particularly G3 to G6 hydroxyl-terminated PAMAM dendrimers, such as G3, G4, G5, and G6 hydroxyl-terminated PAMAM dendrimers.In some embodiments, the high-density hydroxyl groups-containing dendrimers are oligo ethylene glycol (OEG)-like dendrimers. For example, a generation 2 OEG dendrimer (D2-OH-60) as shown in Structure I can be synthesized using highly efficient, robust and atom economical chemical reactions such as Cu (I) catalyzed alkyne–azide click and photo catalyzed thiol-ene click chemistry. Highly dense polyol dendrimer at very low generation in minimum reaction steps can be achieved by using an orthogonal hypermonomer and hypercore strategy, for example as described in WO2019094952. In some embodiments, the dendrimer backbone has non-cleavable polyether bonds throughout the structure to avoid the disintegration of dendrimer in vivo and to allow the elimination of such dendrimers as a single entity from the body (non-biodegradable).Structure I. A generation two (G2) oligo ethylene glycol-like dendrimerIn some embodiments, the dendrimers have a plurality of hydroxyl (-OH) groups on the periphery of the dendrimers. In some embodiments, the surface density of hydroxyl (-OH) groups is at least 1 OH group / nm2 (number of surface hydroxyl groups / surface area in nm2). For example, in some embodiments, the surface density of hydroxyl groups, per nm2, is more than 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 OH groups / nm2, such as at least 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50. In some embodiments, the volumetric density of hydroxyl groups is between about 1 and about 50 groups / nm3, between about 5 and about 30 groups / nm3, or between about 10 and about 20 groups / nm3. In further embodiments, the surface density of hydroxyl (-OH) groups is between about 1 and about 50, or between 5 and 20 OH group / nm2 (number of surface hydroxyl groups / surface area in nm2) while having a molecular weight of between about 100 Da and about 10 kDa, preferably between about 100 Da and 1000 Da. In some embodiments, the amount of the surface hydroxyl groups of the dendrimer is preferably greater than 35%, at least 40%, at least 50%, more than 40%, more than 50%, or in a range from more than 40% to 100%. In some embodiments, the dendrimers may have a fraction of the hydroxyl groups exposed on the outer surface, with the others in the interior core of the dendrimers.In some embodiments, the dendrimer specifically targets a particular tissue region and / or cell types following administration into the body. In some embodiments, the dendrimer specifically targets a particular tissue region and / or cell type without a targeting moiety. In some embodiments, the dendrimers include an effective number of hydroxyl groups for targeting CNS cells and / or PNS cells, such as microglial, astrocytes, and / or neurons associated with a disease, disorder, or injury of the central nervous system or the peripheral nervous system. In some embodiments, the dendrimer specifically targets a particular tissue region and / or cell type without a targeting moiety and the active agent conjugated thereto bind directly to a receptor on the surface and / or interior of target neural and / or glial cells.In some embodiments, the dendrimers are able to specifically target a particular tissue region and / or cell type, preferably the cells and tissues of the central nervous system (CNS) and the eye. In some embodiments, the dendrimers specifically target neurons of the CNS and the eye. Unmodified PAMAM dendrimers with hydroxyl end groups do not enrich in the neurons of brain and / or retinal ganglion cells (RGCs) in the eye as much as these glucose dendrimers. The glucose dendrimers with terminal glucose monosaccharide and a high density of hydroxyl functional groups effectively target the neurons in a generation dependent manner. Examples demonstrate efficacy with generation 2 (G2), and G3 and G4 should be efficacious. G5 and above are more difficult to use.In preferred embodiments, the dendrimers include an effective number of terminal glucose and / or hydroxyl groups for targeting to one or more neurons of the CNS, or the eye. The hydroxyl groups on the dendrimer surface are part of glucose molecules. There are no extra hydroxyls in addition to the glucose molecules on the surface. The number of sugar molecules on the surface is determined by the generation number. All generations are expected to target neurons. In some embodiments, dendrimers are made of glucose and oligoethylene glycol building blocks. Exemplary glucose dendrimers are shown in the Examples, for example, generation 1 dendrimers as shown in Structures IV-VI, and generation 2 dendrimers as shown in FIGs. 1A and 1B. Some exemplary glucose dendrimers include a generation 1 glucose dendrimer having 24 hydroxyl (-OH) end groups, a generation 2 glucose dendrimer having 96 hydroxyl (-OH) end groups, a generation 3 glucose dendrimer having 396 hydroxyl (-OH) end groups, and generation 4 glucose dendrimer having 1584 hydroxyl (-OH) end groups. In a preferred embodiment, the glucose dendrimer is a generation 2 glucose based dendrimer that has 24 glucose molecules at the periphery and 6 embedded glucose molecules in the backbone held together by PEG segments.b.Dendrimers Modified with CarbohydratesIn some embodiments, the dendrimers contain one or more carbohydrate molecules at the termination. These terminal carbohydrate molecules can be prepared by conjugating one or more surface functional groups of a dendrimers, such as amine groups, carboxyl groups, or hydroxyl groups, with one or more carbohydrate molecules. In preferred embodiments, the dendrimers, prior to carbohydrate conjugation, are hydroxyl-terminated dendrimers such as hydroxyl-terminated PAMAM dendrimers and one or more of the hydroxyl groups are conjugated with one or more carbohydrate molecules.In some embodiments, hydroxyl-terminated dendrimers modified with surface glucose molecules selectively target central and / or peripheral neural and / or glial cells in vitro and in vivo; and / or selectively accumulate on the surface and / or within these target neural cells, glial cells, and / or macrophage cells, such that the active agent(s) conjugated thereto bind to one or more receptors on / in the target neural and / or glial cells.In some embodiments, the carbohydrate moieties used to modify one or more surface functional groups of the dendrimers are monosaccharides. Exemplary monosaccharides suitable for modifying the dendrimers include glucose, glucosamine, galactose, mannose, fructose, dehydroascorbic acid, urate, myo-inositol. In some embodiments, the dendrimers are conjugated to glucose and thus contain glucose as terminal moieties / molecules. In some embodiments, hydroxyl-terminated dendrimers are modified with one or more glucose moieties to the dendrimer (“D-Glu”). In some embodiments, the dendrimers are conjugated to galactose. In some embodiments, the dendrimers are conjugated to mannose. In some embodiments, the dendrimers are conjugated to fructose. In some embodiments, the dendrimers are conjugated to one or more monosaccharides other than glucose, such as galactose, mannose, and / or fructose. For example, the carbohydrate moieties are oligosaccharides which terminate in one or more monosaccharides including glucose, glucosamine, mannose, fructose, thus exposing these sugar moieties on the surface for binding.The glucose dendrimers or glucose-modified dendrimers are used to obtain selective uptake by the target cells. The drug conjugated to the dendrimer binds to receptors or other sites of action. In preferred embodiments, the dendrimers or functionally modified dendrimers are conjugated to one or more drugs that have affinity to and are suitable for binding one or more of agent receptors e.g., CB1 receptors, CB2 receptors, and CB3 receptors. In some embodiments, the dendrimers are conjugated to one or more carbohydrates moieties that have affinity to and are suitable for binding one or more non-agent receptors such as G-protein coupled receptors e.g., GPR55, GPR18, GPR3, GPR6, GPR12 GPR40, GPR43, GPR41, GPR120, GPR23, GPR92, GPR84, GPR119, or GPR35; the adenosine receptor such as adenosine A3; the muscarinic acetylcholine receptors e.g., M1 and M4; the serotonin receptors e.g., 5-HT1A, 5-HT2A; opioid receptors e.g., μ− and δ−opioid receptors; and tachykinin NK2 receptors. In some embodiments, the dendrimers are conjugated to one or more carbohydrates moieties, or made of sugar moieties, that have affinity to and are suitable for transport via one or more of GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, GLUT12, GLUT13, and GLUT14. In further embodiments, the dendrimers are conjugated to one or more glucose and / or glucosamine moieties. In other embodiments, the dendrimers are conjugated to one or more oligosaccharides terminating in glucose and / or glucosamine moieties, i.e., glucose and / or glucosamine moieties are exposed on the surface of the dendrimer conjugates suitable for binding to one or more of the GLUTs, agent receptors and / or non-agent receptors. In some embodiments, the dendrimers have a plurality of carbohydrate moieties / molecules such as monosaccharides, e.g., glucose, on the periphery of the dendrimers, or have sugar building blocks for the dendrimers. In some embodiments, the surface density of carbohydrate molecules such as monosaccharides, e.g., glucose, is at least 1 carbohydrate molecule / nm2 (number of surface carbohydrate groups / surface area in nm2). In some embodiments, the surface density of carbohydrate molecules, per nm2, is more than 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 OH groups / nm2, such as at least 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50. For example, surface density of carbohydrate molecules, per nm2, is more than 10. In some embodiments, the volumetric density of surface carbohydrate molecules is between about 1 and about 50 groups / nm3, between about 5 and about 30 groups / nm3, or between about 10 and about 20 groups / nm3. In further embodiments, the surface density of carbohydrate molecules is between about 1 and about 50, between about 5 and about 20, per nm2 (number of surface carbohydrate molecules / surface area in nm2) while each carbohydrate moiety having a molecular weight of between about 100 Da and about 1000 Da. In these embodiments, i.e., one or more surface functional groups of the dendrimer are modified to introduce one or more sugar moieties / molecules at termination, the terminal hydroxyl groups may be part of the terminal sugar moieties / molecules or extra hydroxyl groups that are not modified with sugar moieties / molecules and thus are not part of the sugar moieties / molecules, or a combination thereof. In some embodiments, carbohydrate molecules such as monosaccharides, e.g., glucose, are present in an amount by weight that is between about 1% and 40% of the total weight of the glycosylated dendrimer, for example, between about 2% and 20%, between about 5% and 15%, or between 9 % and 12 % of the total weight of the glycosylated dendrimer. For example, in some embodiments, the carbohydrate moieties are present in an amount that is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the total weight of the glycosylated dendrimer following conjugation. In some embodiments, conjugation of carbohydrate molecules through one or more surface functional groups occurs via about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25% of the total available surface functional groups, preferably hydroxyl groups, of the dendrimers prior to the conjugation. In other embodiments, the conjugation of carbohydrate molecules occurs on less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40% of total available surface functional groups of the dendrimers prior to the conjugation.c.Dendrimers Modified with Polyalkylene GlycolIn some embodiments, the dendrimers contain one or more polyalkylene glycols at the termination. These terminal polyalkylene glycols can be prepared by conjugating one or more of surface functional groups of the dendrimers, such as hydroxyl groups, with a polyalkylene glycol, such as PEG. In some embodiments, the dendrimers, prior to conjugation, are hydroxyl-terminated dendrimers such as hydroxyl-terminated PAMAM dendrimers and at least a portion of the surface hydroxyl groups are conjugated with PEG. In some embodiments, the dendrimers have a plurality of polyalkylene glycols such as PEG, on the periphery of the dendrimers. In some embodiments, the surface density of polyalkylene glycols such as PEG, is at least 1 polyalkylene glycol / nm2 (number of surface polyalkylene glycol / surface area in nm2). In some embodiments, the surface density of polyalkylene glycols, per nm2, is more than 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, such as at least 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50. For example, surface density of polyalkylene glycols, per nm2, is more than 10. In some embodiments, the volumetric density of surface polyalkylene glycols is between about 1 and about 50 groups / nm3, between about 5 and about 30 groups / nm3, or between about 10 and about 20 groups / nm3. In further embodiments, the surface density of polyalkylene glycols such as PEG is between about 1 and about 50, between about 5 and about 20, per nm2 (number of surface polyalkylene glycols / surface area in nm2) while having a molecular weight of between about 100 Da and about 10 kDa. In some embodiments, the polyalkylene glycol molecules such as PEG can be present in an amount by weight that is between about 1% and 40% of the total weight of the pegylated dendrimer, for example, between about 2% and 20%, between about 5% and 15%, or between 9 % and 12 % of the total weight of the pegylated dendrimer. For example, in some embodiments, the polyalkylene glycol molecules, such as PEG, are present in an amount that is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the total weight of the pegylated dendrimer following conjugation. In some embodiments, conjugation of polyalkylene glycol molecules such as PEG through one or more surface functional groups of the dendrimer occurs via about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25% of the total available surface functional groups, preferably hydroxyl groups, of the dendrimers prior to the conjugation. In other embodiments, the conjugation of polyalkylene glycol molecules such as PEG occurs on less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40% of total available surface functional groups of the dendrimers prior to the conjugation.B.Therapeutic AgentsPrior research has conclusively established the major role of both innate and adaptive immunity in the development and progression of atherosclerosis. The innate immune response in atherosclerosis is initiated by chronic inflammation, a hallmark of atherosclerosis. Chronic inflammation, particularly in branch points and other areas with oscillatory shear, causes endothelial cell activation and expression of adhesion molecules E-selectin and VCAM-1, which attracts dendritic cells and monocytes and stimulates monocyte to macrophage differentiation via the local production of macrophage colony stimulating factor (mCSF). The ensuing cholesterol uptake by macrophages results in the formation of foam cells that are characteristic of atherosclerosis. Pro-inflammatory M1-Macrophages further contribute to an aggravation of local inflammation, leading to activation of ECs, promoting VSMC motility and proliferation, and driving a vicious cycle of inflammation and cellular derangements leading to plaque growth. Macrophages in the plaque and dendritic cells act as antigen presenting cells and activate adaptive immune response. Th1 or pro-inflammatory cytokines such as TNF-a and IFN-g promote atherogenic inflammation and increase plaque instability that can lead to co-morbidities such as heart attacks and stroke. Due to the key role played by both the innate and adaptive immune system in plaque formation and progression, targeting the inflammatory system is a promising strategy in treatment of atherosclerosis. Targeting the immune system in atherosclerosis: Previous therapies have focused on binding IL-b (CANTOS study using Canakinumab an IL1b antibody showed some improvement in cardiovascular events). IL1 receptor antagonist anakinra ( MRC-ILA-HEART study, showed short term benefit but not long term), treatment with antibodies targeting IL6 receptors or ligands (tocilizumab and ziltivekimab) showed decrease in inflammation (long term ZEUS study ongoing); use of TNF-a inhibitors seem to be associated with decreased CVD; small molecule anti-inflammatory agents such as colchicine showed an improvement in CV events; CXCL1 neutralizing antibody, MLN1202, a highly specific humanized monoclonal antibody that prevents CCL2 binding, CXCR4 antagonist Plerixafor; immune checkpoint inhibitors targeting CD28, CD80,86, CTLA-4 and PD-1, or CD70, CD 27, CD137 9TNF superfamily), examples of these include--abatacept, a CTLA4-Ig construct that blocks CD80 / CD86 from interacting with CD28 and activating T cells or TRAF-STOP therapy with either SMI 6860766 or 6877002. Other targets include IL2 administration (LILACS and IVORY studies), rituximab (anti-CD20 antibody) targeting B cells. Other small molecules that decrease MACE are: Statins, GLP1 agonists such as semaglutide and analogs (e.g. Ozembic®) , Lp-PLA2 inhibitors such as darapladib, sPLA2 inhibitors such as Verespladib, 5-LO inhibitor, VIA-2291 (atreleuton); methotrexate, PPAR- α / γ agonists such as Tesaglitazar, Metformin have all shown some efficacy. However, trials have either not shown adequate efficacy or drugs have had debilitating side effects that has prevented further progression. Dendrimer-drug compositions of small molecule drugs including PPAR- α / γ agonists [Tesaglitazar], Metformin, glucagon-like peptide-1 (GLP-1) receptor agonists [e.g., Semaglutide (Ozempic®), and sodium-glucose co-transporter 2 (SGLT2) agonists [e.g., canagliflozin (Invokana®)] are described. These debilitating side effects can be prevented by specific delivery of these drugs to macrophages and / or neurons using hydroxyl and glucose dendrimers. C.Dendrimer-Agent ConjugatesDendrimer-active agent conjugates can be formed of agents and / or agent derivatives covalently conjugated or non-covalently attached to a dendrimer, a dendritic polymer, or a hyperbranched polymer. Methods for conjugation of one or more active agents to a dendrimer are known, such as those described in U.S. Published 2011 / 0034422, 2012 / 0003155, and 2013 / 0136697. Covalent conjugates are preferred, but ionic complexes (cation-anion complexes) may also be used.In some embodiments, one or more active agents are covalently conjugated to one or more terminal groups of the dendrimer such as terminal hydroxyl groups. In some embodiments, dendrimer conjugates include one or more active agents conjugated to the dendrimer via one or more spacers. The spacer between a dendrimer and an active agent can be designed to provide a releasable or non-releasable form of the dendrimer conjugate in vivo. For example, the spacer can be cleavable or contain a chemical linkage that is cleavable, for example, by exposure to the intracellular compartments of target neural and / or glial cells or upon binding to the receptor on the surface or in the interior of the target neural and / or glial cells in vivo. Examples of cleavable linkages that can be used in a spacer of the dendrimer-active agent conjugates include, esterase sensitive ester bond, glutathione sensitive disulfide bond, phosphatase-sensitive phosphodiester bond, oligopeptide such as triglycyl peptide linker capable of lysosomal release, acid cleavable hydrazine linkage etc. In some embodiments, the spacer between a dendrimer and active agents can provide desired and effective release kinetics in vivo. In some embodiments, the spacer between the dendrimer and the active agent can be non-cleavable or contain a chemical linkage that is non-cleavable, such as amide, ether, and amino alkyl linkages.Generally, the spacer between the dendrimer and active agent has a length sufficient for the active agent conjugated thereto to reach and bind to the target receptor on the surface and / or inside of the target cell. For example, the spacer between the dendrimer and active agent has a length in a range from 50 Da to 2000 Da, depending on the release kinetics desired, and the receptor binding flexibility desired. The length of the spacer can vary, depending on the location of the target receptor (for example, on the cell surface, in the cytoplasm of the cell, or in an intercellular compartment of the cell) and / or density of the receptor when located on the cell surface. The dendrimer can be a generation 2, generation 3, generation 4, generation 5, generation 6, and up to generation 10. In some embodiments, the dendrimer is conjugated to one or more active agents via spacers containing cleavable (ester, disulfide, phosphodiester, triglycyl peptide, and hydrazine) or non-cleavable (amide, ether, and amino alkyl) linkages. The density of active agents covalently conjugated to or non-covalently attached to the dendrimer can be adjusted based on the specific agents or agent derivatives being delivered, the target receptors, the target neural and / or glial cells, the location of the target neural and / or glial cells, etc. For example, a plurality of active agents conjugated to the dendrimer are on the periphery of the dendrimer and the surface density of the active agent is at least 1 active agent / nm2 (number of active agent conjugated / surface area in nm2), preferably 3-10. For example, in some embodiments, the surface density of active agent per nm2 is more than 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, such as at least 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50. In some embodiments, the volumetric density of active agent is between about 1 and about 50 groups / nm3, between about 5 and about 30 groups / nm3, or between about 10 and about 20 groups / nm3. Typically, the dendrimer-active agent conjugates have a hydrodynamic volume in the nanometer range. For example, in some embodiments, the glucose dendrimer-active agent conjugates including one or more agents or agent derivatives conjugated to the dendrimer have a diameter of about 2 nm to about 100 nm, or more than 100 nm, up to 500 nm, depending upon the generation of dendrimer, the chemical composition and amount of active agent conjugated thereto. In some embodiments, a dendrimer-active agent conjugate including one or more agents or agent derivatives conjugated to the dendrimer has a diameter effective to penetrate brain tissue and to retain on the surface and / or in target neural and / or glial cells for a period of time sufficient for the active agent to bind to the targeted receptors on the surface and / or in the target neural and / or glial cells. In some embodiments, a dendrimer-active agent conjugate including one or more agents or agent derivatives conjugated to the dendrimer has a diameter effective to remain in the peripheral circulation and to retain on the surface and / or in target neural and / or glial cells for a period of time sufficient for the active agent to bind to the targeted receptors on the surface and / or in the target neural and / or glial cells.The dendrimer-active agent conjugates can be neutral, have a positive charge or a negative charge. In some embodiments, the dendrimer-active agent conjugates are neutral. The presence of agents or agent derivatives can affect the surface charge of the dendrimer-active agent conjugates. In some embodiments, the surface charge of the dendrimer conjugated to agents or agent derivatives is between -100 mV and 100 mV, between -50 mV and 50 mV, between -25 mV and 25 mV, between -20 mV and 20 mV, between -10 mV and 10 mV, between -10 mV and 5 mV, between -5 mV and 5 mV, or between -2 mV and 2 mV. The range above is inclusive of all values from -100 mV to 100 mV. In preferred embodiments, the surface charge of the dendrimer-active agent conjugates is neutral or near-neutral, i.e., from about -10 mV to about 10 mV, inclusive. An exemplary dendrimer-active agent conjugate is represented by Formula (I). The dendrimer of the exemplary conjugate contains surface hydroxyl groups, wherein one or more of the surface hydroxyl groups are conjugate to one or more active agents via one or more spacers as shown in Formula (I) below. Formula (I)wherein D can be a generation 1 to generation 10 or generation 2 to generation 10 dendrimer, such as any one of those described above, for example, PAMAM (such as hydroxyl-terminated PAMAM dendrimer) or a glucose-based dendrimer; each occurrence of L can be any suitable chemical moiety appropriate for providing tailored drug release and receptor binding, preferably containing a triazole moiety; Y can be a bond or a linkage selected from secondary amides (-CONH-), tertiary amides (-CONR-), sulfonamide (-S(O)2-NR-), secondary carbamates (-OCONH-; -NHCOO-), tertiary carbamates (-OCONR-; -NRCOO-), carbonate (-O-C(O)-O-), ureas (-NHCONH-; -NRCONH-; -NHCONR-, -NRCONR-), carbinols (-CHOH-, -CROH-), disulfide groups, phosphodiester group , hydrazino group, hydrazones, hydrazides, ester (-C(O)-O-), ether (-O-), and oligopeptide (e.g., triglycyl peptide), wherein R is an alkyl group, an aryl group, or a heterocyclic group; each occurrence of X can be a agents or agent derivatives, wherein a functional group of X (such as an amino group including primary amino, secondary amino, or tertiary amino group; a carboxylic group; or a hydroxyl group) forms a portion of linkage Y; n can be an integer from 1 to 100; and m can be an integer from 16 to 4096. The dendrimer can be PAMAM or a glucose dendrimer, which is 100% hydroxyl. m and n depend on the size of the dendrimer D, n should be such that the weight percent of the drug in the total conjugate is `5-20%. This range is also appropriate for binding and internalization.The oxygen atom shown in Formula (I) is from the surface functional group of the dendrimer, such as a surface hydroxyl group, where the surface hydroxyl group may or may not be part of a terminal sugar moiety / molecule (e.g., glucose). Although not illustrated in Formula (I), one or more hydroxyl groups of the dendrimer that are not conjugated to active agents may be modified with one or more carbohydrates and / or polyalkylene glycols, such as PEG. When administered to a subject in need thereof, the agent and / or agent derivative X of Formula (I) can bind to a target receptor on the surface of the target cell or inside the target cell. In some embodiments, when the agent and / or agent derivative X binds to the target receptor, the agent X remains conjugated to the dendrimer. In these embodiments, following binding, the agent X may be released from the dendrimer or remain conjugated to the dendrimer as an intact dendrimer-active agent conjugate. In some embodiments, the agent and / or agent derivative X is released from the dendrimer at close proximity to the target receptor and then binds to the target receptor. In some embodiments, each occurrence of L can be represented by -A’-L1-B’-L2-, wherein A’ can be a carbonyl (-C(O)-) or a bond (including single, double, and triple bonds, for example a single bond); B’ can be a bond (including single, double, and triple bonds, for example a single bond), an amide, an ester, an ether, a thiol, a dithiol, an aryl, a heteroaryl, a polyaryl, a heteropolyaryl, or a heterocyclic; and L1 and L2 can be independently a bond, an alkylene, a heteroalkylene, an aryl, an aralkyl, an ether, a polyether, a thiol, a dithiol, a thiolether, a polythioether, an oligopeptide, a polypeptide, an oligo(alkylene glycol), or a polyalkylene glycol, or L1 and L2 can be independently composed of a combination of these groups, such as a combination of alkylene and polyether, a combination of alkylene and thiol or dithiol, a combination of alkylene and oligopeptide, a combination of alkylene, polyether, and thiol or dithiol, or a combination of polyether and thiol or dithiol. In some forms, L1-B’-L2- together form a chemical moiety selected from an -alkylene-triazole-di(alkylene glycol)-, a -di(alkylene glycol)-triazole-alkylene-, -alkylene-triazole-oligo(alkylene glycol)-, an -oligo(alkylene glycol)-triazole-alkylene-, an -alkylene-triazole-poly(alkylene glycol)-, -poly(alkylene glycol)-triazole-alkylene-, an -alkylene-triazole-ether-, an -alkylene-triazole-alkylene-, an -alkylene-amide-alkylene-, and combinations thereof. In some embodiments, B’ can be a bond (including single, double, and triple bonds, for example a single bond), an amide group, or a heterocyclic group, such as a triazole group. In some embodiments, L1 can be a bond; an alkylene, such as a C1-C10 alkylene, a C1-C8 alkylene, a C1-C6 alkylene, a C1-C5 alkylene, a C1-C4 alkylene, or a C1-C3 alkylene; or an oligo- or poly-(alkylene glycol), such as where p is an integer from 1 to 20, from 1 to 18, from 1 to 16, from 1 to 14, from 1 to 12, from 1 to 10, from 1 to 8, from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, or 1 or 2. In some embodiments, L2 can be a bond; an alkylene, such as a C1-C10 alkylene, a C1-C8 alkylene, a C1-C6 alkylene, a C1-C5 alkylene, a C1-C4 alkylene, or a C1-C3 alkylene; an oligo- or poly-(alkylene glycol), such as where p is an integer from 1 to 20, from 1 to 18, from 1 to 16, from 1 to 14, from 1 to 12, from 1 to 10, from 1 to 8, from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, or 1 or 2; an oligo- or poly-peptide, such as a triglycyl peptide; a thiol; or a dithiol; or L2 is composed of a combination of two or more of alkylene, oligo- or poly-(alkylene glycol), oligo- or poly-peptide, thiols, and dithiols. For example, L2 is represented by ,where p, q, r, s, t, and u are independently an integer from 0 to 10, from 0 to 8, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, or from 0 to 2, such as 0, 1, or 2; and G’ is a thiol, a dithiol, an oligo-peptide such as a triglycyl peptide, or a poly-peptide.In some embodiments, Y is a linkage that is minimally cleavable in vivo. In some embodiments, Y is a linkage that is cleavable in vivo. In some embodiments, Y is an amide (-CONH-), an ester (-C(O)-O-), an ether (-O-), a phosphodiester, or a disulfide group. In some embodiments, L and Y are both a single bond, and D is directly conjugated to X (an active agent or analog thereof) via an ether linkage. In some embodiments, D is a generation 2 PAMAM dendrimer, a generation 3 PAMAM dendrimer, a generation 4 PAMAM dendrimer, a generation 5 PAMAM dendrimer, a generation 6 PAMAM dendrimer, a generation 1 glucose dendrimer, a generation 2 glucose dendrimer, a generation 3 glucose dendrimer, a generation 4 glucose dendrimer, a generation 5 glucose dendrimer, or a generation 6 glucose dendrimer. More specific exemplary dendrimer-active agent conjugates are shown in the Examples below. In one preferred embodiment, the conjugates are formed of hydroxyl dendrimer and glucose dendrimer-drug conjugates of PPAR-α, PPAR-γ, PPAR- α / γ agonists, including Tesaglitazar, metformin and other drugs in this class.In another preferred embodiment, hydroxyl dendrimer and glucose dendrimer-drug conjugates of GLP-1 agonists including Semaglutide (OZEMPIC®, RYBELSUS®), Dulaglutide (Trulicity®), Exenatide extended release, Exenatide (Byetta®), Liraglutide (Victoza®, Saxenda®) (daily), and Lixisenatide (Adlyxin®).D. ExcipientsBy “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject along with the selected compound without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.Any of the compounds having the formula I can be used therapeutically in combination with a pharmaceutically acceptable carrier. The compounds described herein can be conveniently formulated into pharmaceutical compositions composed of one or more of the compounds in association with a pharmaceutically acceptable carrier. See, e.g., Remington's Pharmaceutical Sciences, latest edition, by E.W. Martin Mack Pub. Co., Easton, PA, which discloses typical carriers and conventional methods of preparing pharmaceutical compositions that can be used in conjunction with the preparation of formulations of the compounds described herein. These most typically would be standard carriers for administration of compositions to humans. In one aspect, humans and non-humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. Other compounds will be administered according to standard procedures used by those skilled in the art.The pharmaceutical compositions described herein can include, but are not limited to, carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions (Park et al., J Control Release, 342:53-65 (2022); Nkanga, et al., Advanced Drug Delivery Reviews, 167:19-46, (2020); Sheikh, et al., Asian Journal of Pharmaceutics, 10(4):S465-S471 (2016); Rhee et al., Pharmaceutical Technology Drug Delivery, p.S6 (2010)). An exemplary approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained. See for example, U.S. Patent No. 9,700,630, WO 2006 / 125620, and KR 101898816.Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions which can also contain buffers, diluents and other suitable additives. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives can also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.Formulations for topical administration can include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like can be necessary or desirable.Compositions for oral administration can include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders can be desirableIII.Methods of TreatmentThe dendrimer-drug conjugates are administered orally, by injection, or to a mucosal membrane to treat atherosclerosis, through the action of the drugs when delivered to macrophages and foamy macrophages in the plaque.The dendrimer-drug conjugates are administered orally, by injection, or to a mucosal membrane to treat obesity, through delivery to adipose macrophages (typically M2-type) in the fat tissues, and on brain microglia / macrophages in the hypothalamus where the arctuate neurons are responsible for the desire to eat.Preferred embodiments include hydroxyl dendrimer and glucose dendrimer-drug conjugates of GLP-1 agonists including Semaglutide (OZEMPIC®, RYBELSUS®), Dulaglutide (TRULICITY®), Exenatide extended release, Exenatide (BYETTA®), Liraglutide (VICTOZA®, SAXENDA®) (daily), Lixisenatide (ADLYXIN®) for atherosclerosis, obesity or associated metabolic syndrome.Therapeutic approaches to metabolic syndrome (“MetS”) are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (“PPARs”) are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (“TGs”), blood glucose, and abdominal adiposity. PPARs may be classified into α, β / δ and γ subtypes. The PPAR-α agonists, mainly fibrates and variants thereof such as pemafibrate) and omega-3 fatty acids, lower triglycerids. These mainly affect TG catabolism and, particularly with fibrates, raise the levels of high-density lipoprotein cholesterol (“HDL-C”). PPAR-γ agonists, mainly glitazones, show a smaller activity on TGs but are powerful glucose-lowering agents. Newer PPAR-α / δ agonists, e.g., elafibranor, have been designed to achieve single drugs with TG-lowering and HDL-C-raising effects, in addition to the insulin-sensitizing and antihyperglycemic effects of glitazones. They also hold promise for the treatment of non-alcoholic fatty liver disease (NAFLD) which is closely associated with the MetS. PPARα agonists including fibrates and PPARγ agonists such as thiazolidinediones are used for the treatment of hypertriglyceridemia and type 2 diabetes, respectively. PPARδ activation enhances mitochondrial and energy metabolism. In one embodiment, PPAR-α / γ Agonists (“PPARs”) are transcription factors that regulate genes involved in lipid and carbohydrate metabolism as well as cell proliferation. PPAR-α regulates the expression of genes involved in lipid and lipoprotein metabolism. PPAR- γ regulates fatty acid storage and increases expression of proteins involved in lipid and glucose metabolism6. Both PPAR-α and PPAR- γ agonists inhibit macrophage foam cell formation14. Peroxisome proliferator-activated receptors (PPAR) in macrophages are involved in both atherosclerosis and obesity. Tesaglitazar is a dual PPAR- α / γ agonist, and has anti-inflammatory and anti-atherogenic qualities. Prior research showed that Tesaglitazar significantly improved lipid profile in diabetic and non-diabetic patients with insulin resistance. In mice, Tesaglitazar yielded benefits including decreased plasma cholesterol and atherosclerotic plaque and improved inflammatory markers. However, issues with toxicity arose during phase 3 clinical trials. Patients given Tesaglitazar experienced peripheral edema, weight gain, impairments in renal function, a dose-dependent reduction in hemoglobin, myocardial ischemia, and aggravation of congestive heart failure, and the trials were ended. Clinical development was halted due to off-target side effects that included formation of fibrosarcoma, increased cardiovascular risk and weight gain. Specific macrophage localization should reduce or prevent Tesaglitazar related side effects. Other side effects include anemia, leukopenia, edema, increased CV risks. Weight gain is noted in some studies. Other glitazars (dual PPAR agonists) have been associated with myocardial dysfunction, more significant CV events (8-9 other tested and failed). Toxicity was observed at the highest dose of Tesaglitazar of 4.1mg / kg daily PO for 12 to 24 weeks. Specific macrophage localization using dendrimers should reduce or prevent Tesaglitazar related side effects.In preferred embodiments, the conjugates are formed of hydroxyl dendrimer and glucose dendrimer-drug conjugates of PPAR-α, PPAR-γ, PPAR- α / γ agonists, including Tesaglitazar, metformin and other drugs in this class, and used for treating atherosclerosis, through the action on macrophages and foamy macrophages in the plaque. Other specific exemplary dendrimer-active agent conjugates include hydroxyl dendrimer and glucose dendrimer-drug conjugates of GLP-1 agonists including Semaglutide (OZEMPIC®, RYBELSUS®), Dulaglutide (TRULICITY®), Exenatide extended release, Exenatide (BYETTA®), Liraglutide (VICTOZA®, SAXENDA®) (daily), and Lixisenatide (ADLYXIN®).The conjugates should be useful for treating obesity using compositions, through the action on adipose macrophages (typically M2-type) in the fat tissues, and on brain microglia / macrophages in the hypothalamus.The term “preventing” as used herein refers to administering a compound prior to the onset of clinical symptoms of a disease or conditions so as to prevent a physical manifestation of aberrations associated with the disease or condition.By “treatment” and “treating” is meant the medical management of a subject with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. It is understood that treatment, while intended to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder, need not actually result in the cure, amelioration, stabilization or prevention. The effects of treatment can be measured or assessed as described herein and as known in the art as is suitable for the disease, pathological condition, or disorder involved. Such measurements and assessments can be made in qualitative and / or quantitative terms. Thus, for example, characteristics or features of a disease, pathological condition, or disorder and / or symptoms of a disease, pathological condition, or disorder can be reduced to any effect or to any amount.By the term “effective amount” of a compound as provided herein is meant a nontoxic but sufficient amount of the compound to provide the desired result. As will be pointed out below, the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease that is being treated, the particular compound used, its mode of administration, and the like. Thus, it is not possible to specify an exact “effective amount.” However, an appropriate effective amount can be determined by one of ordinary skill in the art using only routine experimentation.The dosages or amounts of the compounds described herein are large enough to produce the desired effect in the method by which delivery occurs. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the subject and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician based on the clinical condition of the subject involved. The dose, schedule of doses and route of administration can be varied.The efficacy of administration of a particular dose of the compounds or compositions according to the methods described herein can be determined by evaluating the particular aspects of the medical history, signs, symptoms, and objective laboratory tests that are known to be useful in evaluating the status of a subject in need for the treatment of atherosclerosis, obesity, metabolic syndrome, or symptoms thereof. These signs, symptoms, and objective laboratory tests will vary, depending upon the particular disease or condition being treated or prevented, as will be known to any clinician who treats such patients or a researcher conducting experimentation in this field. For example, if, based on a comparison with an appropriate control group and / or knowledge of the normal progression of the disease in the general population or the particular individual, a subject’s physical condition is shown to be improved, (2) the progression of the disease or condition is shown to be stabilized, or slowed, or reversed, or (3) the need for other medications for treating the disease or condition is lessened or obviated, then a particular treatment regimen will be considered efficacious.The compounds and pharmaceutical compositions described herein can be administered to the subject in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Thus, for example, a pharmaceutical composition described herein can be administered to a subject vaginally, rectally, intranasally, orally, by inhalation, or parenterally, for example, by intradermal, subcutaneous, intramuscular, intraperitoneal, intrarectal, intraarterial, intralymphatic, intravenous, intrathecal and intratracheal routes. Parenteral administration, if used, is generally characterized by injection and includes intravenous (IV), subcutaneous (SC), intramuscular (IM), epidural and intra-articular injection, as well as surgical insertion of depots in the organ or tissue of interest (Bittner, et al., BioDrugs., 32:425-440 (2018); Lee et al., J. Pharm. Investig., 49: 459-476 (2019); Chaudhary et al., Crit. Rev. Ther. Drug Carrier Syst., 36:137-181 (2019).The disclosed compositions and methods can be further understood through the following enumerated paragraphs.1. A composition containing a hydroxyl dendrimer covalently conjugated to at least one drug, wherein the drug contains a PPAR-α agonist; a PPAR-γ agonist; a dual PPAR agonist (e.g., a PPAR- α / γ agonists); a GLP-1 receptor agonist (e.g., semaglutide); metformin; an SGLT2 agonist, a GIP-1 receptor agonist or antagonist; a dual GLP-1 / GIP-1 receptor agonist (e.g., tirzepatide); a mitochondrial uncoupler (e.g., niclosamide); or a combination thereof.2. A composition containing a glucose dendrimer covalently conjugated to at least one drug, wherein the drug contains a PPAR-α agonist; a PPAR-γ agonist; a dual PPAR agonist (e.g., a PPAR- α / γ agonists); a GLP-1 receptor agonist (e.g., semaglutide); metformin; an SGLT2 agonist, a GIP-1 receptor agonist or antagonist; a dual GLP-1 / GIP-1 receptor agonist (e.g., tirzepatide); a mitochondrial uncoupler (e.g., niclosamide); a cannabinoid 1 receptor (CB1R) antagonist, or a combination thereof.3. The composition of any of the preceding paragraphs, wherein the drug contains a PPAR-α agonist; a PPAR-γ agonist; or a dual PPAR agonist (e.g., a PPAR- α / γ agonists) selected from the group composed of tesaglitazar, fenofibrate, WY-14643, oleoylethanolamide, GW4148, GW 9578, GW2148, or a combination thereof.4. The composition of any of the preceding paragraphs, wherein the drug is a GLP-1 receptor agonist selected from the group composed of semaglutide (such as Ozempic® or Rybelsus®)); Dulaglutide (such as Trulicity®); Exenatide extended release, exenatide (such as Byetta®), and analogs and derivatives thereof; Liraglutide (such as Victoza®, Saxenda®) (daily); and Lixisenatide (such as Adlyxin®); and other incretin mimetics. Compounds in the incretin mimetic class include, but are not limited to, exenatide (such as Byetta, Bydureon), liraglutide (such as Victoza), sitagliptin (such as Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (such as Onglyza, Kombiglyze XR), alogliptin (such as Nesina, Kazano, Oseni), albiglutide (such as Tanzeum) and linagliptin (such as Tradjenta, Jentadueto).5. The composition of any of the preceding paragraphs, wherein the drug is a GIP-1 receptor agonist or antagonist is selected from the group composed of SKL-14959, MA-38472-B1, or a combination thereof.6. The composition of any of the preceding paragraphs, wherein the drug is a dual GLP-1 / GIP-1 receptor agonist selected from the group composed of tirzepatide, NNC0090-2746, NN9709, CT-388, retatrutide, or a combination thereof.7. The composition of any of the preceding paragraphs, wherein the drug is metformin.8. The composition of any of the preceding paragraphs, wherein the drug contains an SGLT2 agonist selected from the group composed of canagliflozin (such as Invokana®), bexagliflozin (such as Brenzavvy®), dapagliflozin (such as Farxiga®), empagliflozin (such as Jardiance®), ertugliflozin (Steglatro®), or a combination thereof.9. The composition of any of the preceding paragraphs, wherein the drug contains a mitochondrial uncoupler selected from the group composed of niclosamide, BAM15, carbonyl cyanide 4-(trifluoro-methoxy)phenylhydrazone (FCCP), carbonyl cyanide-3-chlorophenylhydrazone (CCCP), a dinitrophenol, analogs of these molecules, or a combination thereof.10. The composition of any of the preceding paragraphs, wherein the drug contains a CB1R antagonist selected from the group composed of AJ5012, JD5037, 3,4-diarylpyrazoline, 1,5-diarylpyrrole-3-carboxamides, methylsulfonamide azetidine, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-piperidino-1H-pyrazole-3-carboxamide (rimonabant), or a combination thereof.11. The composition of any of the preceding paragraphs, wherein the covalent conjugation contains a covalent link between a modified or unmodified surface group or interior group of the hydroxyl dendrimer or the glucose dendrimer, wherein the covalent link contains an amide, ester, disulfide, ether, or phosphate linkage.12. The composition of any of the preceding paragraphs, wherein the covalent conjugation contains a covalent link that is cleavable at a pH selected from neutral, acidic, or basic.13. The composition of any of the preceding paragraphs, wherein the hydroxyl dendrimer or glucose dendrimer is based on a polyamidoamine (PAMAM) dendrimer of generation 1 – generation 7.14. The composition of any of the preceding paragraphs, wherein the dendrimer is a glucose dendrimer, preferably a generation 1, a generation 2, or a generation 3 glucose dendrimer.15. The composition of any of the preceding paragraphs, wherein the dendrimer is based on a generation 2 – generation 7 PAMAM dendrimer, modified by a sugar moiety, wherein the sugar moiety is selected from the group composed of glucose, galactose, mannose, and fructose.16. The composition of any of the preceding paragraphs, wherein the hydroxyl dendrimer or the glucose dendrimer has at least a 10-fold increase in drug solubility in comparison to the drug in free form or wherein the hydroxyl dendrimer, the glucose dendrimer, or both increase durability of effect in comparison to the drug in free form.17. The composition of any of the preceding paragraphs, wherein the hydroxyl dendrimer is based on a higher generation dendrimer, preferably generation 3, 4, 5, or 6 PAMAM dendrimer (such as hydroxyl-terminated PAMAM dendrimer), or the glucose dendrimer is a generation 1, 2, 3, or higher glucose dendrimer, or functionalized with poly(ethylene glycol), wherein the conjugate is confined to the peripheral circulation.18. The composition of any of the preceding paragraphs, wherein the drug has a loading between about 2% and about 35% by weight.19. The composition of any of the preceding paragraphs, further containing a pharmaceutically acceptable excipient.20. Formulations in a dosage for treatment of an individual in need of treatment of atherosclerosis, treatment of obesity, treatment of diabetes, treatment of metabolic syndrome, control of blood sugar, lowering blood pressure, treatment of lipid disorders, treatment of fatty liver disease, treatment / prevention of kidney diseases, or treatment of symptoms thereof, comprising the composition of any of the preceding paragraphs.21. The formulations of any of the preceding paragraphs for treatment of an obese individual, wherein fat mass loss is higher than lean mass loss.22. The formulations of any of the preceding paragraphs for treatment of an obese individual, wherein weight loss is achieved without appreciable appetite loss.23. The formulations of any of the preceding paragraphs for treatment of an obese individual, wherein treatment converts white fat cells to brown fat cells.24. A method of treating one or more symptoms of atherosclerosis, abnormal blood sugar, low blood pressure, lipid disease, fatty liver disease, kidney disease, obesity, or metabolic disorders associated therewith, and combinations thereof, the method comprising administering to an individual in need thereof, the composition of any of the preceding paragraphs, or the formulations of any of the preceding paragraphs.25. A method of treating a disease or disorder, the method comprising using the composition of any of the preceding paragraphs or the formulations of any of the preceding paragraphs in combination with an existing treatment.26. A method of treating a disease or disorder, the method comprising using the composition of any of the preceding paragraphs or the formulations of any of the preceding paragraphs to prevent recurrence of the disease of disorder, following termination or reduction of existing treatment.27. The method of any of the preceding paragraphs, wherein the formulation selectively delivers the hydroxyl dendrimer-drug conjugate or the glucose dendrimer-drug conjugate to macrophages and foamy macrophages in an atherosclerotic plaque.28. The method of any of the preceding paragraphs, wherein the formulation selectively delivers the hydroxyl dendrimer-drug conjugate or the glucose dendrimer-drug conjugate to adipose macrophages in fat tissues, and / or brain microglia / macrophages in the hypothalamus of the individual.29. The method of any of the preceding paragraphs, wherein the individual has Type-2 diabetes and the hydroxyl dendrimer-drug conjugate or the glucose dendrimer-drug conjugate is administered to the individual with Type-2 diabetes in an amount effective to alleviate one or more symptoms of Type-2 diabetes.30. The method of any of the preceding paragraphs, wherein the individual is an obese individual and the hydroxyl dendrimer-drug conjugate or the glucose dendrimer-drug conjugate are administered to the obese individual in an amount to cause weight loss.31. The method of any of the preceding paragraphs, wherein the glucose dendrimer-drug conjugate is administered to an obese individual in an amount to cause weight loss.32. The method of any of the preceding paragraphs, wherein fat mass loss is higher than lean mass loss.33. The method of any of the preceding paragraphs, wherein weight loss is achieved without appreciable appetite loss.34. The method of any of the preceding paragraphs, wherein treatment converts white fat cells to brown fat cells.35. The method of any of the preceding paragraphs, wherein the obese individual is a human.36. The method of any of the preceding paragraphs, wherein the hydroxyl dendrimer-drug conjugate or the glucose dendrimer-drug conjugate does not cause symptoms of toxicity.37. The method of any of the preceding paragraphs, wherein the formulation is administered via a route selected from the group composed of mucosal administration, enteral administration or injection, intranasal, intravenous, oral, sublingual, subcutaneous, inhalable, transdermal, or intraperitoneal.ExamplesExample 1:PAMAM-OH dendrimer selectively delivers agent to macrophages in atherosclerotic plaque. Materials and MethodsThe feasibility of selective drug delivery to macrophages in atherosclerotic plaque was investigated using PAMAM-OH dendrimer conjugated Cy5 (D-Cy5). ApoE- / - mice were fed a high fat diet (“HFD”) for 4 months, to cause significant plaque buildup, as shown in FIG. 1. Mice then received D-Cy5 (10 mg / kg; intraperitoneal injection). After 24 hours, aortas were harvested, fixed, stained for CD68 (macrophages) and DAPI (nuclei), and imaged by confocal microscopy. ResultsRepresentative confocal images obtained 24h post intraperitoneal injection of D-Cy5 in control and atherosclerotic ApoE- / - show that -Cy5 was clearly internalized by macrophages in the atherosclerotic plaque, as shown by the Cy5 signal accompanied by positive CD68 and nuclei stain, whereas the healthy control showed no D-Cy5 uptake, confirming PAMAM-OH dendrimers conjugated to agents deliver drug payload to macrophages in plaque. Example 2:PAMAM-OH-Tesa decreases arterial stiffness and body weight in atherosclerotic mice. Atherosclerosis is associated with arterial stiffening, which can be assessed by PWV (higher PWV= higher aortic stiffness), the gold standard in vivo index of arterial stiffness in mice. Materials and MethodsMale ApoE- / - mice on a high fat diet (“HFD”) exhibited a rapid increase in PWV, greater than what is expected with natural aging, indicating the progression of atherosclerosis. After 4 months on HFD, mice were randomized into two groups: 1) treatment group: HFD plus D-Tesa for 6 weeks (20 µg / kg twice weekly by oral gavage) and 2) untreated group: mice continued to receive HFD during the treatment period. Plaque burden was evaluated in the baseline (16 wks HFD), untreated (16wks HFD+ 6 wks HFD), and D-Tesa treated (16wks HFD+ 6 wks HFD & treatment) groups using Oil Red O (ORO) staining and determined percent plaque area / total area as a marker for plaque burden with ImageJ.Body composition analysis by qMRI. 4 mo male ApoE- / - mice were fed HFD for 16 weeks and then randomized to receive: 1) vehicle (control), 2) D-Tesa (20 μg / kg, twice weekly), 3) Free -Tesa (20 μg / kg, twice weekly) for 3 weeks. Mice continued to receive HFD. Body weight, and qMRI assessment of %Fat mass and %Lean mass was determined. (n = 3-5 mice per group; *p<0.05, **p<0.01 by 1-way ANOVA with Tukey’s post hoc analysis)ResultsFIG. 2A-2D are graphs of the % change in body weight (2A), grams body weight (2B), % fat mass (2C), and % lean mass (2D) for mice on a HFD treated with free Tesa compared to dendrimer conjugated Tesa (D-Tesa). D-Tesa decreases the body weight induced by the high fat diet. D-Tesa treatment demonstrated that body weight increased due to HFD administration but decreased after D-Tesa treatment FIG. 3A-3C show D-Tesa ameliorates markers of atherosclerosis.PWV is ameliorated with D-Tesa treatment (FIG. 3A) while free Tesaglitazar did not show this effect. Body weight (FIG.3C) showed an increase due to HFD administration but decreased after D-Tesa treatment (n=6-12 male mice per group). (FIG. 3C). During treatment, untreated mice did not lose weight, but D-Tesa treated mice exhibited a steady decrease in fat and increase in lean mass (n=8-9 male mice per group). HFD caused an expected increase in body weight. Although treated mice continued HFD feeding, D-Tesa treatment led to significant weight loss while untreated mice continued to gain weight.D-Tesa leads to weight loss in male mice. One of the main side effects of tesaglitazar was weight gain. Surprisingly, it was found that mice that receive D-Tesa lose weight despite continuing on HFD without a decrease in degree of food intake. This indicates that the loss of weight is not due to a decrease in food intake or decrease in appetite. While cationic dendrimers have been shown to induce weight loss arising from non-specific accumulation in various tissues with associated toxicity, hydroxyl dendrimer used in the study is non-toxic and does not cause weight loss by itself. This is also reflected in the data in which weight gain was similar in HFD fed mice that received empty dendrimer and those that received HFD alone. The results indicate that the weight loss in the HFD+D-Tesa group arises from the action of tesaglitazar released intracellularly in macrophages in adipose tissue.Importantly, D-Tesa treatment reduces fat mass, while increasing lean mass, which is a highly desirable outcome in weight loss, diabetes, heart drugs. Typically, many drugs used for weight loss (e.g. semaglutide, Ozempic) and diabetes are shown to decrease both fat mass and lean mass. Even though the fat mass loss is desirable from a weight loss objective, the lean mass loss is not desirable, especially in older patients. When patients stop taking these drugs, the fat mass may come back, but the lean mass does not, causing health issues. In contrast, the effect seen here with D-Tesa with selective loss of fat mass with increase in lean mass is very surprising and unexpected. This may indicate conversion of white adipose tissue to brown adipose tissue. The increase in energy expenditure may also indicate an increase in brown adipose tissue.Blood pressure (BP) was unaffected by HFD and D-Tesa treatment, confirming that changes in PWV are due to changes in aortic mechanics and not simply due to BP elevation.FIG. 3A shows that PWV (m / s) decreases at 40 weeks and longer with treated with D-Tesa treatment compared to untreated and free tesaglitazar. Systolic (3B), blood pressure was unchanged throughout experiment. (n=6-16 male mice per group).FIG. 4 is a graph of the percent lesion area comparing treatment with D-Tesa and untreated mice on a HFD.Impairments in vasoreactivity are halted by D-Tesa. Relaxation of PE pre-constricted aorta from baseline, untreated, and D-Tesa treated induced by increasing concentrations of acetylcholine (Ai) and sodium nitroprousside (Bi). See FIG. 5A-5D graphs of relaxation (% PE Max) versus dose of D-Tesa (5A, 5C) and log EC50 (5B, 5D) for Ach dose (5A, 5C) or SNP dose (5C, 5D).In summary, after 6 weeks, D-Tesa treated mice exhibited a lower PWV compared to untreated mice despite being on HFD. D-Tesa Treatment also slows plaque progression. Plaque deposition 6 weeks after baseline showed a significant increase in the untreated mice (FIG. 4). D-Tesa treated mice had significantly lower plaque burden than untreated mice. This demonstrates that D-Tesa can be used to lower plaque burden. The data demonstrates that targeting PPARs specifically in macrophages is sufficient to ameliorate plaque burden.Moreover, D-Tesa treatment ameliorates the severity of aortic endothelial and smooth muscle cell (SMC) dysfunction. Endothelial dysfunction, characterized by reduced agonist induced endothelial dependent vasorelaxation, is a known hallmark of atherosclerosis. Targeting inflammatory cells with D-Tesa also ameliorates endothelial dysfunction in atherosclerotic mice. Endothelial dependent vasorelaxation of aortic rings (preconstructed with phenylephrine) was evaluated by wire myography using acetylcholine (10-9-10-5M). Untreated mice have greater endothelial dysfunction compared to mice at baseline, as evidenced by lower -LogEC50. D-Tesa treatment shows a significantly increased -LogEC50 compared to the untreated group, similar to that of the baseline group, showing preserved endothelial function even as D-Tesa treated mice continue on HFD. The dose response to sodium nitroprusside shows a decrease in -LogEC50 in the untreated group compared to baseline, indicating SMC dysfunction. However, there is a significant improvement in -LogEC50 in the D-Tesa group (vs. untreated group, showing preserved SMC function.Example 3:D-Tesa upregulates PPAR-α and PPAR-γ in the aortaMaterials and MethodsAortic PPAR-α and PPAR-γ expression was evaluated by Western blotting. Segments of the thoracic descending aorta from ApoE(- / -) mice fed HFD ± D-Tesa treatment were homogenized and PPAR-α and PPAR-γ were probed for on separate blots with GAPDH for normalization. ResultsPPAR-α (FIG.6A) and PPAR-γ (FIG.6B) protein expression increases in D-Tesa treated versus untreated mice, demonstrating successful D-Tesa delivery and release of functional Tesaglitazar in the area of injury.Example 4: D-Tesa decreases body weight in obese mice in spite of continuing HFD that is not seen with free tesaglitazar. FIG. 7A-7F demonstrates efficacy of D-Tesa and that it does not show the side effects of free Tesa. VCO2 (FIG. 7A) and VO2 (FIG. 7B) are increased in D-Tesa treated mice versus vehicle and free Tesa treated mice, leading to an increased energy expenditure (FIG. 7C). Despite greater food intake (FIG. 7D), body weight in D-Tesa treated mice is significantly lower than vehicle treated mice after 3 weeks (FIG. 7E). Edema measured by degree of paw edema, a common side effect of Tesaglitazar, is not seen in D-Tesa treated mice but is observed in free Tesaglitazar treated mice (FIG. 7F).Metabolic measurements done on the mice after treatment demonstrated that there was no decrease in food intake in the D-Tesa treated mice and in fact there was an increase in the intake of the HFD noted (FIG. 7D). Despite greater food intake (FIG. 7D), body weight in D-Tesa treated mice is significantly lower than vehicle treated mice after 3 weeks (FIG. 7E). Metabolic measurements also showed an increase in VCO2 (7A) and VO2 (FIG. 7B) in D-Tesa treated mice versus vehicle and free Tesa treated mice, leading to an increased energy expenditure (7C). This may be due to increased brown adipose tissue in D-Tesa treated mice when compared to white adipose tissue that is usually associated with low energy expenditure in the untreated and free tesa treated obese mice. One notable known side effect of free Tesaglitazar treatment is peripheral edema. Free Tesaglitazar treated mice demonstrated significant increase in paw edema (thickness in mm in FIG. 7F) that was not seen in the vehicle treated mice. However, D-Tesa treated mice did not exhibit edema when compared to the vehicle treated mice (FIG. 7F). This demonstrated D-Tesa’s ability to avoid a side effect of the free drug through macrophage specific targeting. There was also no change in activity seen in the D-Tesa treated mice which indicates that the weight loss is not associated with negative effects.Example 5:Glucose dendrimer localization in plaque associated macrophagesMacrophages in atherosclerosis plaque, in adipose tissue macrophages and in microglia express increased glucose transporters (Glut) and have increased localization of GD which enables greater delivery of the drug to these cells. Glucose dendrimer also localizes in the hypothalamus (region responsible for appetite and feeding) of the brain only in obese mice.Example 6:Efficacy of dendrimer-tesaglitazar as a potential atherosclerosis treatment. Materials and MethodsStudy designApoE- / - mice used in this study were purchased from the Jackson Laboratory or generated in house from mice also purchased from the Jackson Laboratory. C57Bl / 6J mice were obtained from Jackson Laboratory and used as healthy controls. Atherosclerosis was induced by starting mice on a high fat diet (Inotiv Teklad, Catalog # TD.88137) at 22-25 weeks of age. Chow fed ApoE- / - mice and healthy C57Bl / 6J mice were maintained on regular chow for the entirety of the study. At the conclusion of the study, mice were anesthetized with 2% isoflurane. Paw thickness measurements were obtained using digital calipers. Mice were injected with heparin and serum collected via cardiac puncture. Euthanasia was completed under anesthesia by extraction of the heart.All animal procedures and protocols used in this study are approved by the Johns Hopkins University Animal Care and Use Committee (ACUC). Mice were housed in the Johns Hopkins University School of Medicine animal facilities and given access to food and water ad libitum. Animal housing was temperature controlled with a 12hr light / dark cycle.Preparation and characterization of D-TesaTesaglitazar was conjugated onto the surface of a generation 4 hydroxyl terminated polyamidoamne (PAMAM-OH) dendrimer as previously described20. Briefly, each dendrimer was synthesized to include 10 Tesaglitazar molecules attached via cleavable ester linkage. Mass spectrometry was conducted to confirm product formation and HPLC was conducted to ensure synthesis purity.In vitro THP-1 cell studies THP-1 monocyte cells were purchased from ATCC. Monocyte cells were seeded in 6 well plates at 1x106 cells per well. Cells were incubated with RPMI 1640 medium supplemented with 10% FBS, 1% PSY (phytoene synthase-1), and phorbol 12-myristate 13-acetate (PMA) for 24h to induce monocyte to macrophage transformation. Cells were then incubated in serum starved in DMDM / F12 (1:1) supplemented with 1% PSY for 24h. Cells were incubated with oxLDL for 24 hours followed by incubation with free Tesaglitazar, D-Tesa, or left untreated (control) for 24 hours. Cells were lysed in MPER or subjected to nuclear fractionation using NE-PER nuclear cytoplasmic extraction kit (Thermo Fisher, Catalog # 78833) according to manufacturer’s instructions.D-Cy5 localization studiesDendrimer Cy5 (D-Cy5) was synthesized as previously described. 38-week-old ApoE- / - mice on HFD for 16 weeks and age matched C57Blk / 6J mice on regular chow were administered PAMAM-OH D-Cy5 at 10 mg / kg (i.p.). Upon sacrifice, the aorta was isolated, cleaned off, and fixed overnight in 10% formalin. Aortic tissue was stained using DAPI and an antibody against CD68. Adipose tissue was isolated and fixed in 10% formalin for 30 min and subsequently cryopreserved in 30% sucrose overnight. Adipose tissue was then mouthed in OCT and sectioned using a Leica cryostat to a thickness of 20µm. Adipose sections were stained using DAPI and TREM2. IF imaging was conducted on a Leica SP8 confocal microscope.Pulse wave velocity measurements Mice were anesthetized with 2% isoflurane and then placed on a heated EKG pad (Indus Instruments) to monitor heart rate. A 10MHz doppler was used to measure the cardiac pulse along the thoracic and abdominal aorta. Pulse wave velocity is calculated by dividing the distance between the two points and the time it took for the pulse to transverse the two points.Blood pressure measurement Before enrollment in the study, mice underwent gradual habituation to bloop pressure measurement. Mice were first immobilized in a blood pressure cone and placed it under a heating lamp. Blood pressure was then measured in conscious mice using a tail cuff (CODA Scientific noninvasive blood pressure system).ORO (Oil Red O) staining and lesion analysis Aorta were collected upon sacrifice and bisected longitudinally. Plaque depositions were determined using a commercially available ORO kit (abcam). Plaque was quantified along the ascending aorta, aortic arch, and descending aorta. Percent plaque area was determined using ImageJ.Western blottingFlash frozen tissues were ground into powder and homogenized in RIPA buffer (Sigma-Aldrich) with a protease inhibitor (Roche). Bradford assay was conducted to quantify protein concentration of the tissue homogenates using manufacturer’s instructions (BioRad). Protein samples were run through SDS-PAGE on 4%-15% MP TGX gels (BioRad, Mini®PROTEAN™ Precast Gels) and transferred to nitrocellulose paper (BioRad Trans-Blot Turbo transfer system). Blots were blocked in 3% nonfat dry milk in TBST (Tris-buffered saline with Tween 20) for 1hr and subsequently incubated overnight with primary antibody diluted in 3% nonfat dry milk in TBST. Following three, five-minute washes in TBST, blots were incubated for 1 hr with HRP (Horseradish peroxidase) conjugated secondary antibodies and imaged for chemiluminescent detection (Cytiva). Antibodies used were PPAR-α (Invitrogen, Catalog #MA1-822), PPAR-γ (Invitrogen, Catalog #MA5-14889), ABCA1 (Novus Biologicals, Catalog #NB400-105), iNOS (Novus Biologicals, Catalog #NB300-605), Arg1 (Novus Biologicals, Catalog # NBP1-32731), and GAPDH (Novus Biologicals, Catalog #NB300-221).Wire myographyAortic rings isolated from mice in this study were subjected to vasoreactivity studies as previously described. Briefly, 2mm aortic segments were mounted onto a wire myograph (DMT) and preconstructed with 10-6 M of phenylephrine. Endothelium dependent vasorelaxation was determined with increasing concentration of acetylcholine (10-9 M to 10^-5 M). Endothelium independent vasorelaxation was determined by first pre-constricting the vessels with phenylephrine followed by incubation with increasing concentration (10-9 M to 10^-5 M).Puller Passive stiffness of aortic rings was determined as previously reported. Briefly, 1.5mm aortic rings were first imaged to for subsequent measurement of lumen diameter (D), wall thickness (t) and vessel length (l) in ImageJ. The rings were then mounted onto two parallel pins on an electromagnetic puller (DMT) and pulled at a constant rate until failure. Data on the displacement and force exerted by the ring in response to the deformation was continuously recorded during the pull. Force (F) / displacement (d) data was converted to stress (S) / strain (λ) data by normalizing the data to its individual parameters of side (S=F / 2˟t˟l and λ=D / d). Nonlinear regression was performed to determine the stress-strain strain curves, represented by the equation S=αeβ˟λ , where α and β are constant. The incremental modulus (Einc) was found by taking the first derivative of the stress strain curve at a strain of 1.5 for the elastin mediated Einc and a strain of 2.5 for the collagen mediated Einc.Electrochemiluminescent multiplex assaySerum samples collected mice were analyzed using a V-PLEX proinflammatory Panel 1 Mouse kit (Meso Scale Diagnostics, Catalog #K15048D-1) using the manufacturer’s instructions. The multiplex assay was conducted using a 1:2 dilution of serum and each sample was run in duplicate. The protein concentration of each serum sample was determined using a Bradford assay (BioRad) and used to normalize the concentration of each analyte.Metabolic Testing Quantitative MRI (qMRI) and indirect calorimetry experiments were run in collaboration with the Johns Hopkins Center for Metabolism & Obesity Research.For qMRI, mice were weighed before being guided into an insertion tube. A plunger is gently inserted into the tube to correctly position and immobilize the mouse for measurement. The insertion tube is inserted into the EchoMRI-100 to initiate data collection.Indirect calorimetry was conducted using a 24 cage CLAMS indirect calorimeter (Columbus Instruments). Mice were signally housed and provided HFD and water ad libitum. Bodyweight and food intake were monitored daily. Each cage is continuously provided with fresh room air that is periodically sampled to collect data on oxygen consumed and carbon dioxide produced.Statistical analysisData are presented at mean ± standard error of the mean. Sample size (n) is reported for all data collection. Statistical analysis was conducted in Prism 8. For normally distributed data, two means were compared using Student’s t-test. For data with more than one means, 1-way ANOVA was used. 2-way ANOVA was used for grouped analysis. Statistical significance was considered at p<0.05.ResultsD-Tesa mediated activation of PPAR-α / γ leads to anti-inflammatory phenotype and increased cholesterol efflux in THP-1 derived macrophagesThe performance of D-Tesa was examined in vitro to ensure that the dendrimer formulation successfully delivers Tesaglitazar to cells and activates PPAR-α / γ in atherosclerotic macrophages. To this end, THP-1 monocytes were stimulated with PMA to a macrophage phenotype, incubated with oxLDL to induce foam cell formation, and then randomized to receive D-Tesa, free Tesaglitazar, or vehicle (DMSO) (Figure 8A). Oil red O staining shows that there is decreased lipid deposition in D-Tesa treated macrophages versus vehicle and free drug (Figure 8B).Comparison of nuclear translocation of PPAR-α / γ following free or D-tesa treatment revealed that the dendrimer conjugate is able to upregulate the protein expression of both PPAR-α and PPAR-γ to a greater magnitude than the free drug (Figure 8C-8E). This upregulation is also associated with higher protein levels of ABCA1 (Figure 8F and 8G), a well-established cholesterol efflux transporter and a target gene of PPAR-γ. Additionally, THP-1 derived macrophages treated with D-Tesa exhibited a similar phenotype switch from a pro-inflammatory to anti-inflammatory as macrophages treated with the free drug, evidenced by the with loss of iNOS (Figure 8H)and increase in Arg1 (Figure 8I).Thus, in vitro, D-Tesa similar PPAR-α / γ activation, while eliciting a superior cholesterol efflux and anti-inflammatory effect compared to the free drug.PAMAM-OH dendrimers deliver payload in vivo to resident macrophages in the WAT and aortic plaque. Whether dendrimers can deliver payload to cells within the WAT (white adipose tissue) and plaque was investigated. To visualize drug delivery, an atherosclerotic apoE- / - mouse was administered a cy5 labeled D-Tesa (D-Tesa-cy5) P.O., followed by IF (immunofluorescence) staining of white blood cells, aorta, and WAT. (Figure 9A). A smear of the buffy coat revealed that the dendrimer conjugate was not taken up by circulating white blood cells (Figure 9B). Sectioned WAT showed that D-Tesa-cy5 was internalized by TREM2 positive macrophages (Figure 9C). Likewise, the conjugate showed uptake in aortic macrophages, as evidenced by dendrimer colocalization with CD68 positive cells (Figure 9D). This colocalization was only seen with atherosclerotic ApoE- / - mice, and not in healthy age matched wildtype control mice. Images taken at increasing depths into plaque show the dendrimer was able to penetrate deep into plaque, which is a main difficulty in treating atherosclerosis (Figures 16A-16D).D-Tesa treatment halts aortic plaque progression through improved cholesterol efflux in male and female apoE- / - mice.The in vivo efficacy of D-Tesa was investigated in male and female apoE- / - mice. 22–25-week-old mice were given high fat diet (HFD) for 12 weeks before being randomly assigned to one of four groups. The first group, 1) baseline, was sacrificed immediately after 16 weeks on HFD to provide physiological data before treatment, 2) D-Tesa (20mg / kg twice a week P.O.), 3) free Tesaglitazar (20mg / kg twice a week P.O), 4) vehicle controls (DI water twice a week P.O.). mice continued HFD (high fat diet) for the duration of the treatment period (Figure 10A). Oil Red O staining (ORO) was performed on aorta isolated from baseline, vehicle treated, and D-Tesa treated mice (Figure 10B). Vehicle treated mice exhibited a significant increase in plaque deposition when compared to mice at baseline. However, atherosclerotic mice treated with D-Tesa have significantly lowered amount of plaque than vehicle treated mice (Figure 10C). Through Western Blotting (Figures 10D and 10I), this benefit was shown to be from an increase in ABCA1 (Figure 10E and 10J) as well as apoA (Figure 10F and 10G), the apolipoprotein responsible for high density lipoprotein mediated cholesterol efflux. Additionally, there was a modulation of macrophages from the proinflammatory phenotype, indicated by iNOS (Figure 10G and 10L), to the anti-inflammatory macrophage phenotype, indicated by Arg1 (Figure 10H and 10M).ApoE- / - mice treated with D-Tesa have improved active and passive aortic stiffness. During high fat diet (HFD) administration and treatment period, the following parameters were monitored: weight, blood pressure, and pulse wave velocity (PWV), the gold standard for determining arterial stiffness. During the 16-week HFD administration, males and females demonstrated an increase in PWV, correlating the development of atherosclerosis. Males exhibited a statistically significant increase in the first 8 weeks which tapered off in the following 8 weeks. Females also demonstrated a significant increase in PWV for the first 8 weeks and another significant increase in the following 8 weeks, revealing a sex difference in the progression of arterial stiffness in atherosclerosis. During the 6-week treatment period, male and female mice on D-Tesa demonstrated a significant decrease in PWV that is not seen in free Tesaglitazar treated mice (Figure 11A and 11H). During the entire study, neither male nor female mice demonstrated significant changes in blood pressure (Figure 11B and 11I).Upon sacrifice, aortic rings were subject to ex vivo tensile testing to generate stress strain curves and the passive vessel stiffness of isolated aortic rings were determined (Figure 11C and 11J). Vehicle treated male and female ApoE- / - mice had an increased collagen mediated stiffness when compared to ApoE- / - mice at baseline and age matched chow fed control mice. In both sexes, D-Tesa treatment modestly improved elastin mediated stiffness (Figure 11D and 11K), but significantly decreased collagen medicated stiffness when compared to vehicle treated mice (Figure 11E and 11L). This decrease in passive vessel stiffness in both males and females corresponded with PWV data showing that D-Tesa treated mice exhibit lower aortic stiffness. In males, the benefit of increased strain at failure was also observed, with similar strains at failure compared to vehicle treated and free Tesaglitazar treated mice (Figure 11F and 11G). This trend was not observed in females, presenting a sex-based difference of the therapy.D-Tesa halts the progression endothelial dysfunction due to progression of atherosclerosis.Aortic rings were also used to determine vasoreactivity using acetylcholine (Ach) to determine endothelium dependent vasodilation and sodium nitroprusside (SNP) to determine endothelium independent vasodilation after phenylephrine preconstruction. In males, it was observed that endothelium mediated vasodilation of the vehicle treated group was significantly impaired six weeks after baseline (Figure 12A). However, a significant positive impact of D-Tesa on the ach (acetylcholine) dose response was observed when comparing the LogEC50 (Figure 12B) and max relaxation (Figure 12C) to the vehicle group that is not seen in the free Tesaglitazar treated mice. In females, the same trends were observed (Figure 12G). This may be due to the cardioprotection shown by females, which is evidenced by the deceased difference in max relaxation (Figure 12G) and LogEC50 (Figure 12H) in the vehicle versus baseline in female compared to male apoE- / - mice. Additionally, in both male (Figure 12D-12F) and female (Figure 12J-12L) atherosclerotic mice, SNP mediated vasodilation remained constant, indicating that the differences seen in the ach dose response were likely due to protection of the endothelium as opposed to difference in smooth muscle cell function of the aorta.Selective delivery of Tesaglitazar to macrophages in adipose tissue induces browning and causes weight lossD-Tesa treatment caused a decrease in body weight that was not observed in vehicle or free Tesaglitazar treated mice (Figure 13A). Body composition testing revealed that even though body weight decreased, the percentage of weight that was from lean mass, or muscle mass, increased (Figure 13B). The decrease in total bodyweight was not due to appetite suppression, as D-Tesa treated mice ate significantly more than vehicle and free drug treated mice (Figure 13C).Western blotting revealed that D-Tesa treated mice had an anti-inflammatory effect on the adipose tissue as evidenced by the decrease in iNOS and increase in arg1 (Fig 13D-13F). The dendrimer conjugate also induced an increase in uncoupling protein 1 (UCP-1), a marker for brown adipose tissue, to the same extent as free Tesaglitazar (Figure 13G). This browning causes a phenotypic change of adipocytes to decrease in size, with D-Tesa treatment causing a significant reduction in adipocyte size compared to those of vehicle and free Tesaglitazar treated mice (Figure 13H-13I). Metabolic testing in male mice was conducted to investigate any benefit on body composition exhibited by D-Tesa treatment. It was observed that D-Tesa significantly increases the volume of oxygen consumed (VO2) (Figure 13J) and the volume of carbon dioxide produced (VCO2) (Figure 13L) compared to vehicle and free Tesaglitazar treated mice. Because both parameters were increased, the RER (respiratory exchange ratio) of all three groups remains the same (Figure 13M). However, this revealed that D-Tesa treated mice had significantly increased levels of energy expenditure (EE) (Figure 13N).Macrophage targeted delivery of Tesaglitazar avoids side effects associated with free drug treatment Since D-Tesa utilizes a macrophage targeted delivery of free Tesaglitazar, whether the dendrimer conjugation would allow avoidance of the adverse consequences seen in clinical trials was tested. Aside from weight gain, the other cited side effect of Tesaglitazar was decreased renal function leading to peripheral edema. Paw thickness was measured using digital calipers and indeed, free Tesaglitazar caused swelling of all four paws. However, this same degree of swelling was not observed in D-Tesa treated male ApoE- / - mice (Figure 14A). Additionally, there was a modest drop in hemoglobin associated with free Tesaglitazar treatment that was not observed with D-Tesa (Figure 14B). Western blotting of entire kidney (Figure 14C) showed that there was an increase in iNOS (inducible nitric oxide synthase) (Figure 14D) with no effect on arg1 (Figure 14E) in Free tesa treated mice that was not observed with D-Tesa treatment. There were similar levels of PPAR-α protein expression (Figure 14F) in both free Tesaglitazar and D-Tesa treated groups showing that targeted PPAR activation does not confer that same renal toxicity as systemic activation. Similar trends were observed in female apoE- / - mice (Figures 17A-17F).Physiological benefit of D-Tesa therapy is recapitulated in LDLr- / - mice with intact apoE mediated cholesterol efflux.Since ApoE- / - mice developed atherosclerosis through impaired cholesterol efflux, the experiments in male and female LDLr- / - mice were repeated, which have intact apoE mediated cholesterol efflux. Both male and female LDLr- / - mice showed a significant decrease in percent change in body weight that is not seen in vehicle or free Tesaglitazar treatment (Figure 15A and 15H). Free Tesaglitazar resulted in significant paw edema when compared to vehicle treated mice. However, this side effect was not seen with D-Tesa treatment (Figure 15B and 15I). PWV is decreased after D-Tesa treatment in male atherosclerotic LDLr- / - mice, but not in females (Figure 15C and 15J). Blood pressure was constant throughout the experiment (Figure 15D and 15J). After treatment, passive vessel stiffness was unchanged in male (Figure 15E), but decreased in female mice (Figure 15K). Acetylcholine mediated vasoreactivity studies on isolated aorta showed that endothelial function was superior in male and female LDLr- / - mice treated with D-Tesa (Figure 15F and 15L), which was highlighted by the significantly higher max relaxation compared to vehicle and free Tesaglitazar (Figure 15G and 15M).The Ldlr KO mouse is another widely used model of atherosclerosis where exposure to HFD leads to plaque along with stiffening of the vessels and weight gain. The data in Figures 15A-15M demonstrate efficacy in the model where that treatment with D-tesa led to improved vessel reactivity and deceased weight both in males and females. This indicates that the therapeutic benefits of D-tesa are seen irrespective of the type of model leading to atherosclerosis and weight gain. DiscussionObesity and atherosclerosis are chronic inflammatory diseases linked by infiltration of macrophages into adipose tissue and arteries, respectively. Obesity accelerates atherosclerosis, with every one-point increase in BMI raising the risk for atherosclerosis and coronary heart disease by ten percent1. Atherosclerosis is the main contributor to cardiovascular disease, the leading cause of mortality worldwide2. In addition, obesity increases the risk of premature death in males and females by two to three-fold when compared to individuals with a BMI between 23.5 and 24.93.To date, there are no therapies to cure atherosclerosis. Despite major advances in the diagnosis and treatment of atherosclerosis, the need for therapies that directly target the plaque remains. Most recently, the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) trial showed a reduction in systemic inflammation and cardiovascular events using a monoclonal antibody against interleukin-1β4. Ongoing research for atherosclerosis therapy includes inactivation of cytokine release5,6 and improving efferocytosis in plaque7,8. Currently, the only treatment option to reduce severe plaque burden is surgical intervention. This option is limited for severe cases and although it alleviates burden, it does not address the underlying cause of the disease. The immune system has emerged as a target to treat atherosclerosis and obesity, as macrophages are the main cell type that drive the disease progression. Macrophages resident in atherosclerotic plaque drive systemic inflammation and contribute to the accumulation of foam cells within atheroma.Peroxisome proliferator activated receptors (PPARs) are transcription factors of particular interest for treating chronic inflammation associated with obesity and atherosclerosis. Two isotypes of PPARs, PPAR-α and PPAR-γ, have been explored for anti-atherosclerotic and anti-inflammatory functions. PPAR-α regulates expression of genes involved in lipid and lipoprotein metabolism4. Activation of PPAR-α decreases cholesterol ester levels and lipoprotein accumulation, while also increasing fatty acid beta oxidation9. PPAR-γ regulates fatty acid storage and increases expression of proteins involved in lipid and glucose metabolism4. Additionally, PPAR-γ decreases macrophage accumulation in plaque by decreasing monocyte infiltration into the intima and inhibiting vascular smooth muscle cell migration and transdifferentiation10. Both PPAR-α and PPAR-γ are expressed in macrophages and have well established anti-inflammatory properties. PPAR-α and PPAR-γ have been shown to both inhibit the acetylation of p65 NF-κB as well as cause the deacetylation of p65 NF-κB, leading to the inactivation of NF-κB11. PPAR-γ activation has shown potent macrophage polarization to an anti-inflammatory phenotype. PPAR-α and PPAR-γ have been reported to inhibit foam cell formation through regulation of genes that improve reverse cholesterol transport5.Tesaglitazar is a PPAR agonist of particular interest as it is a dual PPAR-α / γ agonist. Prior research showed that Tesaglitazar improved lipid profile in diabetic and non-diabetic patients with insulin resistance11,14. In mice, it yielded benefits including decreased plasma cholesterol15 and atherosclerotic plaque and improved inflammatory marker16. However, issues with toxicity arose during phase 3 clinical trials. Patients given Tesaglitazar experienced peripheral edema, weight gain, impairments in renal function17, a dose-dependent reduction in hemoglobin (anemia)18, myocardial ischemia, and aggravation of congestive heart failure19. The trials were therefore terminated due to the lack of benefit compared to side effect profile arising from off-target effects.In this study, it was hypothesized that targeting inflamed macrophages in aortic plaque and white adipose tissue using a dendrimer conjugated formulation would achieve benefits against obesity and atherosclerosis and avoid PPAR activation in healthy tissue. To leverage the benefit of this dual PPAR-α / γ and avoid adverse side effects, Tesaglitazar conjugated onto a generation 4 hydroxyl terminated polyamidoamine (PAMAM-OH) dendrimer nanoparticle (D-Tesa) was tested. These dendrimers are nontoxic and are unmetabolized through kidneys, as demonstrated in humans. The preferential uptake of PAMAM-OH dendrimers into activated macrophages in multiple preclinical animal species which led to positive therapeutic outcomes has been shown. Also shown were that D-Tesa has a higher solubility than the free drug and achieves a sustained intracellular release20.The effect of sex is an established variable in cardiometabolic disorders. Women exhibit protection against cardiometabolic dysfunction until menopause, a benefit hypothesized to be from estrogen21. For example, the risk of myocardial infarction, stroke, or other major adverse cardiovascular events is higher for men before the age of 60, but higher for woman over the age of 6022. Studies report that intimal-media thickness, a parameter of atherogenesis, is higher in men than women at 35 years of age, but at 75 years of age, this difference is not reported23. In this study, male and female mice were utilized to elucidate sex-specific effects on the development and treatment of atherosclerosis.There were two commonly used mouse models used in atherosclerosis research; the apolipoprotein E knockout mouse (ApoE- / -) and the low-density lipoprotein knockout mouse (LDLr- / -). Both models are on C57Blk / 6 background. LDLr- / - mice lack the LDL receptor, causing a delayed clearance of LDL resulting in increased cholesterol levels in the plasma. On a regular chow diet these mice do not develop atherosclerosis, as they need a source of high cholesterol from a diet high in fat to facilitate atherogenesis. The lipid profile of LDLr- / - resembles that of a human with hypercholesterolemia. ApoE- / - mice are deficient of apolipoprotein E, a protein required for the metabolism of fat in mammals. ApoE- / - mice develop lesions that correspond more closely to human atheroma. Since both models mimic the disease progression of atherosclerosis and obesity, the efficacy of D-Tesa on both mouse models was examined. The present study demonstrated D-Tesa’s ability to deliver Tesaglitazar into atherosclerotic macrophages, address the cause of and improve atherosclerosis, and decrease obesity. D-Tesa’s mechanism in vitro was confirmed in THP-1 derived macrophages transformed into foam cells using elevated concentrations of oxidized LDL. D-Tesa treatment showed upregulation of PPAR-α / γ, the cholesterol efflux transporter ABCA1, and the anti-inflammatory marker of Arg1 at the same, or greater magnitude in cells treated with free Tesaglitazar. Dendrimer conjugation allows for improved efficacy, owing to dendrimer-mediated macrophage targeting, improved solubility, and intracellular release. Conducting these studies in THP-1 cells also provides insight into the drugs ability to translate into humans, as these monocytes are of human origin.The conjugate’s efficacy was evaluated in vivo. To obtain the best indication of translation, this study was designed to replicate clinical presentation and a treatment regimen with a high likelihood of compliance. The ApoE- / - model of atherosclerosis was used. Mice were fed a high fat diet starting at 22-25 weeks of age for 16 weeks prior to the start of treatment. It is well established that ApoE- / - mice on HFD for 16 weeks develop robust plaque deposits accompanied by fibrous caps in the aorta. This age group was chosen because it is the equivalent to a middle-aged human being, i.e., the group that would benefit most from this treatment in the clinic.The dendrimer localization studies show that hydroxyl terminated PAMAM dendrimers are able to deliver payload into aortic plaque deposits, as deep as ~90% into atheroma. It is believed that this is the first report of a therapy being delivered into atherosclerotic plaques. Because payload can be delivered into plaque macrophages, an improved inflammatory profile was observed in both male and female treated atherosclerotic mice. Interestingly, it was found that free Tesaglitazar causes an increase in the proinflammatory markers INF-γ and KC / GRO, likely due to off target activation in other organs such as the kidney or adipose tissue. However, this increase was not seen in D-Tesa treated mice because of its macrophage specific delivery.The first marker of atherosclerotic burden tested was active arterial stiffening, via PWV. Once mice start on HFD, there was an increase in PWV that is commensurate with the time they are on HFD. Sex-based difference were found in the progression of arterial stiffening; males develop arterial stiffness rapidly, which tapers off after eight weeks on HFD and females exhibit this stiffening much more gradually due to cardioprotection. After 6 weeks of biweekly D-Tesa treatment, it was observed that both males and females show a significantly lower PWV, almost at the same magnitude as before starting HFD. Arterial stiffening was a major cause and consequence of adverse cardiovascular disease which can lead to more severe complications such as heart failure on account of the increased load the heart undergoes from noncompliant vessels. Ex vivo tensile testing also revealed that passive vessel stiffness was improved after D-Tesa treatment, in agreement with active vessel stiffness. Aorta isolated from D-Tesa treated male mice can withstand higher stresses at the same max strain, indicating that the aorta from D-Tesa treated males are less fragile, as they can handle more strain at the same level of max deformation before failure. Throughout the experiments, blood pressure in both males and females remained constant, despite the onset of atherosclerosis and weight gain; in agreement with the literature showing that obesity precedes hypertension. This also shows that differences in arterial stiffness are due to true changes in the mechanical properties of the aorta, and not due to differences in the distending pressure experienced from hypertension.Vasoreactivity studies show that D-Tesa was able to halt endothelial dysfunction, another marker of cardiovascular health. It was found that the endothelial cells within the aorta of D-Tesa treated mice have preserved function which is not seen in vehicle or free Tesaglitazar treated mice, likely due to the decreased inflammatory profile produced by plaque macrophages which are in close proximity to endothelial cells.This the delivery also avoided side effects associated with free Tesaglitazar. Thus, it is believed that dendrimer conjugation may provide the benefits of the free drug while avoiding the dose dependent side effects typically experienced in clinical trials. Specifically, the increased peripheral edema from the free drug treatment in the form of increased paw edema was observed. This swelling was due to PPAR activation in healthy renal tissue, which is not experienced in mice treated with D-Tesa. In addition to decreasing plaque burden and addressing the root cause of the atherosclerosis, D-Tesa treated mice also had the benefit of decreasing body weight in obese atherosclerotic male and female mice. This decrease in weight was not due to apatite suppression, which differentiates it from current therapies for glucagon like peptide-1 (GLP-1) activation. The data shows that this weight loss was due to macrophage mediated browning of adipose tissue, as evidenced by the upregulation UCP-1. This browning leads to the improved metabolic parameters of increased VO2, VCO2, and EE. Interestingly, it was also found in adipose tissue that iNOS, a marker for proinflammatory macrophages, is significantly upregulated in the adipose tissue free Tesaglitazar treated mice when compared to vehicle treated mice, suggesting the proinflammatory effect of systemic activation in the adipose tissue. This effect was not seen in D-Tesa treated mice, contributing to the benefit of targeted treatment. Weight loss further contributed to the benefit of D-Tesa, and future dendrimer conjugated therapies for obesity. Weight gain is a comorbidity to in diseases beyond atherosclerosis and cardiovascular disease. This data shows the potential of dendrimer technology to be used to combat weight gain via macrophage driven browning of adipose tissue.After just 6 weeks, these benefits were seen at much lower dose (2 / 7ths) of free Tesaglitazar used in previous studies, even as the mice were kept on high fat diet. Previous studies that use free Tesaglitazar had changed their mice from HFD to regular chow upon initiation of treatment. However, the present design showed that D-Tesa can achieve a therapeutic effect even upon the continuation of an atherogenic diet. The improved safety profile of D-Tesa compared to free Tesaglitazar, combined with the ease of oral treatment administration, presents a promising therapeutic that targets the immune system to address the root causes of plaque progression, thereby addressing the pressing needs of atherosclerosis treatment.References1. Hu F. Obesity Epidemiology. Oxford University Press; 2008.2. Cardiovascular diseases (CVDs). who.int / news-room / fact-sheets / detail / cardiovascular-diseases-(cvds)3. Adams KF, et al.,N Engl J Med. 2006;355:763-778.4. Ridker PM, et al. N Engl J Med. 2017;377:1119-1131.5. Fatkhullina AR, et al. Immunity. 2018;49:943-957 e949.6. Fatkhullina AR, et al. Biochemistry (Mosc). 2016;81:1358-1370.7. Flores AM, et al., Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis. Nat Nanotechnol. 2020;15:154-161.8. Jarr KU, et al., The pleiotropic benefits of statins include the ability to reduce CD47 and amplify the effect of pro-efferocytic therapies in atherosclerosis. Nat Cardiovasc Res. 2022;1:253-262.9. Rigamonti E, et al., Regulation of macrophage functions by PPAR-alpha, PPAR-gamma, and LXRs in mice and men. Arterioscler Thromb Vasc Biol. 2008;28:1050-1059.10. Yin L, et al., The Role of Peroxisome Proliferator-Activated Receptor Gamma and Atherosclerosis: Post-translational Modification and Selective Modulators. Front Physiol. 2022;13:826811.11. Korbecki J, et al. Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors. Inflamm Res. 2019;68:443-458.12. Fagerberg B, et al. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha / gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia. 2005;48:1716-1725.13. Schuster H, et al. Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha / gamma agonist, improves apolipoprotein levels in non-diabetic subjects with insulin resistance. Atherosclerosis. 2008;197:355-362.14. Goldstein BJ, Rosenstock J, Anzalone D, Tou C, Ohman KP. Effect of tesaglitazar, a dual PPAR alpha / gamma agonist, on glucose and lipid abnormalities in patients with type 2 diabetes: a 12-week dose-ranging trial. Curr Med Res Opin. 2006;22:2575-2590.15. Zadelaar AS, et al. Dual PPARalpha / gamma agonist tesaglitazar reduces atherosclerosis in insulin-resistant and hypercholesterolemic ApoE*3Leiden mice. Arterioscler Thromb Vasc Biol. 2006;26:2560-2566.16. Chira EC, et al. Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha / gamma agonist, reduces atherosclerosis in female low density lipoprotein receptor deficient mice. Atherosclerosis. 2007;195:100-109.17. Bays H, et al. A double-blind, randomised trial of tesaglitazar versus pioglitazone in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2007;4:181-193.18. Insulin, other hypoglycemic drugs, and glucagon. Annual 31 ed.; 2009.19. Kalliora C, Drosatos K. The Glitazars Paradox: Cardiotoxicity of the Metabolically Beneficial Dual PPARalpha and PPARgamma Activation. J Cardiovasc Pharmacol. 2020;76:514-526.20. DeRidder L, Dendrimer-tesaglitazar conjugate induces a phenotype shift of microglia and enhances beta-amyloid phagocytosis. Nanoscale. 2021;13:939-952.21. Ryczkowska K, et al.. Menopause and women's cardiovascular health: is it really an obvious relationship? Arch Med Sci. 2023;19:458-466.22. Sturlaugsdottir R, et al. Prevalence and determinants of carotid plaque in the cross-sectional REFINE-Reykjavik study. BMJ Open. 2016;6:e012457.23. Sinning C, et al. Sex differences in early carotid atherosclerosis (from the community-based Gutenberg-Heart Study). Am J Cardiol. 2011;107:1841-1847.Example 7:Synthesis and Characterization of a Dendrimer conjugated to the GLP-1 Agonist SemaglutideThe Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, was functionalized with azide linker while Glucose dendrimer (GD2) was functionalized with acetylene group for click reaction. The acid group of semaglutide was reacted with Azido-PEG4-OH to obtain Semaglutide-PEG4-OH. The GD2 was partially functionalized with acetylene group (5) using NaH and Propargyl bromide conditions. Further, the semaglutide-PEG4-azide conjugated to glucose dendrimer using Cu(I) catalyzed click (CuAAC) reaction in the presence of catalytic amount of CuSO4.5H2O and sodium ascorbate to obtain GD2-Semaglutide conjugate. The traces of copper were removed by dialyzing with ethylenediaminetetraacetic acid (EDTA). The final GD2-drug conjugates were characterized by NMR and HPLC (Purity > 98%). Loading 24 weight percent, the payload is one, and the molecular weight is 16.9 kDa. Figure 19 shows the structure of the GD-Semaglutide conjugate.Example 8:Mitochondrial Targeting with Glucose Dendrimers and Hydroxyl DendrimersGlucose dendrimers (GD) show significantly improved uptake in adipocytes and adipose macrophages, compared to hydroxyl dendrimer (Figure 20). Hydroxyl dendrimers (HD) demonstrate relatively modest uptake, but hydroxyl dendrimer-drug conjugates were still active. Since glucose dendrimer showed higher uptake into these target cells, it was believed that the conjugates with glucose dendrimers would be more active. More importantly, glucose dendrimers show a significant uptake into the mitochondria of adipocytes and adipose macrophages. The mitochondrial uptake of GD is significantly higher than that of HD (Figure 20).Therefore, glucose dendrimers (and to some lesser extent, hydroxyl dendrimers) may be able to deliver ‘mitochondrial uncouplers’ to adipocytes and adipose macrophages, thereby significantly improving the efficacy of these drugs, reducing dose requirements. More importantly, such targeting would reduce the toxicity of these drugs, which has been a major challenge.Example 9:Synthesis of Glucose Dendrimer-Niclosamide conjugate (GD-Niclosamide)Mitochondrial uncouplers were covalently conjugated to the dendrimers, for superior mitochondrial delivery. Figure 21 shows a synthesis scheme for the synthesis of esterase cleavable niclosamide clickable conjugate (Niclosamide- PEG-N3).To a 39.7mmol (1.3 excess) of azido-PEG4-acid dissolved in anhydrous DMF (Dimethylformamide) were added 1.5 mmol excess of EDC.HCl and 1.5 mmol excess dimethylamino pyridine (DMAP) under continuous stirring. The solution was then slowly added in to a 30mmol of nilcosamide dissolved in anhydrous DMF in presence of two volume excess of anhydrous pyridine under stirring. The reaction mixture was left stirring for 18h under nitrogen and then added two volumes excess 1N HCL and ethyl acetate. The conjugate was then separated in ethyl acetate, the DMF water layer was further extracted two times in ethyl acetate. The combined ethyl acetate was washed two times in 1N HCl and then three times with saturated brine. The organic phase was then dried under reduced pressure to afford the PEG linker nilcosamide conjugate. The conjugate was then used without further purification.Synthesis of GD-propagylThe GD-propargyl was synthesized as previously described (Sharma A, Sah N, Sharma R, et al. Development of a novel glucose-dendrimer based therapeutic targeting hyperexcitable neurons in neurological disorders, Bioeng Transl Med. 2024;e10655). Synthesis of GD-Niclosamide conjugateThe propargylated GD dissolved in DMF in microwave vial, added 1.2 equivalent niclosamide-PEG azide linker were added and equal volume of water were also added. A 5mol% of copper sulphate and 5mol% sodium ascorbate were dissolved in water were then added to the microwave vial containing the GD and niclosamide azide linker. A minimum quantity of THF were added to facilitate the solubility of the components for the click reaction. The click reaction was performed for 16hours at 50oC. The RT cooled reaction mixture were then dialyzed against DMF for 24h and then added 3mL of 0.5M EDTA solution. The reaction mixture was then dialyzed extensively against water to remove copper impurities and EDTA removal. The final product was then freeze-dried and characterized by H-NMR and analytical HPLC. H-NMR Testing and HPLC of GD-Niclosamide conjugateThe H- NMR confirmed the characteristic protons of newly formed triazoles by click reaction (d) and the aromatic protons of the niclosamide (b,c,d and e) (Figure 22A). The internal triazole protons of the GD (`30 protons) were used to integrate the drug protons to calculate the number of molecules conjugated. The analytical HPLC clearly showed the newly formed conjugate at 335nm (characteristic for the drug) with over 98% purity (Figure 22B).Example 10:Synthesis of Glucose Dendrimer-Tirzepatide conjugate (GD-tirzepatide)Figure 23 shows the synthesis scheme for an exemplary GD-GIP1 conjugate, GD-tirzepatide. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the method and compositions described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A composition comprising a hydroxyl dendrimer covalently conjugated to at least one drug, wherein the drug comprises a PPAR-α agonist; a PPAR-γ agonist; a dual PPAR agonist (e.g., a PPAR- α / γ agonists); a GLP-1 receptor agonist (e.g., semaglutide); metformin; an SGLT2 agonist, a GIP-1 receptor agonist or antagonist; a dual GLP-1 / GIP-1 receptor agonist (e.g., tirzepatide); a mitochondrial uncoupler (e.g., niclosamide); or a combination thereof.

2. A composition comprising a glucose dendrimer covalently conjugated to at least one drug, wherein the drug comprises a PPAR-α agonist; a PPAR-γ agonist; a dual PPAR agonist (e.g., a PPAR- α / γ agonists); a GLP-1 receptor agonist (e.g., semaglutide); metformin; an SGLT2 agonist, a GIP-1 receptor agonist or antagonist; a dual GLP-1 / GIP-1 receptor agonist (e.g., tirzepatide); a mitochondrial uncoupler (e.g., niclosamide); a cannabinoid 1 receptor (CB1R) antagonist, or a combination thereof.

3. The composition of claim 1 or 2, wherein the drug comprises a PPAR-α agonist; a PPAR-γ agonist; or a dual PPAR agonist (e.g., a PPAR- α / γ agonists) selected from the group consisting of tesaglitazar, fenofibrate, WY-14643, oleoylethanolamide, GW4148, GW 9578, GW2148, or a combination thereof.

4. The com=pposition of claim 1 or 2, wherein the drug is a GLP-1 receptor agonist selected from the group consisting of semaglutide (such as Ozempic® or Rybelsus®)); Dulaglutide (such as Trulicity®); Exenatide extended release, exenatide (such as Byetta®), and analogs and derivatives thereof; Liraglutide (Victoza®, Saxenda®) (daily); and Lixisenatide (Adlyxin®); and other incretin mimetics.

5. The composition of claim 1 or 2, wherein the drug is a GIP-1 receptor agonist or antagonist is selected from the group consisting of SKL-14959, MA-38472-B1, or a combination thereof.

6. The composition of claim 1 or 2, wherein the drug is a dual GLP-1 / GIP-1 receptor agonist selected from the group consisting of tirzepatide, NNC0090-2746, NN9709, CT-388, retatrutide, or a combination thereof.

7. The composition of claim 1 or 2, wherein the drug is metformin.

8. The composition of claim 1 or 2, wherein the drug comprises an SGLT2 agonist selected from the group consisting of canagliflozin (such as Invokana®), bexagliflozin (such as Brenzavvy®), dapagliflozin (such as Farxiga®), empagliflozin (such as Jardiance®), ertugliflozin (Steglatro®), or a combination thereof.

9. The composition of claim 1 or 2, wherein the drug comprises a mitochondrial uncoupler selected from the group consisting of niclosamide, BAM15, carbonyl cyanide 4-(trifluoro-methoxy)phenylhydrazone (FCCP), carbonyl cyanide-3-chlorophenylhydrazone (CCCP), a dinitrophenol, analogs of these molecules, or a combination thereof.

10. The composition of claim 1 or 2, wherein the drug comprises a CB1R antagonist selected from the group consisting of AJ5012, JD5037, 3,4-diarylpyrazoline, 1,5-diarylpyrrole-3-carboxamides, methylsulfonamide azetidine, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-piperidino-1H-pyrazole-3-carboxamide (rimonabant), or a combination thereof.

11. The composition of any one of claims 1 to 10, wherein the covalent conjugation comprises a covalent link between a modified or unmodified surface group or interior group of the hydroxyl dendrimer or the glucose dendrimer, wherein the covalent link comprises an amide, ester, disulfide, ether, or phosphate linkage.

12. The composition of any one of claims 1 to 11, wherein the covalent conjugation comprises a covalent link that is cleavable at a pH selected from neutral, acidic, or basic.

13. The composition of any one of claims 1 to 12, wherein the hydroxyl dendrimer or glucose dendrimer is based on a polyamidoamine (PAMAM) dendrimer of generation 1 – generation 7.

14. The composition of any one of claims 2 to 13, wherein the dendrimer is a glucose dendrimer, preferably a generation 1, a generation 2, or a generation 3 glucose dendrimer.

15. The composition of any one of claims 1 to 13, wherein the dendrimer is based on a generation 2 – generation 7 PAMAM dendrimer, modified by a sugar moiety, wherein the sugar moiety is selected from the group consisting of glucose, galactose, mannose, and fructose.

16. The composition of any one of claims 1 to 15, wherein the hydroxyl dendrimer or the glucose dendrimer has at least a 10-fold increase in drug solubility in comparison to the drug in free form or wherein the hydroxyl dendrimer, the glucose dendrimer, or both increase durability of effect in comparison to the drug in free form.

17. The composition of any one of claims 1 to 16, wherein the hydroxyl dendrimer is based on a higher generation dendrimer, preferably generation 3, 4, 5, or 6 PAMAM dendrimer (such as hydroxyl-terminated PAMAM dendrimer), or the glucose dendrimer is a generation 1, 2, 3, or higher glucose dendrimer, or functionalized with poly(ethylene glycol), wherein the conjugate is confined to the peripheral circulation.

18. The composition of any one of claims 1 to 17, wherein the drug has a loading between about 2% and about 35% by weight.

19. The composition of any one of claims 1 to 18, further comprising a pharmaceutically acceptable excipient.

20. Formulations in a dosage for treatment of an individual atherosclerosis, treatment of obesity, diabetes, treatment of metabolic syndrome, control of blood sugar, lowering blood pressure, treatment of lipid disorders, treatment of fatty liver disease, treatment / prevention of kidney diseases, or treatment of symptoms thereof, comprising the composition of any one of claims 1 to 19.

21. The formulations of claim 20 for treatment of an obese individual, wherein fat mass loss is higher than lean mass loss.

22. The formulations of claim 20 or 21 for treatment of an obese individual, wherein weight loss is achieved without appreciable appetite loss.

23. The formulations of any one of claims 20 to 22 for treatment of an obese individual, wherein treatment converts white fat cells to brown fat cells.

24. A method of treating one or more symptoms of atherosclerosis, abnormal blood sugar, low blood pressure, lipid disease, fatty liver disease, kidney disease, obesity, or metabolic disorders associated therewith, and combinations thereof, the method comprising administering to an individual in need thereof, the composition of any one of claims 1 to 19, or the formulations of claim any one of claims 20 to 23.

25. A method of treating a disease or disorder, the method comprising using the composition of any one of claims 1 to 19 or the formulations of any one of claims 20 to 23 in combination with an existing treatment.

26. A method of treating a disease or disorder, the method comprising using the composition of any one of claims 1 to 19 or the formulations of any one of claims 20 to 23 to prevent recurrence of the disease of disorder, following termination or reduction of existing treatment.

27. The method of any one of claims 24 to 26, wherein the formulation selectively delivers the hydroxyl dendrimer-drug conjugate or the glucose dendrimer-drug conjugate to macrophages and foamy macrophages in an atherosclerotic plaque.

28. The method of any one of claims 24 to 27, wherein the formulation selectively delivers the hydroxyl dendrimer-drug conjugate or the glucose dendrimer-drug conjugate to adipose macrophages in fat tissues, and / or brain microglia / macrophages in the hypothalamus of the individual.

29. The method of any one of claims 24 to 28, wherein the individual has Type-2 diabetes and the hydroxyl dendrimer-drug conjugate or the glucose dendrimer-drug conjugate is administered to the individual with Type-2 diabetes in an amount effective to alleviate one or more symptoms of Type-2 diabetes.

30. The method of any one of claims 24 to 29, wherein the individual is an obese individual and the hydroxyl dendrimer-drug conjugate or the glucose dendrimer-drug conjugate are administered to the obese individual in an amount to cause weight loss.

31. The method of claim 30, wherein the glucose dendrimer-drug conjugate is administered to an obese individual in an amount to cause weight loss.

32. The method of claim 30 or 31, wherein fat mass loss is higher than lean mass loss.

33. The method of any one of claims 30 to 32, wherein weight loss is achieved without appreciable appetite loss.

34. The method of any one of claims 30 to 33, wherein treatment converts white fat cells to brown fat cells.

35. The method of any one of claims 30 to 34, wherein the obese individual is a human.

36. The method of any one of claims 24 to 35, wherein the hydroxyl dendrimer-drug conjugate or the glucose dendrimer-drug conjugate does not cause symptoms of toxicity.

37. The method of any one of claims 24 to 36, wherein the formulation is administered via a route selected from the group consisting of mucosal administration, enteral administration or injection, intranasal, intravenous, oral, sublingual, subcutaneous, inhalable, transdermal, or intraperitoneal. 

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