Dendrimer conjugates of antidepressants and antipsychotics and methods of use thereof

Abstract

Developed are formulations of dendrimers conjugated to one or more antidepressants or antipsychotics, which have higher selectivity for targeting cell types and reduced risk of side effects, and methods for using the same.Preferably, the antidepressants or antipsychotics conjugated to the dendrimers selectively bind to one or more receptors on or within target cells.The formulations are suitable for enteral or parenteral delivery to treat one or more diseases, conditions, and injuries in the central and peripheral nervous systems.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention is generally in the field of antipsychotic / antidepressant formulations, specifically dendrimer-antipsychotic / antidepressant conjugates, for selective delivery to nervous system and peripheral sites of disease and to specific receptors on target cells.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 401,483, filed August 26, 2022, entitled "DENDRIMER CONJUGATES OF ANTIDEPRESSANT AND ANTIPSYCHOTIC AGENTS AND THEIR METHODS OF USE," by The Johns Hopkins University, listed inventors Kunal Parikh, Kannan Rangaramanujam, Sujatha Kannan, and Anjali Sharma, which is incorporated herein by reference in its entirety.

[0003] STATEMENT OF FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT none. [Background technology]

[0004] Background of the Invention Depression is a chronic and recurrent illness that may require lifelong treatment using various modalities. A significant proportion of patients with depression remain inappropriately treated, particularly in primary care settings. Nonadherence and premature discontinuation of treatment are important factors that may contribute to poor outcomes. Adverse effects associated with antidepressant (AD) use are some of the most common factors leading to nonadherence and treatment discontinuation. Studies have shown that up to 43% of patients with depression may discontinue antidepressants due to adverse effects encountered during treatment. Existing first-line treatments have significant side effects, are ineffective in up to 33% of patients, and can take up to six weeks to achieve clinical efficacy in responding patients.

[0005] The treatment of depression underwent a major transformation with the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors in the 1950s. Since then, the search for more selective and perhaps better-tolerated antidepressants for AD has continued. Rational drug development has led to selective serotonin reuptake inhibitors (SSRIs). SSRIs have become the first-line treatment for depression, among other conditions. Following the marketing success of SSRIs, many new generation antidepressants have been approved for the treatment of depression, including serotonin and noradrenaline reuptake inhibitors (e.g., venlafaxine, desvenlafaxine, and duloxetine), bupropion (a noradrenaline and dopamine reuptake inhibitor), mirtazapine (a noradrenaline and selective serotonin antagonist), and trazodone (a serotonin antagonist and reuptake inhibitor). Agomelatine (5-HT 2C With the exception of melatonin receptor agonists with receptor antagonist properties, all other agents act primarily by modulating monoaminergic neurotransmission. More recently, the U.S. Food and Drug Administration (FDA) has approved four additional antidepressants for the treatment of depression: vilazodone, levomilnacipran, vortioxetine, and the dextromethorphan / bupropion combination.

[0006] For many years, efforts have been made to develop more effective antidepressants with better safety and tolerability profiles. Tricyclic antidepressants (TCAs) increase levels of two neurotransmitters, norepinephrine and serotonin, and block the action of another neurotransmitter, acetylcholine. This can restore balance to these neurotransmitters in the brain and reduce depression. In addition to relieving depression, tricyclic antidepressants also provide sedation and block some of the effects of histamine.

[0007] There is no clear evidence supporting clinically significant differences in the efficacy and tolerability of the various newer antidepressants, and controversy continues. No clinically significant differences have been found in the efficacy of SSRIs and TCAs. Differences in tolerability between TCAs and SSRIs appear to be minor. Furthermore, concerns have been raised regarding the safety and tolerability of long-term use of newer generation antidepressants.

[0008] The Center for Adverse Reaction Monitoring (CARM) continues to receive reports of sexual dysfunction associated with the use of antidepressants and antipsychotics. Since 1965, the most frequently reported medications have been fluoxetine, citalopram, paroxetine, venlafaxine, risperidone, and clozapine. Sexual dysfunction can be divided into four categories:

[0009] Sexual desire disorders (including partial or complete lack of libido).

[0010] Sexual arousal disorders, including erectile dysfunction and lack of vaginal lubrication.

[0011] Orgasmic disorders, including premature ejaculation, delayed ejaculation, or absence of orgasm (anorgasmia); as well as ejaculatory dysfunction.

[0012] Sexual pain disorders, including dyspareunia and vaginismus.

[0013] The prevalence of sexual dysfunction in major depression can reach up to 70% of patients. In most cases, this takes the form of a lack of libido. Although sexual desire tends to improve with treatment of depression, successful antidepressant treatment often causes other adverse effects on sexual function. Antidepressant-related sexual dysfunction may also result from inadequate treatment of depression, comorbid alcohol abuse, comorbid physical illness, relationship problems, or a combination of these factors.

[0014] Managing sexual dysfunction during antidepressant treatment can be difficult, in part because of its often multifactorial etiology. Options for troubled patients include reducing the dose (which may increase the risk of relapse), discontinuing the drug (which may compromise treatment compliance, does not allow for spontaneity, and patients on antidepressants with short half-lives may experience withdrawal symptoms), switching antidepressants (which may increase the risk of relapse or various side effects), continuing treatment ("wait and see"), or adding an antagonist (e.g., a phosphodiesterase inhibitor, which may cause additional side effects).

[0015] Newer generation antidepressants (ADs) are widely used as first-line treatment for major depressive disorder and are considered safer than tricyclics. While some side effects are transient and may resolve within a few weeks of treatment, potentially serious adverse events may persist or occur later. These include gastrointestinal symptoms (nausea, diarrhea, gastric bleeding, dyspepsia), hepatotoxicity, weight gain and metabolic abnormalities, cardiovascular disorders (heart rate, QT interval prolongation, hypertension, orthostatic hypotension), genitourinary symptoms (urinary retention, incontinence), sexual dysfunction, hyponatremia, osteoporosis and fracture risk, bleeding, central nervous system disorders (lowered seizure threshold, extrapyramidal side effects, cognitive impairment), sweating, sleep disorders, affective disorders (apathy, switching, paradoxical effects), ocular symptoms (glaucoma, cataracts), and hyperprolactinemia. Occasionally, these adverse events persist even after discontinuation of the drug, leading to iatrogenic comorbidities. Other areas of concern include suicidality, safety in overdose, discontinuation syndrome, risks during pregnancy and lactation, and risk of malignancy. Therefore, rational selection of AD should consider potential benefits and risks, likelihood of response to treatment options, and vulnerability to adverse events. The findings of such reviews should alert physicians to carefully assess the appropriateness of AD prescriptions on an individual basis and to consider alternative treatments, if available.

[0016] Generally, a significant proportion of patients do not achieve complete response or remission. Antipsychotics are commonly used as adjunctive therapy in adults. To date, the U.S. Food and Drug Administration has approved four atypical antipsychotics (aripiprazole, quetiapine, brexpiprazole, and olanzapine) for this purpose. However, augmentation with antipsychotics is associated with higher discontinuation rates and more adverse events (AEs) than antidepressant monotherapy. In children and adolescents with depression, adjunctive antipsychotic therapy with antidepressants is more frequently associated with movement disorders and seizures than antidepressant monotherapy.

[0017] Individuals with attention deficit disorder and its variants (including those diagnosed with and experiencing symptoms of attention deficit disorder) ("ADHD") are a separate class of individuals for whom current treatments have limited effectiveness and numerous side effects. ADHD medications include methylphenidate, amphetamine, atomoxetine, clonidine, guanfacine, viloxazine, and their analogs / modifications. These medications are commonly used for patients with depression, PTSD, and bipolar disorder. See https: / / www.webmd.com / add-adhd / adhd-medication-chart and https: / / www.additudemag.com / adhd-medication-for-adults-and-children.

[0018] Some of them have a similar mechanism of action to antidepressants / antipsychotics such as atomoxetine (SNRI), viloxazine (SNRI), and methylphenidate, which block the reuptake of dopamine and norepinephrine. Examples of antidepressants currently used to treat the symptoms of ADHD include bupropion, desipramine, imipramine, and nortriptyline.

[0019] ADHD medications are generally divided into stimulant and non-stimulant medications. Both are commonly associated with significant side effects associated with systemic, non-targeted delivery. While non-stimulant medications are typically less effective than stimulants, they are used in up to 30% of patients who cannot tolerate or do not benefit from stimulant medications. There is a significant need for alternatives with reduced side effects and improved selectivity. It is therefore an object of the present invention to provide formulations and methods of use thereof that increase the specificity of delivery for particular cells and receptors, reduce the side effects of antidepressants and antipsychotics, and improve treatment efficacy (including onset of action). [Prior art documents] [Non-patent literature]

[0020] [Non-Patent Document 1] https: / / www.webmd.com / add-adhd / adhd-medication-chart [Non-patent document 2] https: / / www.additudemag.com / adhd-medication-for-adults-and-children Summary of the Invention [Means for solving the problem]

[0021] Summary of the Invention Developed are formulations of dendrimers conjugated to one or more antidepressants or antipsychotics, which have higher selectivity for targeting cell types and reduced risk of side effects, and methods for using the same.Preferably, the antidepressants or antipsychotics conjugated to the dendrimers selectively bind to one or more receptors on or within target cells.The formulations are suitable for enteral or parenteral delivery to treat one or more diseases, conditions, and injuries in the central and peripheral nervous systems.

[0022] Representative antidepressants and antipsychotics include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), benzodiazepines, GABA modulators (e.g., neurosteroids), antipsychotics, atypical antipsychotics, or their analogs. Preferred dendrimers include glucose dendrimers and PAMAM dendrimers, which may be modified by hydroxylation, PEGylation, or other means to alter incorporation of functional groups. Preferred glucose dendrimers include G1, G2, and G3 glucose dendrimers, while preferred PAMAM dendrimers include G3, G4, G5, and G6 hydroxyl-terminated PAMAM dendrimers. In preferred embodiments, the antidepressant or antipsychotic agent is conjugated to the dendrimer by a linker, preferably hydrolytically cleavable. In some forms, the linker comprises a triazole moiety.

[0023] The formulations may be administered orally, to a mucosal surface, or by injection.

[0024] The formulations are useful for the prevention, treatment or management of symptoms of disorders such as major depressive disorder, treatment-resistant depression and postpartum depression, post-traumatic stress disorder, panic disorder, social anxiety disorder, anorexia nervosa, suicidal ideation, obsessive-compulsive disorder, premenstrual dysphoric disorder, anorexia, substance abuse disorders, epilepsy, bipolar disorder, autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, cluster headache, migraine, seizures, fibromyalgia, narcolepsy, obesity, Alzheimer's disease, Tourette's syndrome, pain (including neuropathic pain and chronic pain), phobias and cardiovascular disease. [Brief explanation of the drawings]

[0025] [Figure 1]1A and 1B are schematic diagrams showing an exemplary synthetic route to a dendrimer-fluoxetine conjugate with a non-cleavable linker using click chemistry: Fluoxetine is first conjugated to a linker containing an azide moiety (FIG. 1A), and then conjugated to a dendrimer modified with surface alkyne groups via an azide-alkyne click reaction (FIG. 1B).

[0026] [Figure 2] 2A and 2B are schematic diagrams showing an exemplary synthetic route for dendrimer-paroxetine conjugates with non-cleavable linking groups: Paroxetine is first conjugated to a linker containing an azide moiety (FIG. 2A), and then conjugated to a dendrimer modified with surface alkyne groups via an azide-alkyne click reaction (FIG. 2B).

[0027] [Figure 3] 3A and 3B are schematic diagrams showing an exemplary synthetic route for a dendrimer-venlafaxine conjugate having an enzymatically cleavable ester linking group. Venlafaxine is first conjugated to a linker containing an azide moiety (FIG. 3A), and then conjugated to a dendrimer modified with surface alkyne groups via an azide-alkyne click reaction (FIG. 3B).

[0028] [Figure 4] 4A and 4B are schematic diagrams showing an exemplary synthetic route for a dendrimer-venlafaxine analog conjugate having a non-cleavable amide linker. The venlafaxine analog is first conjugated to a linker containing an azide moiety (FIG. 4A), and then conjugated to a dendrimer modified with surface alkyne groups via an azide-alkyne click reaction (FIG. 4B).

[0029] [Figure 5]5A and 5B are schematic diagrams showing an exemplary synthetic route for a dendrimer-citalopram analog conjugate with a non-cleavable amide linker. The citalopram analog is first conjugated to a linker containing an azide moiety (FIG. 5A), and then conjugated to a dendrimer modified with surface alkyne groups via an azide-alkyne click reaction (FIG. 5B).

[0030] [Figure 6] FIG. 6 is a schematic diagram showing a synthetic route to a glucose dendrimer-fluoxetine conjugate with a non-cleavable linking group.

[0031] [Figure 7] FIG. 7 is a schematic diagram showing a synthetic route for the synthesis of glucose dendrimer-paroxetine conjugates with non-cleavable linking groups.

[0032] [Figure 8] FIG. 8 is a schematic diagram showing a synthetic route for the synthesis of a glucose dendrimer-venlafaxine conjugate with an enzymatically cleavable ester linking group.

[0033] [Figure 9] FIG. 9 is a schematic diagram showing a synthetic route for the synthesis of a glucose dendrimer-venlafaxine analog conjugate with a non-cleavable amide linker.

[0034] [Figure 10] FIG. 10 is a schematic diagram showing a synthetic route for the synthesis of a glucose dendrimer-citalopram analog conjugate with a non-cleavable amide linker.

[0035] [Figure 11-1] FIG. 11 is a schematic diagram of a stepwise synthetic route for the synthesis of glucose dendrimer-DMT analog conjugates bearing non-cleavable amino-alkyl linkers. [Figure 11-2] Same as above.

[0036] [Figure 12-1] FIG. 12 is a schematic diagram of a stepwise synthetic route for the synthesis of a glucose dendrimer-lysergic acid diethylamide (LSD) conjugate with a non-cleavable amino-alkyl linker. [Figure 12-2] Same as above.

[0037] [Figure 13] FIG. 13 is a schematic representation of the major pharmacological targets, involved signaling cascades, hormonal modulation, and main behavioral outcomes following their administration of LSD, psilocybin, DMT, MDMA, and ketamine in both animals and humans.

[0038] [Figure 14-1] Figure 14A is a schematic representation of the synthesis of a PAMAM dendrimer-norketamine conjugate. Figure 14B is a schematic representation of the synthesis of a glucose dendrimer-norketamine conjugate. [Figure 14-2] Same as above.

[0039] [Figure 15-1]Figure 15A shows a graph of the NMDAR1A / 2B antagonist assay for glucose dendrimer-ketamine (IC50 = 4.54 μM), hydroxyl dendrimer-ketamine (IC50 > 100), and norketamine (IC50 = 6.96 μM). Figure 15B shows the % binding efficacy of logarithmic concentrations (micromolar) of compounds in an assay for the D2L human dopamine GPCR cell-based agonist cAMP. Norketamine (filled circles), glucose dendrimer-ketamine EC50 = 13.08 μmolar (open circles), and hydroxyl dendrimer-ketamine EC50 = 4.263 μmolar (triangles). Figure 15C shows the % efficacy of logarithmic concentrations (micromolar) of ketamine in an assay for the TA1 human trace amine GPCR cell-based agonist cAMP. Norketamine (closed circles), glucose dendrimer-ketamine EC50 = 13.08 micromolar (open circles) and hydroxyl dendrimer-ketamine EC50 = 4.263 micromolar (triangles). [Figure 15-2] Same as above.

[0040] [Figure 16-1] Figures 16A and 16B are graphs of the composite neurobehavioral score (Figure 16A) and survival probability after birth (Figure 16B) of wild-type, knockout saline (control) versus knockout mice treated with dendrimer-ketamine conjugate. Figure 16C is a graph of the distance traveled (m). Figure 16D is a graph of the speed at which the mice traveled. Figure 16E is a graph of the time spent in the corner. [Figure 16-2] Same as above. [Figure 16-3] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0041] Detailed Description of the Invention I. Definition The term "antidepressant" refers to a compound that modulates the reuptake of one or more monoamines (such as serotonin, noradrenaline, norepinephrine, and dopamine) into presynaptic cells. In some forms, "antidepressants" inhibit the reuptake of monoamines (such as serotonin, noradrenaline, norepinephrine, and dopamine) into presynaptic cells. The continued presence of these monoamines in the synaptic space enhances postsynaptic receptor stimulation, thus increasing postsynaptic transmission. In some forms, these effects likely correct or compensate for the physiological defects that may underlie depression. Examples of drugs that inhibit monoamine reuptake include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). In some forms, "antidepressants" refer to compounds that inhibit the breakdown of monoamines (such as serotonin, noradrenaline, and dopamine) into storage vesicles in presynaptic cells. Preservation of these monoamines presumably improves the efficiency of synaptic transmission, which may correct or compensate for the physiological deficits underlying depression. Drugs that inhibit monoamine breakdown include monoamine oxidase inhibitors (MAOIs). In other forms, "antidepressants" refer to compounds that increase serotonin reuptake (tianeptine), increase serotonin and / or norepinephrine release (mirtazapine), act directly on serotonin and melatonin receptors (agomelatine), or otherwise affect synaptic neurotransmission. These drugs, including methylphenidate, amphetamine, atomoxetine, clonidine, guanfacine, viloxazine, and ADHD medications such as gabapentin and lithium / lithium salts, are conjugated or complexed with dendrimers for selective delivery to neurons and activated microglia to prevent, treat, or manage various disorders. In some forms, "antidepressants" can also improve mental health or neurological disorders through their anti-inflammatory effects.

[0042] The term "antipsychotic" refers to a psychotropic compound administered to manage one or more symptoms of a mental illness (e.g., including delusions, hallucinations, paranoia, or thought disorder), for example, psychosis, schizophrenia, and bipolar disorder, as well as a range of other disorders, such as symptoms associated with mood disorders, anxiety disorders, or non-neurological disorders. Antipsychotics inhibit dopaminergic transmission, or dopaminergic and serotonergic transmission, and can also exert noradrenergic, cholinergic, and / or histaminergic blocking effects.

[0043] The 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 nucleic acids, nucleic acid analogs, small molecules with a molecular weight of less than 2 kD, more typically less than 1 kD, peptidomimetics, proteins or peptides, carbohydrates or sugars, lipids, or combinations thereof. The term also encompasses pharmaceutically acceptable, pharmacologically active derivatives of drugs, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, and analogs. 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 locate, precisely target, and confirm a pathological process. Diagnostic agents can label target cells, allowing for subsequent detection or imaging of these labeled target cells.

[0044] An "analog" in relation 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, which provides a quantitative measure of similarity between two compounds based on their molecular descriptors. Preferably, molecular descriptors are 2D properties such as fingerprints, topological indices, and maximum common substructures, or 3D properties such as overall shape and molecular field. The Tanimoto coefficient ranges between 0 for a pair of dissimilar molecules and 1 for identical molecules (inclusive). A compound can be considered an analog of the specified compound if it has a Tanimoto coefficient between 0.5 and 1.0 (inclusive), preferably between 0.7 and 1.0 (inclusive), and most preferably between 0.85 and 1.0 (inclusive) relative to the specified compound. A compound is functionally similar to the specified compound if it induces the same pharmacological or physiological effect, or both, as the specified compound. "Analog" can also refer to modifications, including, but not limited to, hydrolysis, reduction, or oxidation products of a compound. Hydrolysis, reduction, and oxidation reactions are known in the art.

[0045] The term "therapeutically effective amount" refers to an amount of a therapeutic agent that, when incorporated into and / or onto a dendrimer, produces some desired effect at a reasonable benefit / risk ratio applicable to any medical treatment. The effective amount may vary depending on factors such as the disease or condition being treated, the specific targeting construct being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound without necessitating undue experimentation. In some embodiments, the term "effective amount" refers to the amount of a therapeutic or prophylactic agent that relieves or reduces one or more disease symptoms.

[0046] The terms "inhibit" or "reducing," in the context of inhibition, refer to a decrease or reduction in activity and amount. This can be complete inhibition or reduction, or partial inhibition or reduction, of activity or amount. Inhibition or reduction can be compared to a control or standard level. Inhibition can be 5, 10, 25, 50, 75, 80, 85, 90, 95, 99, or 100%. For example, a dendrimer composition comprising one or more inhibitors can inhibit or reduce the activity and / or amount of affected neurons by about 10%, 20%, 30%, 40%, 50%, 75%, 85%, 90%, 95%, or 99% from the activity and / or amount of the same cells in a comparable tissue of a subject not administered or treated with the dendrimer composition. In some embodiments, inhibition and reduction are compared at the level of mRNA, protein, cells, tissues, and organs. For example, inhibition and reduction of the rate of neuronal loss, the rate of brain weight loss, or the rate of hippocampal volume loss compared to untreated control subjects.

[0047] The terms "treating" or "preventing" refer to improving, reducing, or otherwise halting the development or progression of a disease, disorder, or condition in an animal that may be susceptible to, but has not yet been diagnosed with, a disease, disorder, and / or condition; inhibiting, e.g., slowing the progression of, a disease, disorder, or condition; and alleviating, e.g., causing regression of, a disease, disorder, and / or condition. Treating a disease or condition includes improving at least one symptom of a particular disease or condition even when the underlying pathophysiology is unaffected, such as treating a subject's pain by administering an analgesic drug even when such a drug does not treat the cause of the pain. Desired effects of treatment include slowing the rate of disease progression, improving or alleviating the disease state, and remission or improved prognosis. For example, an individual is successfully "treated" when one or more symptoms associated with depression are reduced or eliminated, including, but not limited to, reduced levels of anxiety, agitation, or restlessness; amelioration of feelings of sadness, fear, emptiness, or hopelessness; an increase in the quality of life of an individual affected by the disease; a reduction in the dosage of other medications required to treat the disease; and a slowing of the progression of the disease.

[0048] The phrases "pharmaceutically acceptable" or "biocompatible" refer to compositions, polymers, and other materials and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating substance, that is involved in carrying or transporting a subject composition from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the subject composition and not injurious to the patient.

[0049] The term "biodegradable" generally refers to a material that, under physiological conditions, breaks down or erodes into smaller units or chemical species that can be metabolized in vivo, excreted, or excreted. The degradation time is a function of composition and geometry.

[0050] The term "dendrimer" includes, but is not limited to, a molecular architecture having an inner core, an inner layer or "generation" of repeating units regularly attached to this initial core, and an outer surface of terminal groups attached to the outermost generation.

[0051] 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 can be functionalized by introducing a molecule that makes it a strong nucleophile or a strong electrophile.

[0052] The term "targeting moiety" refers to a moiety that is localized to or distant from a specific location. The moiety can be, for example, a protein, a nucleic acid, a nucleic acid analog, a carbohydrate, or a small molecule. The location can be a tissue, a specific cell type, an intracellular compartment, or a molecule such as a receptor.

[0053] The term "prolonged residence time" refers to an increase in the time required for a drug to clear from a patient's body or from an organ or tissue of the patient. In certain embodiments, "prolonged residence time" refers to a drug that is cleared with a half-life that is 10%, 20%, 50%, or 75% longer than a comparative standard, such as a comparable drug that is not conjugated to a delivery vehicle, such as a dendrimer. In certain embodiments, "prolonged residence time" refers to a drug that is cleared with a half-life that is 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, or 10,000 times longer than a comparative standard, such as a comparable drug that does not carry a dendrimer that specifically targets a particular cell type.

[0054] The terms "incorporated" and "encapsulated" refer to incorporating, formulating, or otherwise including an agent within and / or on the surface of a composition that allows for release, such as sustained release, of the agent in a desired application. Drugs or other substances can be incorporated into dendrimers by binding (by covalent, ionic, or other bonding interactions) to one or more surface functional groups of such dendrimers, by physical admixture, by enveloping the agent within the dendrimer structure, and / or by encapsulating the agent within the dendrimer structure.

[0055] As used herein, the central nervous system ("CNS") includes the brain and spinal cord. As used herein, the peripheral nervous system ("PNS") refers to nerves other than the brain and spinal cord.

[0056] "Hydroxyl-terminated" in reference to a dendrimer refers to a dendrimer having hydroxyl groups on its surface that are not attached to the termini of the dendrimer via a sugar moiety (such as a saccharide moiety).

[0057] "Sugar-terminated" in reference to a dendrimer refers to a dendrimer that contains sugar moieties (such as saccharide moieties) on its surface, but not within its core.

[0058] "Sugar-based" in reference to dendrimers refers to dendrimers that contain sugar moieties (such as saccharide moieties) in their core, or in their core and on their surface. II. Composition

[0059] Dendrimer-active agent conjugates suitable for the delivery of one or more antidepressants or antipsychotics to one or more target cells, such as nervous system cells, glial cells, and / or peripheral cells, that express the receptors for those antidepressants or antipsychotics, as well as to specific receptors on those cells depending on the drug, have been developed. Generally, antidepressants or antipsychotics bind to receptors on the surface of the target cells and / or to receptors inside the target cells. Exemplary target cells include, but are not limited to, brain cells such as microglia, astrocytes, and / or neurons, e.g., cells within the brain or CNS pathology site; cells in the peripheral nervous system such as peripheral neurons and glia; and / or peripheral cells such as digestive system cells, cardiovascular cells, and immune system cells. The microglia and / or astrocytes to which the antidepressants or antipsychotics are delivered may be activated or inactivated.

[0060] The antidepressant or antipsychotic of the dendrimer-active agent conjugate binds to a target receptor on the surface or inside the target cell. In some embodiments, when the antidepressant or antipsychotic binds to the target receptor, the agent remains conjugated to the dendrimer. In these embodiments, after binding, the agent can be released from the dendrimer or can remain conjugated to the dendrimer. In some embodiments, the antidepressant or antipsychotic is released from the dendrimer in close proximity to the target receptor and then binds to the target receptor on the surface of the target nervous system cell and / or glial cell. A. Dendrimer

[0061] Dendrimers are three-dimensional, hyperbranched, monodisperse, spherical, polyvalent macromolecules containing 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)).

[0062] The term "dendrimer" includes, but is not limited to, a molecular architecture having an inner core ("GO") and layers (or "generations") of repeating units attached to and extending from the inner core, each layer having one or more branch points and an outer surface with terminal groups attached to the outermost generation. In some embodiments, dendrimers have a regular, dendritic or "star-shaped" molecular structure.

[0063] Generally, dendrimers herein have a diameter of 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 and about 2 nm. In some embodiments, the dendrimer has a diameter of less than 5 nm that is effective for penetrating the blood-brain barrier ("BBB") and remaining in proximity to or within target nervous system cells and / or glial cells for delivery of an agent conjugated thereto. In some embodiments, the dendrimer has a diameter that is effective for penetrating the BBB and internalizing into target nervous system cells and / or glial cells, such as neurons, oligodendrocytes, astrocytes, microglial cells, and neuroglial supporting cells, for delivery of an agent conjugated thereto. In some embodiments, dendrimers have a diameter effective to penetrate barrier interfaces, such as the blood-nerve barrier ("BNB"), and internalize into neural and glial cells of the peripheral nervous system, such as neurons, Schwann cells, satellite cells, and neuroglial supporting cells, for delivery of agents conjugated thereto. These are typically greater than 5 nm in diameter. In some embodiments, dendrimers have a diameter effective to remain in the peripheral circulation for delivery of agents conjugated thereto to target cells of the peripheral nervous system. In some embodiments, dendrimers have a diameter effective to remain in the peripheral circulation for delivery of agents conjugated thereto to target cells of the gastrointestinal system, cardiovascular system, and / or immune system.

[0064] In some embodiments, the dendrimer has a molecular weight of 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 >50,000 Da are preferred for peripheral containment.

[0065] In some embodiments, the dendrimer has 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 previous layer of monomer via a linker, such as a polyethylene glycol chain. In a preferred embodiment, the hypercore is dipentaerythritol, and the monosaccharide branching units are glucose-based branching units, such as those shown in Structures II-IV. In the most preferred embodiment, the dendrimer is made entirely from glucose building blocks. While sugar-modified PAMAM dendrimers can also function, dendrimers made from sugars, especially glucose, are most preferred. Particularly preferred glucose dendrimers are G1-G3 glucose dendrimers, such as G1, G2, and / or G3 glucose dendrimers.

[0066] The preferred dendrimer is a glucose dendrimer, although other dendrimers can be used. Suitable dendrimer scaffolds include, but are not limited to, poly(amidoamine) (also known as PAMAM) or STARBURST™ dendrimers; polypropylamine (POPAM), polyethyleneimine, polylysine, polyester, iptycene, aliphatic poly(ether), aromatic polyether dendrimers, and dendrimers of sugars (e.g., glucose, galactose, mannose, fructose, etc.) and their copolymers (e.g., copolymers of sugars and alkylene glycols) (e.g., dendrimers formed with glucose and ethylene glycol building blocks). Dendrimers can have multiple surface functional groups, such as carboxylic acid, amine, hydroxyl, and / or acetamide. The terms "surface functional group" and "end group" are used interchangeably herein. Preferred dendrimers have surface hydroxyl groups that ensure selective uptake into neurons and activated microglia. In some embodiments, one or more of these surface functional groups are further modified with other molecules, such as sugars (e.g., glucose, galactose, mannose, fructose, etc.) and / or polyalkylene glycols, e.g., 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-G6 hydroxyl-terminated PAMAM dendrimers, such as G3, G4, G5, and G6 hydroxyl-terminated PAMAM dendrimers.

[0067] The dendrimer may be of any generation, including but not limited to, 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th or 10th generation.

[0068] In some embodiments, dendrimer-active agent conjugates can be restricted to the peripheral circulation, specifically targeting particular tissue regions and / or cell types, such as peripheral nervous system cells and glial cells, and / or gastrointestinal cells, cardiovascular cells, and / or immune system cells, by using higher generation dendrimers (such as fourth, fifth, or sixth generation PAMAM dendrimers or second, third, or higher generation glucose-based dendrimers). Additionally or alternatively, dendrimer-active agent conjugates can be restricted to the peripheral circulation by appropriate functionalization (such as PEGylation) of the dendrimer.

[0069] In some embodiments, dendrimers may be specifically targeted to particular tissue regions and / or cell types in the central nervous system (CNS), peripheral nervous system (PNS) and / or periphery (such as neurons and glia of the CNS, neurons and / or glia of the PNS, and / or peripheral cells such as digestive system cells, cardiovascular cells and / or immune system cells) by using dendrimers of certain generations, such as second generation (G2), G3, G4 and G5 PAMAM dendrimers and / or glucose dendrimers.

[0070] The term "PAMAM dendrimer" refers to a poly(amidoamine) dendrimer that can contain different cores with amidoamine building blocks and can have carboxylic acid, amine, acetamide, and / or hydroxyl termini of any generation. In some embodiments, the dendrimer is a fourth, fifth, or sixth generation ("G") dendrimer. In the most preferred embodiment, the dendrimer is made entirely from glucose building blocks. While sugar-modified PAMAM dendrimers can also function, dendrimers made from sugars, especially glucose, are most preferred. Monosaccharide-based dendrimers

[0071] In some embodiments, the branching unit comprises a monosaccharide. In some embodiments, the monosaccharide branching unit is conjugated to the core or to a previous layer of monomers via a linker such as a polyethylene glycol chain. In some embodiments, the monosaccharide branching unit is a glucose-based branching unit. In some embodiments, the branching unit can include a PEG and / or alkyl chain linker between different dendrimer generations. For example, glucose layers are connected by a PEG linker and a triazole ring. In some embodiments, the branching unit is the same for each generation of dendrimers generated from the core. Thus, for example, the branching unit is a glucose-based branching unit for generating a first-generation dendrimer, a second-generation dendrimer, and a third-generation dendrimer.

[0072] In some embodiments, the dendrimer has a hypercore (e.g., dipentaerythritol) and one or more monosaccharide branching units. In some embodiments, the hypercore is dipentaerythritol and the monosaccharide branching units are glucose-based branching units. In further embodiments, the spacer molecule is an alkyl(CH2) n - It can also be a hydrocarbon-like unit.

[0073] In some embodiments, dendrimers synthesized using glucose building blocks and having surfaces made primarily of glucose moieties enable specific targeting of cells, including injured neurons, ganglion cells, and other nervous system cells, in the brain, eye, and / or peripheral nervous system. In some embodiments, glucose-based dendrimers selectively target or are concentrated within target nervous system cells and / or glial cells. In some embodiments, glucose-based dendrimers selectively target or are concentrated on the surface of target nervous system cells and / or glial cells. In some embodiments, glucose-based dendrimers selectively target or are concentrated within target nervous system cells and on the surface of target nervous system cells and / or glial cells. In some embodiments, glucose-based dendrimers selectively target or are concentrated within damaged, diseased, and / or overactive neurons and / or glial cells.

[0074] In some cases, the dendrimer comprises a number of sugar molecules and terminal groups, such as glucose and / or hydroxyl groups, effective for targeting one or more neurons and / or glia in the CNS, PNS, and / or eye. The terminal hydroxyl groups of these dendrimers may be terminal glucose molecules, or extra hydroxyl groups that are not part of glucose molecules, or a combination thereof. In some embodiments, all of the terminal hydroxyl groups are part of terminal glucose molecules. In some embodiments, the number of sugar molecules on the end of the dendrimer is determined by the generation number.

[0075] In some embodiments, the dendrimers are made from glucose and oligoethylene glycol building blocks. Exemplary glucose dendrimers are shown in structures V and VII.

[0076] Some exemplary glucose dendrimers include a first-generation glucose dendrimer with 24 hydroxyl (-OH) end groups, a second-generation glucose dendrimer with 96 hydroxyl (-OH) end groups, a third-generation glucose dendrimer with 396 hydroxyl (-OH) end groups, and a fourth-generation glucose dendrimer with 1584 hydroxyl (-OH) end groups. For example, the glucose dendrimer is a second-generation glucose-based dendrimer with 24 glucose molecules on the periphery and 6 embedded glucose molecules in the backbone held together by PEG segments.

[0077] Dendrimer compositions, termed "glucose dendrimers," have been developed that can selectively accumulate within neurons, particularly within the nuclei of damaged and / or overactive neurons. These dendrimers can also accumulate at high levels within activated microglia. However, compared to hydroxyl dendrimers, which primarily accumulate within microglia, these dendrimers primarily target neurons. Glucose dendrimers are described in U.S. Patent Application No. 63 / 327,610, "Dendrimer Compositions for Targeted Delivery of Therapeutics to Neurons," filed April 5, 2022, by Johns Hopkins University, inventors Kannan Rangaramanujam, Rishi Sharma, Anjali Sharma, Sujatha Kannan, Nirnath Sah, Mira Sachdeva, and Siva P. Kambhampati.

[0078] Glucose dendrimers comprise (a) a central core, (b) one or more branching units based on the monosaccharide glucose, optionally conjugated with a linker, 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 units are conjugated to the central core via a linker, such as a hydrocarbon or oligoethylene glycol chain. In a preferred embodiment, the branching unit is β-D-glucopyranoside tetraethylene glycol azide, having the following structure: [ka] or a peracetylated derivative thereof.

[0079] In some embodiments, the glucose dendrimer is a first, second, third, fourth, fifth or sixth generation dendrimer. In one embodiment, the dendrimer has the following structure: [ka] It is a first generation dendrimer having the following structure:

[0080] In a preferred embodiment, the dendrimer has the following structure: [ka] It is a second generation dendrimer having the following structure:

[0081] In some embodiments, one or more therapeutic, prophylactic, and / or diagnostic agents are encapsulated within, associated with, and / or conjugated to the dendrimer at a concentration of between about 0.01% and about 30% by weight, preferably between about 1% and about 20% by weight, and more preferably between about 5% and 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 agent conjugated to the dendrimer is an anti-inflammatory agent, an antioxidant, or an immunomodulatory agent. In other embodiments, the dendrimer is conjugated to one or more diagnostic agents, such as a fluorescent dye, a near-infrared dye, a SPECT imaging agent, a PET imaging agent, and a radioisotope.

[0082] In some embodiments, the dendrimer and therapeutic, prophylactic, or diagnostic agent are conjugated by one or more linkers or coupling agents, such as one or more hydrocarbon or oligoethylene glycol chains. Exemplary linking groups are disulfide, ester, ether, thioester, and amide linking groups. PAMAM dendrimers

[0083] The term "PAMAM dendrimer" refers to any generation poly(amidoamine) dendrimer, including but not limited to, PAMAM dendrimers of generations 1 through 10, which can contain different cores with amidoamine building blocks and can be carboxylic acid, amine, acetamide, and / or hydroxyl terminated. In some embodiments, the dendrimer is a 4th, 5th, or 6th generation ("G") dendrimer. In some embodiments, the PAMAM dendrimer is hydroxyl terminated or surface modified with monosaccharides.

[0084] In general, the complete architecture of a dendrimer can be distinguished into an interior core moiety followed by radially linked branching units (i.e., generations) that are further modified with chemical functional groups bearing desired terminal groups on the exterior surface of the dendrimer.

[0085] In some embodiments, the dendrimers are in nanoparticle form, as described in US 2011 / 0034422, US 2012 / 0003155, and US 2013 / 0136697. For example, the molecular weight of the dendrimer can be varied to prepare polymeric nanoparticles that form particles with properties, such as drug release rate, that are optimized for a particular application.

[0086] In some embodiments, different variants of dendrimers, including but not limited to dendrons and tectodendrimers, can be used as delivery vehicles to conjugate and deliver one or more active agents. Dendrons are dendritic wedges that contain one type of functional group (functional group, f=1) at the core and another functional group (f=8, 16, 32, etc...) at the periphery. Tectodendrimers generally consist of a central dendrimer with multiple dendrimers attached at its periphery. 1. Core

[0087] In some embodiments, dendrimers are prepared using methods in which dendrimers are assembled from a multifunctional core that is extended outward through a series of reactions, allowing for the stepwise addition of branching units (i.e., generations) around the core.

[0088] 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"-nitrilotripropionic acid, ... ",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, ethylenediamine, propane-1,3-diamine, butane-1,4-diamine, 2,2',2"-nitrilotris(ethane-1- Examples of suitable core moieties include cyclodextrins, alpha cyclodextrins, beta cyclodextrins, gamma cyclodextrins, cucurbituril, benzene-1,2,3,4,5,6-hexathiol, monosaccharides, disaccharides, trisaccharides, oligosaccharides, or azide- or alkyne-modified portions thereof. In some embodiments, the core moiety is chitosan. Thus, azide- or alkyne-modified chitosans are suitable for conjugation to branching units using click chemistry.

[0089] 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 the core moiety are shown in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0090] Exemplary chemical structures suitable as branching units include monosaccharides. In some embodiments, the monosaccharide branching units are conjugated to the core or previous layer of monomers via a linker such as a polyethylene glycol chain. In a preferred embodiment, the monosaccharide branching units are glucose-based branching units. Exemplary glucose-based branching units are shown in Structures II-IV. These are spacer molecules, and therefore, alkyl(CH2) n - It can also be a hydrocarbon-like unit.

[0091] The branching units are PEG or alkyl chain linkers between different dendrimer generations, e.g., glucose layers are attached via PEG linkers and triazole rings.

[0092] In a preferred embodiment, the branching units are the same for each generation of dendrimer produced from the core. Thus, in one embodiment, the branching units are glucose-based branching units to produce the first generation dendrimers shown in structures V-VII.

[0093] In some embodiments, the branching unit is a hypermonomer, i.e., AB n These are building blocks. Exemplary hypermonomers include the AB4, AB5, AB6, AB7, and AB8 building blocks. The hypermonomer strategy dramatically increases the number of available end groups. An exemplary AB4 hypermonomer is peracetylated β-D-glucopyranoside tetraethylene glycol azide, shown in Structure III.

[0094] The chemical structures listed in Table 1 are also suitable as building blocks for forming branching units of dendrimers. For example, branching units of dendrimers 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)propane)), 3,3',3"-nitrilotriisopropyl ether, ... )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, Formed by ethylenediamine, 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, monosaccharides, disaccharides, trisaccharides, oligosaccharides, or their azide-modified moieties, alkyne-modified moieties, or combinations thereof.

[0095] Other examples of chemical structures 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 glycols such as ethylene glycol, and combinations thereof. In some embodiments, the branching unit is chitosan. Thus, azide-modified chitosan or alkyne-modified chitosan is suitable for conjugation to a 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 linear or branched polyethyleneglycerol. 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. 2.Surface functional groups

[0096] The surface functional groups / molecules of the dendrimer include, but are not limited to, primary amine end groups, hydroxyl end groups, carboxylic acid end groups, acetamide end groups, sugar molecules, oligo- or poly-alkylene glycols, and / or thiol end groups. In some embodiments, the desired terminal functional groups can be added by one of the conjugation methods to the core and branching units.

[0097] In some embodiments, the surface functional groups are hydroxyl groups, such as the hydroxyl groups of the PAMAM dendrimer of the second generation PEG dendrimer shown in Structure I, or the terminal glucose hydroxyl groups of dendrimers prepared with glucose-based branching units shown in Structures V and VII. In some embodiments, the desired surface functional groups can be modified or added by one of the conjugation methods to the core and branching units. Exemplary surface functional groups include hydroxyl, amine, carboxylic acid, acetamide, and thiol end groups, and combinations thereof.

[0098] In some embodiments, the dendrimers may specifically target particular tissue regions and / or cell types, such as cells and tissues of the central nervous system (CNS), peripheral nervous system (PNS), and / or 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 of first generation (G1), G2, G3, G4, and G5, preferably G1, G2, and / or G3.

[0099] In some embodiments, the dendrimer comprises a number of terminal glucose and / or hydroxyl groups effective to target one or more neurons and / or glia of the CNS, PNS and / or eye.

[0100] Glucose dendrimers are preferred. In some embodiments, dendrimers are made from glucose and oligoethylene glycol building blocks. Exemplary first-generation glucose dendrimers are shown in structure VI, and second-generation glucose dendrimers are shown in structure VIII.

[0101] In some embodiments, dendrimers have a plurality of surface functional groups (also referred to herein as surface or peripheral functional groups), such as hydroxyl (-OH), amine, acetamide, and / or carboxyl groups, at the periphery of the dendrimer. In some embodiments, the surface density of such peripheral functional groups is at least 1 group / nm 2 (number of surface functional groups / surface area (nm 2 For example, in some embodiments, the surface density of surface functional groups, such as hydroxyl groups, is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50 OH groups / nm 2 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more OH groups / nm 2In some embodiments, the volume density of surface functional groups, such as hydroxyl groups, is from about 1 to about 50 groups / nm 3 Between about 5 and about 30 groups / nm 3 Between about 10 and about 20 groups / nm 3 In a further embodiment, the surface density of surface functional groups, such as hydroxyl groups, is between about 1 and about 50 groups / nm 2 Preferably, between 5 and 20 groups / nm 2 (number of surface functional groups / surface area (nm 2 )), while each surface functional group moiety has a molecular weight between about 100 Da and about 10 kDa, preferably between about 100 Da and 1000 Da.

[0102] In some embodiments, the amount of surface functional groups on the dendrimer, such as any one of the above, e.g., hydroxyl groups, is at least 40%, at least 50%, greater than 40%, greater than 50%, or in the range of greater than 40% to 100%.

[0103] In some embodiments, one or more of the surface functional groups, such as any one of those described above, on the outer periphery of the dendrimer are further modified by conjugation with one or more carbohydrate molecules and / or one or more polyalkylene glycols, such as polyethylene glycol. 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 dendrimers surface-modified with sugar moieties (having >10% of surface groups modified with sugars, particularly glucose), and glucose dendrimers (where the dendrimer is made from glucose building blocks) are preferred. For delivery to the brain, constructs with a total molecular weight of <30,000 Da are preferred. For primarily peripheral circulation restriction, constructs with a total molecular weight of >50,000 Da are preferred. When dendrimers are formed from or include terminal sugar moieties / sugar molecules, such as glucose, the terminal hydroxyl groups of these dendrimers may be part of the terminal sugar moiety / sugar molecule, or extra hydroxyl groups that are not part of the sugar moiety / sugar molecule, or a combination thereof. In some embodiments, all of the terminal hydroxyl groups are part of the terminal sugar moiety / sugar molecule. a. Hydroxyl-terminated dendrimers

[0104] In some embodiments, the dendrimer contains multiple hydroxyl groups. Some exemplary densely hydroxyl-containing dendrimers include commercially available polyester dendritic polymers, such as hyperbranched 2,2-bis(hydroxyl-methyl)propionic acid polyester polymers (e.g., hyperbranched bis-MPA polyester-64-hydroxyl, 4th generation), and dendritic polyglycerols. In some embodiments, the hydroxyl-terminated dendrimers include hydroxyl-terminated PAMAM dendrimers, particularly G3-G6 hydroxyl-terminated PAMAM dendrimers, such as G3, G4, G5, and G6 hydroxyl-terminated PAMAM dendrimers.

[0105] In some embodiments, the dense hydroxyl-containing dendrimer is an oligoethylene glycol (OEG)-like dendrimer. For example, the second-generation OEG dendrimer (D2-OH-60) 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 photocatalytic thiol-ene click chemistry. Highly dense polyol dendrimers of very low generation with minimal reaction steps can be achieved by using an orthogonal hypermonomer and hypercore strategy, as described, for example, in WO2019094952. In some embodiments, the dendrimer backbone has non-cleavable polyether bonds throughout the structure (non-biodegradable), avoiding dendrimer collapse in vivo and enabling the excretion of such dendrimers from the body as a single entity. [ka]

[0106] In some embodiments, the dendrimer has a plurality of hydroxyl (-OH) groups at the periphery of the dendrimer. In some embodiments, the surface density of the hydroxyl (-OH) groups is at least 1 OH group / nm 2 (number of surface hydroxyl groups / surface area (nm 2 For example, in some embodiments, nm 2 The surface density of hydroxyl groups per nm is greater 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 OH groups / nm 2 In some embodiments, the volume density of hydroxyl groups is from about 1 to about 50 groups / nm 3 Between about 5 and about 30 groups / nm 3 Between about 10 and about 20 groups / nm 3 In a further embodiment, the surface density of hydroxyl (—OH) groups is between about 1 and about 50 OH groups / nm 2 or 5-20 OH groups / nm2 (number of surface hydroxyl groups / surface area (nm 2 )), while having a molecular weight between about 100 Da and about 10 kDa, preferably between about 100 Da and 1000 Da. In some embodiments, the amount of surface hydroxyl groups on the dendrimer is preferably greater than 35%, at least 40%, at least 50%, greater than 40%, greater than 50%, or in the range of greater than 40% to 100%. In some embodiments, the dendrimer may have a percentage of hydroxyl groups exposed on the outer surface, with other hydroxyl groups present in the interior core of the dendrimer.

[0107] In some embodiments, the dendrimer specifically targets a particular tissue region and / or cell type after administration to 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 dendrimer contains a number of hydroxyl groups effective to target CNS and / or PNS cells, such as microglia, astrocytes, and / or neurons, associated with a disease, disorder, or injury of the central or 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 to the dendrimer binds directly to receptors on and / or within the target nervous system cells and / or glial cells.

[0108] In some embodiments, dendrimers may specifically target specific tissue regions and / or cell types, preferably cells and tissues of the central nervous system (CNS) and eye. In some embodiments, dendrimers specifically target neurons of the CNS and eye. Unmodified PAMAM dendrimers with hydroxyl terminal groups are as abundant as these glucose dendrimers, but are not enriched in brain neurons and / or retinal ganglion cells (RGCs) of the eye. Glucose dendrimers with terminal glucose monosaccharides and a high density of hydroxyl functional groups effectively target neurons in a generation-dependent manner. Examples demonstrate that the efficacy of using second generation (G2), G3, and G4 is effective. G5 and above are more difficult to use.

[0109] In a preferred embodiment, the dendrimer comprises a number of terminal glucose and / or hydroxyl groups effective for targeting one or more neurons in the CNS or eye. The hydroxyl groups on the surface of the dendrimer are part of glucose molecules. There are no extra hydroxyls other than the glucose molecules on the surface. The number of sugar molecules on the surface is determined by the number of generations. It is expected that all generations will target neurons.

[0110] In some embodiments, dendrimers are made from glucose and oligoethylene glycol building blocks. Exemplary glucose dendrimers, such as the first-generation dendrimers shown in Structures IV-VI and the second-generation dendrimers shown in Figures 1A and 1B, are shown in the Examples. Some exemplary glucose dendrimers include a first-generation glucose dendrimer with 24 hydroxyl (-OH) end groups, a second-generation glucose dendrimer with 96 hydroxyl (-OH) end groups, a third-generation glucose dendrimer with 396 hydroxyl (-OH) end groups, and a fourth-generation glucose dendrimer with 1584 hydroxyl (-OH) end groups. In a preferred embodiment, the glucose dendrimer is a second-generation glucose-based dendrimer with 24 glucose molecules on the periphery and 6 embedded glucose molecules in the backbone, held together by PEG segments. B. Carbohydrate-modified dendrimers

[0111] In some embodiments, the dendrimer contains one or more carbohydrate molecules at its terminal end. These terminal carbohydrate molecules can be prepared by conjugating one or more surface functional groups of the dendrimer, such as amine groups, carboxyl groups, or hydroxyl groups, with one or more carbohydrate molecules. In a preferred embodiment, the dendrimer prior to carbohydrate conjugation is a hydroxyl-terminated dendrimer, such as a hydroxyl-terminated PAMAM dendrimer, and one or more of the hydroxyl groups are conjugated with one or more carbohydrate molecules.

[0112] In some embodiments, hydroxyl-terminated dendrimers modified with surface glucose molecules selectively target central and / or peripheral nervous system cells and / or glial cells in vitro and in vivo; and / or selectively accumulate on and / or within these target nervous system cells, glial cells, and / or macrophage cells, such that active agent(s) conjugated to said dendrimers bind to one or more receptors on / in the target nervous system cells and / or glial cells.

[0113] In some embodiments, the carbohydrate moiety used to modify one or more surface functional groups of a dendrimer is a monosaccharide. Exemplary monosaccharides suitable for modifying a dendrimer include glucose, glucosamine, galactose, mannose, fructose, dehydroascorbic acid, urate, and myo-inositol. In some embodiments, the dendrimer is conjugated to glucose and thus contains glucose as a terminal moiety / molecule. In some embodiments, hydroxyl-terminated dendrimers are modified with one or more glucose moieties ("D-Glu"). In some embodiments, the dendrimer is conjugated to galactose. In some embodiments, the dendrimer is conjugated to mannose. In some embodiments, the dendrimer is conjugated to fructose. In some embodiments, the dendrimer is conjugated to one or more monosaccharides other than glucose, such as galactose, mannose, and / or fructose. For example, the carbohydrate moiety may be an oligosaccharide terminated with one or more monosaccharides, including glucose, glucosamine, mannose, fructose, thus exposing these sugar moieties on the surface for attachment.

[0114] The use of glucose dendrimers or glucose-modified dendrimers allows for selective uptake by target cells. Drugs conjugated to the dendrimers bind to receptors or other sites of action. In a preferred embodiment, dendrimers (e.g., glucose or hydroxyl-terminated PAMAM dendrimers) or carbohydrate-functionalized dendrimers are conjugated to one or more carbohydrate moieties that have affinity for and are suitable for binding to one or more of the following serotonin (5HT) receptors: 5HT-1A, 5HT-2B, 5HT-2A, 5HT-2B, 5HT-2C, 5HT-3, and 5HT-4. In some embodiments, the dendrimer has affinity for and is conjugated to one or more carbohydrate moieties suitable for binding to one or more norepinephrine (NE) receptors, e.g., α1A-adrenergic receptor, α1B-adrenergic receptor, α1D-adrenergic receptor, α2A-adrenergic receptor, α2B-adrenergic receptor, α2C-adrenergic receptor, β1-adrenergic receptor, and β2-adrenergic receptor. In some embodiments, the dendrimer has affinity for and is conjugated to one or more carbohydrate moieties suitable for binding directly or indirectly to dopamine D1 and D2 receptors. In some embodiments, the dendrimer is conjugated to one or more carbohydrate moieties that have affinity for, and are suitable for binding to, one or more non-cannabinoid receptors such as G-protein coupled receptors, e.g., GPR55, GPR18, GPR3, GPR6, GPR12, GPR40, GPR43, GPR41, GPR120, GPR23, GPR92, GPR84, GPR119, or GPR35; adenosine receptors, such as adenosine A3; muscarinic acetylcholine receptors, e.g., M1 and M4; 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 dendrimer is conjugated to one or more carbohydrate moieties or made from sugar moieties suitable for affinity to and transport by one or more of GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, GLUT12, GLUT13, and GLUT14. In further embodiments, the dendrimer is conjugated to one or more glucose and / or glucosamine moieties. In other embodiments, the dendrimer is conjugated to one or more oligosaccharides terminated with glucose and / or glucosamine moieties, i.e., the glucose and / or glucosamine moieties are exposed on the surface of the dendrimer conjugate so as to be suitable for binding to one or more of GLUT, GLUT, 5HT receptor, DA receptor, NE receptor, and / or transporter.

[0115] In some embodiments, the dendrimer has a plurality of carbohydrate moieties / molecules, such as monosaccharides, e.g., glucose, or sugar building blocks for dendrimers, at the outer periphery of the dendrimer. In some embodiments, the surface density of carbohydrate molecules, such as monosaccharides, e.g., glucose, is at least one carbohydrate molecule / nm 2 (number of surface carbohydrate groups / surface area (nm 2 In some embodiments, nm 2 The surface density of carbohydrate molecules per nm is greater 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 OH groups / nm 2 For example, nm 2 In some embodiments, the surface density of carbohydrate molecules per nanometer is greater than 10. In some embodiments, the volume density of surface carbohydrate molecules is from about 1 to about 50 groups / nm. 3 Between about 5 and about 30 groups / nm 3 Between about 10 and about 20 groups / nm 3In a further embodiment, the surface density of carbohydrate molecules is between nm 2 Between about 1 and about 50, and between about 5 and about 20 per surface carbohydrate molecule (number of surface carbohydrate molecules / surface area (nm 2 )) while each carbohydrate moiety has a molecular weight between about 100 Da and about 1000 Da. That is, in these embodiments, one or more surface functional groups of the dendrimer are modified at the terminus to introduce one or more sugar moieties / molecule(s), and the terminal hydroxyl groups may be part of a terminal sugar moiety / molecule, or may be part of an extra hydroxyl group that is not modified by a sugar moiety / molecule and therefore not part of a sugar moiety / molecule, or a combination thereof.

[0116] In some embodiments, the carbohydrate molecule, such as a monosaccharide, e.g., glucose, is present in an amount by weight that is between about 1% and 40% of the total weight of the glycosylated dendrimer, e.g., 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 moiety is 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 after conjugation. In some embodiments, conjugation of carbohydrate molecules to one or more surface functional groups occurs with about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25% of the total number of surface functional groups, preferably hydroxyl groups, available prior to conjugation of the dendrimer. In other embodiments, conjugation of carbohydrate molecules occurs with less than 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% of the total number of available surface functional groups on the dendrimer prior to conjugation. c. Dendrimers modified with polyalkylene glycol

[0117] In some embodiments, the dendrimer contains one or more terminal polyalkylene glycols. These terminal polyalkylene glycols can be prepared by conjugating one or more of the dendrimer's surface functional groups, such as hydroxyl groups, with a polyalkylene glycol, such as PEG. In some embodiments, the dendrimer prior to conjugation is a hydroxyl-terminated dendrimer, such as a hydroxyl-terminated PAMAM dendrimer, and at least a portion of the surface hydroxyl groups are conjugated with PEG.

[0118] In some embodiments, the dendrimer has a plurality of polyalkylene glycols, such as PEG, at the periphery of the dendrimer. In some embodiments, the surface density of the polyalkylene glycol, such as PEG, is at least 1 polyalkylene glycol / nm 2 (number of surface polyalkylene glycols / surface area (nm 2 In some embodiments, nm 2 The surface density of polyalkylene glycol per nm is greater 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, 2 In some embodiments, the surface polyalkylene glycol volume density is from about 1 to about 50 groups / nm 3 Between about 5 and about 30 groups / nm 3 Between about 10 and about 20 groups / nm 3 In a further embodiment, the surface density of the polyalkylene glycol, such as PEG, is between nm 2 The number of surface polyalkylene glycols per surface area (nm) is between about 1 and about 50, and between about 5 and about 20 per surface area (nm 2 )) On the other hand, it has a molecular weight between about 100 Da and about 10 kDa.

[0119] In some embodiments, the polyalkylene glycol molecule, such as PEG, may be present in an amount by weight that is between about 1% and 40% of the total weight of the PEGylated dendrimer, e.g., 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 molecule, such as PEG, is 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 after conjugation.

[0120] In some embodiments, conjugation of polyalkylene glycol molecules such as PEG via one or more surface functional groups of the dendrimer is achieved with about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25% of the total number of surface functional groups, preferably hydroxyl groups, available prior to conjugation of the dendrimer. In other embodiments, conjugation of polyalkylene glycol molecules such as PEG is achieved with less than 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% of the total number of available surface functional groups of the dendrimer prior to conjugation. B. Antidepressants and antipsychotics

[0121] The dendrimer is complexed or covalently conjugated to one or more antidepressants and antipsychotics. Exemplary antidepressants and antipsychotics include a range of drug classes, including, but not limited to, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), antipsychotics, atypical antipsychotics, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), benzodiazepines, beta-blockers (BBs), and anticonvulsants. Antidepressants, antipsychotics, and their derivatives typically bind to one or more receptors, thereby modulating the signal transduction of neurotransmitters in the central nervous system. Antidepressants typically inhibit the reuptake of neurotransmitters, particularly serotonin, dopamine, and noradrenaline, via selective receptors, thereby increasing the concentration of these specific neurotransmitters in the synaptic space. Antipsychotic drugs typically reduce neurotransmission in dopamine pathways through either D2 antagonism or partial D2 receptor agonism. Thus, partial antagonism, functional selectivity, and inverse agonism all play important roles in determining cellular responses to specific neurotransmitter receptor ligands. 1. Antidepressants a. Selective serotonin reuptake inhibitors (SSRIs)

[0122] The composition can include a dendrimer complexed to one or more SSRIs. "SSRIs" or "selective serotonin reuptake inhibitors" are a class of drugs that are commonly used as antidepressants in the treatment of major depressive disorder and anxiety disorders. SSRIs are thought to increase the extracellular level of the neurotransmitter serotonin by limiting its reabsorption (reuptake) into presynaptic cells, thereby increasing the level of serotonin available in the synaptic space for binding to postsynaptic receptors.

[0123] SSRIs are known to selectively inhibit serotonin transport by inhibiting serotonin reuptake, specifically by binding to the serotonin transporter (SERT). This action of SSRIs results in a rapid increase in serotonin in the somatodendritic region of serotonergic neurons, leading to desensitization of somatodendritic serotonin-1A autoreceptors. This increases nerve impulse flow. This increased nerve impulse flow increases serotonin release from axon terminals, thereby desensitizing postsynaptic serotonin receptors. Desensitization of these receptors may contribute to the therapeutic effects of SSRIs or may contribute to the development of tolerance to their acute side effects. SSRIs cause a potent but slow disinhibition of 5-HT neurotransmission in the central nervous system (CNS) and peripheral nervous system (PNS). In this case, the antidepressant's effects are mediated by a pathway from the midbrain raphe nucleus to the prefrontal cortex. Because most serotonin in the human body is produced in the gastrointestinal tract, SSRIs affect enteric neurons, thereby increasing serotonin availability and promoting enteric neurogenesis and faster in vitro GI motility. In fact, serotonin receptors are widely expressed in the GI tract, and five of the seven known families, 5-HT1, 5-HT2, 5-HT3, 5-HT4, and 5-HT7 receptors, are expressed in the gastrointestinal tract and can affect gastrointestinal function (Mawe and Hoffman (2013), Nat Rev Gastroenterol Hepatol. 2013 Oct;10(10):564).

[0124] In some forms, one or more SSRIs may be conjugated to the dendrimer, including but not limited to fluoxetine (Prozac™), paroxetine (Paxil™), sertraline (Zoloft™), citalopram (Celexa™), fluvoxamine (Luvox™), escitalopram (Lexapro™). In other embodiments, SSRI-like agents that may be included in the composition include, but are not limited to, one or more of dapoxetine (Priligy), R-fluoxetine, indalpine (Upstene), zimelidine (Zelmid), alaproclate (GEA-654), centopropazine, cericlamine (JO-1017), femoxetine (Malexil; FG-4963), ifoxetine (CGP-15210), omiloxetine, panuramine (WY-26002), pirandamine (AY-23713), and seproxetine ((S)-norfluoxetine).

[0125] In some embodiments, the composition can include one or more SSRI-related compounds in an amount effective to deliver a low dose of the SSRI-related compound. For example, although described as SNRIs, duloxetine (Cymbalta), venlafaxine (Effexor), and desvenlafaxine (Pristiq) can selectively act as serotonin reuptake inhibitors (SRIs). They are at least about 10 times more selective for inhibiting serotonin reuptake than norepinephrine reuptake. The selectivity ratio is about 1:30 for venlafaxine, about 1:10 for duloxetine, and about 1:14 for desvenlafaxine. At low doses, these SNRIs act as SSRIs. Only at higher doses do they also primarily inhibit norepinephrine reuptake. In another example, milnacipran (Ixel, Savella) and its stereoisomer, levomilnacipran (Fetzima), are the only widely marketed SNRIs that both inhibit serotonin and norepinephrine to similar degrees, with a ratio approaching 1:1. In a third example, vilazodone (Viibryd) and vortioxetine (Trintellix) are SRIs that also act as modulators of serotonin receptors and are described as serotonin modulators and stimulators (SMS). Vilazodone is a 5-HT1A receptor partial agonist, while vortioxetine is a 5-HT1A receptor agonist and a 5-HT3 and 5-HT7 receptor antagonist. Litoxetine (SL 81-0385) and rubazodone (YM-992, YM-35995) are SRIs, and ritoxetine is a 5-HT3 receptor antagonist, while rubazodone is also a 5-HT2A receptor antagonist.

[0126] In a preferred embodiment, the dendrimer is conjugated to one or more SSRIs or SSRI derivatives, as shown by structures I-VI below. [ka] [ka] b. Serotonin-norepinephrine reuptake inhibitors (SNRIs)

[0127] The composition may include a dendrimer conjugated to one or more SNRIs. "SNRI" refers to any member of a class of compounds that act on and increase the levels of two monoamine neurotransmitters in the brain: serotonin and norepinephrine (Arroll B, et al., Annals of Family Medicine, 2005;3(5):449-456). SNRIs exert their effects by (i) inhibiting the presynaptic reuptake of serotonin from the synaptic space by binding to the SERT receptor, and (ii) inhibiting the presynaptic reuptake of norepinephrine from the synaptic space by binding to the norepinephrine (NAT) transporter. Noradrenaline (norepinephrine, NE) is found in cell bodies in the pons and medulla. These cell bodies provide neurons that project to the hypothalamus, thalamus, limbic system, locus coeruleus, lateral tegmental area, and cerebral cortex. In the peripheral nervous system, noradrenaline is used as a neurotransmitter by sympathetic ganglia located near the spinal cord or in the abdomen, and by Merkel cells located in the skin. NE is also released directly into the bloodstream by the adrenal glands and abdominal viscera, as well as by sphincter contraction in the GI tract and bladder. Preventing reuptake prolongs the continuous presence of these monoamines in synaptic spaces within the central nervous system (CNS) and peripheral nervous system (PNS). This therefore increases postsynaptic receptor stimulation, resulting in further postsynaptic neurotransmission.

[0128] SNRIs, sometimes referred to as non-tricyclic serotonin and norepinephrine reuptake inhibitors, are often considered to have "dual action" due to their mechanism. However, the specific degree of norepinephrine and serotonin reuptake inhibition is both dose-dependent and drug-dependent. Suitable SNRIs that can be conjugated to dendrimer compositions include, but are not limited to, venlafaxine (Effexor XR™), desvenlafaxine (Pristiq and Khedezla™), duloxetine (Cymbalta, Irenka), milnacipran (Savella), levomilnacipran (Fetzima), tramadol HCl, sibutramine (Meridia), atomoxetine (Strattera), and bicifadine (DOV-220,075) and their derivatives.

[0129] In some embodiments, the SNRI conjugated to dendrimer has stronger binding affinity to serotonin receptor than to norepinephrine receptor.For example, duloxetine and venlafaxine preferentially bind to serotonin receptor than to norepinephrine receptor, thereby increasing the effectiveness of serotonin reuptake compared to norepinephrine reuptake.In some embodiments, the SNRI conjugated to dendrimer has stronger binding affinity to norepinephrine receptor than to serotonin receptor.In some embodiments, the SNRI conjugated to dendrimer has equal binding affinity to serotonin receptor and norepinephrine receptor.

[0130] In some forms, the SNRI conjugated to dendrimer indirectly modulates the signal transduction at non-serotonin and non-epinephrine receptors.In an exemplary embodiment, dendrimer can be conjugated to venlafaxine, a synthetic phenethylamine bicyclic derivative and a substrate of P-glycoprotein (P-gp), which is transported from the brain.At high doses, venlafaxine reduces the presynaptic reuptake of dopamine, thereby increasing dopamine levels, particularly in the prefrontal cortex.The mechanism of action behind the increase in dopamine levels involves the inhibition of norepinephrine transporters.These transporters have a high affinity for dopamine, resulting in the transporter's ability to act on both dopamine and norepinephrine.Therefore, the inhibition of norepinephrine transporters can result in an increase in dopamine. This increase in dopamine occurs specifically in the prefrontal cortex, where dopamine transporters are poor and reuptake is more dependent on the norepinephrine transporter. Venlafaxine also indirectly modulates opioid receptors, muscarinic acetylcholine receptors (mAChRs), histaminergic receptors, and α1 and α2-adrenergic receptors.

[0131] In some embodiments, the dendrimer is conjugated to one or more SNRIs or derivatives thereof in an amount effective to deliver to cells between about 40 mg / day and about 60 mg / day, between about 60 mg / day and about 80 mg / day, between about 40 mg / day and about 100 mg / day, between about 100 mg / day and about 150 mg / day, between about 150 mg / day and about 200 mg / day, between about 200 mg / day and about 250 mg / day, between 250 and 300 mg / day, or between about 350 mg / day and about 450 mg / day of one or more SNRIs or derivatives thereof.

[0132] In some embodiments, dendrimers conjugated to SSRIs can exert anti-inflammatory effects on certain cells, which may improve the effectiveness of treating mental health and neurological disorders.

[0133] In some embodiments, conjugation of SSRIs to dendrimers, resulting in improved pharmacokinetics and receptor targeting, can also significantly shorten the time required for onset of action.

[0134] In a preferred embodiment, the dendrimer is conjugated to one or more SSRIs or SSRI derivatives, as shown by Formulas VIII-XI below. [ka] [ka] C. Atypical antidepressants

[0135] The composition can comprise a dendrimer conjugated to one or more atypical antidepressants. "Atypical antidepressants" refers to any antidepressant that acts in a different way from most other antidepressants. Atypical antidepressants are often used in patients with major depression who have inadequate response or intolerable side effects during first-line treatment with SSRI. Suitable atypical antidepressants that can be conjugated to dendrimers include, but are not limited to, agomelatine, bupropion, mianserin, mirtazapine, nefazodone, opipramol, tianeptine and trazodone.

[0136] In an exemplary embodiment, the dendrimer can be complexed with agomelatine. Agomelatine is a receptor agonist for melatonin MT1 and MT2 receptors, as well as a receptor antagonist for serotonin 5-HT2C and 5-HT2B receptors. By antagonizing 5-HT2C, it disinhibits / increases the release of noradrenaline and dopamine, particularly in the frontal cortex. Therefore, agomelatine is sometimes classified as a norepinephrine-dopamine disinhibitor. The antagonism of 5-HT2B is presumed to be the antidepressant property that agomelatine shares with some atypical antipsychotics, such as aripiprazole.

[0137] In a second exemplary embodiment, the dendrimer can be conjugated to mirtazapine. Mirtazapine has a dual mode of action. It is a noradrenergic-specific serotonergic antidepressant (NaSSA) that acts by antagonizing adrenergic alpha2 autoreceptors and alpha2 heteroreceptors and by blocking 5-HT2 and 5-HT3 receptors. Therefore, mirtazapine enhances norepinephrine release and 5-HT1A-mediated serotonergic transmission. Mirtazapine is extensively metabolized in the liver by the cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4.

[0138] In a third exemplary embodiment, the dendrimer can be complexed with nefazodone. Nefazodone is a phenylpiperazine compound structurally related to trazodone and has been described as a serotonin antagonist and reuptake inhibitor (SARI). Nefazodone acts primarily as a potent antagonist of the serotonin 5-HT2A receptor and, to a lesser extent, as an antagonist of the serotonin 5-HT2C receptor. Nefazodone also has high affinity for α1-adrenergic receptors and serotonin 5-HT1A receptors, and relatively low affinity for α2-adrenergic receptors and dopamine D2 receptors. Nefazodone also has high affinity for serotonin, norepinephrine, and dopamine transporters, and therefore acts as a weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).

[0139] In a fourth exemplary embodiment, the dendrimer can be conjugated to trazodone. Trazodone is a mixed agonist and antagonist of various serotonin receptors, an antagonist of adrenergic receptors, a weak histamine H1 receptor antagonist, and a weak serotonin reuptake inhibitor. In some forms, trazodone is an antagonist of 5-HT2A and 5-HT2B receptors, a partial agonist of 5-HT1A receptors, and an antagonist of alpha 1 and alpha 2 adrenergic receptors.

[0140] In another exemplary embodiment, the dendrimer can be conjugated to bupropion, a dopamine and noradrenaline reuptake inhibitor. Bupropion reduces the presynaptic reuptake of dopamine and noradrenaline and acts as an antagonist of several nicotinic acetylcholine receptors. Bupropion is generally metabolized to three known active metabolites: hydroxybupropion (R,R-hydroxybupropion and S,S-hydroxybupropion) and its diastereoisomers, threohydrobupropion and erythrohydrobupropion.

[0141] In yet another exemplary embodiment, the dendrimer can be conjugated to mianserin. Mianserin is a tetracyclic antidepressant with antihistamine and sedative-hypnotic properties, but little anticholinergic activity. Mianserin appears to exert its effects through antagonism of histamine and serotonin receptors and inhibition of norepinephrine reuptake. More specifically, mianserin binds to histamine H1 receptors, serotonin 5-HT receptors, and hydroxybenzoates. 1D , 5-HT 1F , 5-HT 2A , 5-HT 2B , 5-HT 2CMianserin is an antagonist / inverse agonist at most or all of the 5-HT3, 5-HT6, and 5-HT7 receptors, as well as the adrenergic α1 and α2 receptors, and is also a norepinephrine reuptake inhibitor. As a high-affinity H1 receptor inverse agonist, mianserin has potent antihistamine effects (e.g., sedation). Conversely, mianserin has low affinity for muscarinic acetylcholine receptors and therefore lacks anticholinergic properties. Mianserin has been shown to be a potentially significant partial agonist at kappa-opioid receptors, albeit with low affinity. d. Tricyclic antidepressants (TCAs)

[0142] The composition can include a dendrimer conjugated to one or more tricyclic antidepressants. "Cyclic antidepressant" refers to any antidepressant that is designated as tricyclic or tetracyclic, depending on the number of rings in its chemical structure, i.e., three (tri) or four (tetra). Tricyclic antidepressants achieve their effects by acting on approximately five different neurotransmitter pathways (Stahl et al., Prim. Care Companion J. Clin. Psychiatry 2004;6(4):159). Tricyclic antidepressants block the reuptake of serotonin and norepinephrine at presynaptic terminals, increasing the concentrations of these neurotransmitters in the synaptic space. The increased concentrations of norepinephrine and serotonin at the synapse may contribute to the antidepressant effect of tricyclic antidepressants. Furthermore, in some forms, they can act as competitive antagonists at postsynaptic alpha cholinergic (alpha1 and alpha2), muscarinic, and histaminergic (H1) receptors. The structure of the receptor greatly influences the binding affinity of TCAs.

[0143] The chemical structure of TCAs consists of a three-ring structure to which a secondary or tertiary amine is attached. Secondary amines include desipramine, nortriptyline, and protriptyline, while tertiary amines include amitryptiline, clomipramine, doxepin, imipramine, and trimipramine. Tertiary amines tend to block serotonin reuptake more effectively, while secondary amines block norepinephrine uptake more effectively. The combination of various amine structure and chemical composition variables influence TCA receptor affinity and binding, contributing to the many adverse effects seen with TCAs.

[0144] Suitable tricyclic antidepressants that may be conjugated to dendrimers include, but are not limited to, amitriptyline (e.g., Elavil, Endep), amitriptyline oxide (e.g., Amioxid, Ambivalon, Equilibrin), clomipramine (e.g., Anafranil), desipramine (e.g., Norpramin, Pertofrane), dibenzepin (e.g., Noveril, Victoril), dimetacrine (e.g., Istonil), dosulepin (e.g., Prothiaden), doxepin (e.g., Adapin, Sinequan), imipramine (e.g., Examples include Tofranil), lofepramine (e.g., Lomont, Gamanil), amoxapine, melitracen (e.g., Dixeran, Melixeran, Trausabun), nitroxazepine (e.g., Sintamil), nortriptyline (e.g., Pamelor, Aventyl), noxiptiline (e.g., Agedal, Elronon, Nogedal), opipramol (e.g., Insidon), pipofezin (e.g., Azafen / Azaphen), protriptyline (e.g., Vivactil) and / or trimipramine (e.g., Surmontil).

[0145] Suitable tetracyclic antidepressants that can be conjugated to dendrimers include, but are not limited to, maprotiline (Ludiomil; which may also be classified as a TCA and grouped with a secondary amine), mianserin (Tolvon), mirtazapine (Remeron), setiptiline (Tecipul), amoxapine (Asendin; which is often also classified as a TCA and may also be grouped with a secondary amine), and quetiapine (Seroquel; an atypical antipsychotic sometimes used as an adjunct antidepressant). Other tetracyclic antidepressants that can be conjugated to dendrimers include, but are not limited to, benzoctamines (e.g., Tacitin), loxapine (e.g., Adasuve, Loxitane), mazindol (e.g., Mazanor, Sanorex), aptazapine (CGS-7525A; a close analog of mirtazapine), esmirtazapine (ORG-50,081; the (S)-(+) enantiomer of mirtazapine), oxaprotiline (C 49-802 BDA; a close analog of maprotiline), and cyclazindol (WY-23,409; a close analog of mazindol). Benzoctamines (e.g., Tacitin) are tetracyclic compounds closely related to maprotiline; the two compounds differ only in the length of their side chains, but benzoctamines are typically used as anxiolytics. Loxapine (e.g., Adasuve, Looxitane) is a typical antipsychotic that produces amoxapine as its primary metabolite and is said to have antidepressant properties, but is not generally considered a tetracyclic antidepressant. Drugs containing four rings that are not all fused together but can still be classified as tetracyclic include mazindol. Mazindol (Mazanor, Sanorex) is a monoamine reuptake inhibitor commonly used as an appetite suppressant and has antidepressant properties. e. Monoamine oxidase inhibitors (MAOIs)

[0146] The compositions may include a dendrimer conjugated to one or more monoamine oxidase inhibitors (MAOIs).

[0147] Monoamine oxidase inhibitors are responsible for blocking the monoamine oxidase enzyme (Shulman KI, et al., CNS drugs. 2013;27(10):789-797). Monoamine oxidase enzyme breaks down various types of neurotransmitters from the brain: norepinephrine, serotonin, dopamine, and tyramine. MAOIs inhibit the breakdown of these neurotransmitters, thus increasing their levels and allowing them to continue to affect cells affected by depression.

[0148] There are two types of monoamine oxidase, A and B. MAO A is distributed mostly in the placenta, gastrointestinal tract, and liver, while MAO B is found in the brain, liver, and platelets. The ratio of MAO-A to MAO-B varies throughout the body. In the human brain, the ratio of MAO-A to MAO-B is 25% to 75%, while in the liver, the ratio is 50% to 50%. In the intestine, the ratio is 80% to 20%, and in peripheral adrenergic neurons, the ratio is 90% to 10%.

[0149] Serotonin and norepinephrine are substrates of MAO A, whereas phenylethylamine, methylhistamine, and tryptamine are substrates of MAO B. Dopamine and tyramine are metabolized by both MAO A and B. Selegiline and rasagiline are irreversible and selective inhibitors of MAO type B, whereas safinamide is a reversible and selective MAO B inhibitor.

[0150] In some embodiments, the dendrimer is conjugated to one or more reversible and / or irreversible MAOIs. Reversible inhibitors of monoamine oxidase A (RIMAs) are a subclass of MAOIs that selectively and reversibly inhibit the MAO-A enzyme. Suitable reversible MAOIs include, but are not limited to, befloxatone (MD-370,503), brofaromine (Consonar), furazolidone (Furoxone), linezolid (Zyvox), moclobemide (Aurorix), and / or toloxatone (Humoryl). Some MAOIs covalently bind to the monoamine oxidase enzyme, thereby irreversibly inhibiting the enzyme. The bound enzyme cannot function, and enzyme activity is thus blocked until the cell produces new enzyme. Suitable irreversible MAOIs that can be conjugated to the dendrimers include, but are not limited to, clorgyline, iproniazid (marsilid), isocarboxazid (Marplan), nialamide (Niamid), pargyline (Eutonyl), phenelzine (Nardil), procarbazine (Matulane), rasagiline (Azilect), selegiline, l-deprenyl (Eldepryl and Emsam), and tranylcypromine (parnate). f. Benzodiazepines

[0151] The composition can include dendrimers conjugated to one or more benzodiazepines. "Benzodiazepines" (BZDs, BDZs, BZs) are a class of psychoactive drugs whose core chemical structure is a condensation of a benzene ring and a diazepine ring. Benzodiazepines act on the benzodiazepine receptor (BZ-R) in the central nervous system (CNS). The receptor is a protein containing five transmembrane subunits that form a central chloride channel, i.e., the GABA-A receptor. The five subunits are composed of two alpha, two beta, and one gamma subunit. The extracellular portions of the alpha and beta subunit proteins form receptor sites for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The extracellular portions of the alpha and gamma subunit proteins form the binding sites for benzodiazepines. Activation of the BZ-R induces a conformational change in the central pore, allowing chloride ions to enter the neuron. The influx of chloride anions hyperpolarizes the neuron, reducing the firing of action potentials in that neuron.

[0152] In some embodiments, the benzodiazepine conjugated to the dendrimer is an ultra-short-acting benzodiazepine. Non-limiting examples of ultra-short-acting benzodiazepines include, but are not limited to, flunitrazepam, diazepam, and midazolam. In some embodiments, the benzodiazepine conjugated to the dendrimer is a short-acting benzodiazepine. Non-limiting examples of short-acting benzodiazepines include, but are not limited to, alprazolam, chlordiazepoxide, and lorazepam. In some embodiments, the benzodiazepine conjugated to the dendrimer is a long-acting benzodiazepine. Non-limiting examples of long-acting benzodiazepines include, but are not limited to, clonazepam, oxazepam, and prazepam. g. Other antidepressants

[0153] The compositions may include dendrimers conjugated to one or more beta-blockers, neurosteroids and / or anticonvulsants (Wang M., Neurosteroids and GABA-A Receptor Function. 2011;2).

[0154] "Beta-blockers," also known as beta-adrenergic blockers, block norepinephrine and epinephrine (adrenaline) from binding to beta-receptors on nerves. Blocking these transmitters reduces and helps control some of the physical symptoms of anxiety. They also slow heart rate and help lower blood pressure. Non-limiting examples of beta-blockers include fluoxetine, paroxetine, duloxetine, and bupropion.

[0155] As used herein, "neurosteroid" refers to a steroid produced in the brain or transported into the brain to alter neuronal excitation. Suitable neurosteroids include, but are not limited to, brexanolone (allopregnanolone) and SGE-217, and GABA modulators such as ganaxolone, minaxolone, and zuranolone.

[0156] "Anticonvulsant" as used herein refers to an agent used to prevent, reduce or control seizure attacks, and includes antidepressants, steroids and other drugs. 2. Antipsychotics A typical antipsychotic

[0157] The composition can include a dendrimer conjugated to one or more typical antipsychotics, also known as first-generation antipsychotics. Typical antipsychotics generally work by inhibiting dopaminergic neurotransmission. Their efficacy is maximized by blocking activity at D2 dopamine receptors in the brain (Wang Shanghai Archives of Psychiatry. 2013;25(3):134-140). In some forms, typical antipsychotics may also have noradrenergic, cholinergic, and histaminergic blocking properties. The one or more typical antipsychotics conjugated to the dendrimer can belong to one of the following subclasses: phenothiazines, butyrophenones, thioxanthenes, dihydroindolones, dibenzepines, and / or diphenylbutylpiperidines. i. Phenothiazine

[0158] The composition can include a dendrimer conjugated to one or more phenothiazines. Phenothiazines are the largest chemical group of typical antipsychotics, comprising over 40 compounds (grouped into three subtypes). Phenothiazines share the same tricyclic structure with different side chains attached at the nitrogen atom of the central ring. The activity of this group can be influenced by substitution at the 2- or 10-position. Phenothiazines are classified into three subclasses based on substitution at the 10-position: aliphatic, piperidine, and piperazine phenothiazines.

[0159] In some forms, the one or more phenothiazines conjugated to the dendrimer are aliphatic (low / medium potency drugs) phenothiazines. Suitable aliphatic phenothiazines include, but are not limited to, chlorpromazine, levomepromazine, promazine, and triflupromazine.

[0160] In some embodiments, the one or more phenothiazines conjugated to the dendrimer are piperidine phenothiazines. Piperidine phenothiazines are low or medium potency drugs. Suitable piperidine phenothiazines include, but are not limited to, mesoridazine, pericyazine, pipotiazine, and thioridazine.

[0161] In some embodiments, the one or more phenothiazines conjugated to the dendrimer are piperazine phenothiazines. Piperazine phenothiazines are medium or high potency drugs. Suitable piperazine phenothiazines include, but are not limited to, perphenazine, fluphenazine, and trifluoperazine.

[0162] In an exemplary embodiment, the phenothiazine conjugated to the dendrimer has the formula shown in Formula X1 below. [ka] ii. Non-phenothiazine

[0163] The composition can include a dendrimer conjugated to one or more non-phenothiazines. The non-phenothiazines that can be conjugated to the dendrimer can be one or more of a butyrophenone, a thioxanthene, a dihydroindolone, a dibenzepine, and / or a diphenylbutylpiperidine.

[0164] In some forms, the dendrimer is conjugated with one or more butyrophenones and / or diphenylbutylpiperidines.Butyrophenones and diphenylbutylpiperidines are highly potent drugs.Non-limiting examples of butyrophenones include, but are not limited to, benperidol, droperidol and haloperidol.Non-limiting examples of diphenylbutylpiperidines include, but are not limited to, fluspirilene and pimozide.

[0165] In some embodiments, the dendrimer is conjugated to one or more of thioxanthenes, dibenzepins, and / or dihydroindolones. Thioxanthenes, dibenzepins, and dihydroindolones are low or medium potency drugs. Non-limiting examples of thioxanthenes include, but are not limited to, clopenthixol, flupenthixol, thiothixene, and zuclopenthixol. Non-limiting examples of dihydroindolones include, but are not limited to, molindone. Non-limiting examples of dibenzepins include, but are not limited to, clotiapine and loxapine. b. Atypical antipsychotics

[0166] The compositions can include dendrimers conjugated to one or more atypical antipsychotics. The term "atypical" refers to antipsychotic medications that produce minimal extrapyramidal side effects (EPS) at clinically effective antipsychotic doses, have a low tendency to cause tardive dyskinesia (TD) with long-term treatment, and treat both the positive and negative signs and symptoms of mental health disorders, such as schizophrenia. Suitable atypical antipsychotics that may be conjugated to the dendrimer compositions include, but are not limited to, clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), zotepine, cariprazine, brexiprazole, asenapine (Saphris), iloperidone (Fanapt), amisulpride, blonanserin, melperone, perospirone, remoxipride, sertindole, sulpiride, lurasidone (Latuda), and paliperidone (Invega), the active metabolite of risperidone.

[0167] Typically, the dendrimer is conjugated to one or more atypical antipsychotic drugs that have high selectivity for serotonin (5-HT) and dopamine (D) receptors. More preferably, the one or more atypical antipsychotic drugs bind as antagonists of 5-HT2A and D2 receptors. For example, dendrimers have been conjugated to one or more of clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), zotepine, cariprazine, brexiprazole, asenapine (Saphris), iloperidone (Fanapt), amisulpride, blonanserin, melperone, perospirone, remoxipride, sertindole, sulpiride, lurasidone (Latuda), and paliperidone (Invega), the active metabolite of risperidone.

[0168] The dendrimer can be conjugated to one or more atypical antipsychotic drugs with selectivity for one or more other receptors. For example, some atypical antipsychotic drugs are also potent serotonin-1A (5-HT1A; aripiprazole), serotonin-1C (5-HT1C; clozapine, olanzapine, risperidone), histamine-1 (H1; olanzapine, quetiapine), and α1- (aripiprazole, clozapine, olanzapine, paliperidone, quetiapine) and α2-adrenergic (clozapine, olanzapine, paliperidone, quetiapine, risperidone) receptor blockers. In another example, some atypical antipsychotic drugs, such as clozapine, olanzapine, and quetiapine, bind to the histamine-1 (H1) receptor with affinity comparable to that for D2, 5-HT2A / 2C, and α2-adrenergic receptors.

[0169] In some embodiments, dendrimers can be conjugated with one or more atypical antipsychotic drugs that have different effects on the central nervous system and nervous system in a tissue-specific manner.For example, risperidone and aripiprazole, although they have an inhibitory effect on the firing activity of 5-HT neurons, can independently increase cortical 5-HT levels and potentiate the escitalopram-induced increase in 5-HT concentration in the frontal cortex.In addition, risperidone enhances the anxiolytic and antidepressant-like behavioral effects of escitalopram.

[0170] Drugs particularly useful for treating ADHD and its symptoms can be conjugated to dendrimers for use in treating individuals. These include ADHD medications such as methylphenidate, amphetamine, atomoxetine, clonidine, guanfacine, viloxazine, and their analogs / modifications. These medications are commonly used for patients with depression, PTSD, and bipolar disorder. See https: / / www.webmd.com / add-adhd / adhd-medication-chart and https: / / www.additudemag.com / adhd-medication-for-adults-and-children / . In some forms, conjugation to dendrimers can significantly improve the efficacy of non-stimulant ADHD medications.

[0171] Some of them have a similar mechanism of action to antidepressants / antipsychotics such as atomoxetine (SNRI), viloxazine (SNRI), and methylphenidate, which block the reuptake of dopamine and norepinephrine. Examples of antidepressants currently used to treat the symptoms of ADHD include bupropion, desipramine, imipramine, and nortriptyline. C. Coupling Agents and Spacers

[0172] The dendrimer-active agent conjugates can be formed from one or more active agents covalently conjugated to the dendrimer or non-covalently bound to the dendrimer. In a preferred embodiment, the one or more active agents are covalently conjugated to the dendrimer.

[0173] Optionally, one or more active agents are conjugated to the dendrimer via one or more spacers. The term "spacer" includes chemical moieties and functional groups used to link the active agent to the dendrimer. A spacer can be either a single chemical entity or two or more chemical entities linked together. A spacer can include any small chemical entity, peptide, or polymer with sulfhydryl, thiopyridine, succinimidyl, maleimide, vinyl sulfone, carbonate, etc.

[0174] In some embodiments, the spacer through which the active agent is conjugated to the dendrimer contains various linking groups, such as disulfide, ester, carbonate, carbamate, thioester, hydrazine, hydrazide, ether, and amide linking groups. The spacer between the dendrimer and the active agent can be designed to provide a releasable or non-releasable form of the dendrimer conjugate in vivo. In some embodiments, conjugation between the active agent and the dendrimer is via an appropriate spacer, including an ester bond between the active agent and the dendrimer. In some embodiments, one or more spacers between the dendrimer and the active agent can provide a desired effective release rate in vivo. These spacers may contain cleavable linking groups (e.g., ester, disulfide, phosphodiester, triglycyl peptide, hydrazine) or non-cleavable linking groups (e.g., amide, ether, and aminoalkyl). Conjugation between the active agent and the dendrimer can be performed using reactions known in the art, such as click chemistry, acid-amine coupling, and Steglich esterification.

[0175] In some embodiments, conjugation between the active agent and the dendrimer is via a spacer containing a disulfide, ester, ether, thioester, carbamate, carbonate, hydrazine, ether, or amide linking group, or a combination thereof. In some embodiments, conjugation between the active agent and the dendrimer is via a suitable spacer, including an ester or amide linking group between the agent and the dendrimer, depending on the desired release rate of the agent.

[0176] The spacer can be selected from the classes of compounds terminated with sulfhydryl, thiopyridine, succinimidyl, maleimide, vinyl sulfone, and carbonate groups. The spacer can include a thiopyridine-terminated compound such as dithiodipyridine, N-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP), succinimidyl 6-(3-[2-pyridyldithio]-propionamido)hexanoate LC-SPDP, or sulfo-LC-SPDP. The spacer can also include peptides, linear or cyclic, inherently containing a sulfhydryl group, such as glutathione, homocysteine, cysteine ​​and its derivatives, arg-gly-asp-cys (RGDC), cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)), cyclo(Arg-Gly-Asp-d-Tyr-Cys), cyclo(Arg-Ala-Asp-d-Tyr-Cys), etc. The spacer can also be a mercapto acid derivative, such as 3-mercaptopropionic acid, mercaptoacetic acid, 4-mercaptobutyric acid, thiolan-2-one, 6-mercaptohexanoic acid, 5-mercaptovaleric acid, and other mercapto derivatives, such as 2-mercaptoethanol and 2-mercaptoethylamine. The spacer may be thiosalicylic acid and its derivatives, (4-succinimidyloxycarbonyl-methyl-alpha-2-pyridylthio)toluene, (3-[2-pyridylthio]propionyl hydrazide). The spacer may have a maleimide terminus, in which case the spacer comprises a polymer or a small chemical entity such as bis-maleimidodiethylene glycol and bis-maleimidotriethylene glycol, bis-maleimidoethane, bismaleimidohexane, etc. The spacer may comprise a vinyl sulfone such as 1,6-hexane-bis-vinyl sulfone. The spacer may comprise a thioglycoside such as thioglucose. The spacer may be a reduced protein such as bovine serum albumin and human serum albumin, or any thiol-terminated compound capable of forming a disulfide bond.The spacer can include maleimide, succinimidyl and / or thiol-terminated polyethylene glycol. D. Dendrimer-Drug Conjugates

[0177] The dendrimer-active agent conjugates can be formed from antidepressants and / or antipsychotics covalently or non-covalently conjugated to a dendrimer, dendritic polymer, or hyperbranched polymer. Methods for conjugating one or more active agents to dendrimers are known, such as those described in U.S. Publication Nos. 2011 / 0034422, 2012 / 0003155, and 2013 / 0136697.

[0178] In some embodiments, one or more active agents are covalently conjugated to one or more terminal groups of the dendrimer, such as a terminal hydroxyl group. In some embodiments, the dendrimer conjugate comprises one or more active agents conjugated to the dendrimer via one or more spacers. The spacer between the dendrimer and the active agent can be designed to provide a releasable or non-releasable form of the dendrimer conjugate in vivo. For example, the spacer may be cleavable or may contain a chemical linking group that is cleavable, for example, upon exposure to the intracellular compartment of a target nervous system cell and / or glial cell, or upon binding to a receptor on or within a target nervous system cell and / or glial cell in vivo. Examples of cleavable linking groups that can be used in the spacer of a dendrimer-active agent conjugate include an esterase-sensitive ester bond, a glutathione-sensitive disulfide bond, a phosphatase-sensitive phosphodiester bond, an oligopeptide such as a triglycyl peptide linker capable of lysosomal release, an acid-cleavable hydrazine linking group, and the like. In some embodiments, the spacer between the dendrimer and the active agent can provide a desired effective release rate in vivo, hi some embodiments, the spacer between the dendrimer and the active agent can be non-cleavable or can include non-cleavable chemical linking groups such as amide, ether, and aminoalkyl linking groups.

[0179] Generally, the spacer between the dendrimer and the active agent is long enough to allow the active agent conjugated to the spacer to reach and bind to a target receptor on the surface and / or inside the target cell. The length of the spacer can vary depending on the location of the target receptor (e.g., on the cell surface, in the cytoplasm of the cell, or in the intercellular compartment of the cell) and / or the density of the receptor if located on the cell surface.

[0180] Dendrimers can be second, third, fourth, fifth, sixth and up to tenth generation. In some embodiments, dendrimers are conjugated to one or more active agents via spacers containing cleavable (ester, disulfide, phosphodiester, triglycyl peptide and hydrazine) or non-cleavable (amide, ether and aminoalkyl) linking groups.

[0181] The density of active agents covalently conjugated to the dendrimer or non-covalently bound to the dendrimer can be adjusted based on the particular antidepressant and / or antipsychotic agent being delivered, the target receptor, the target nervous system cells and / or glial cells, the location of the target nervous system cells and / or glial cells, etc. For example, multiple active agents conjugated to the dendrimer may be present on the outer periphery of the dendrimer, with a surface density of active agents of at least 1 active agent / nm 2 (number of conjugated active agents / surface area (nm 2 For example, in some embodiments, 1 nm 2 The surface density of the activator per nanoparticle is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50 OH / nm 2 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more OH / nm 2 In some embodiments, the volume density of the active agent is from about 1 to about 50 groups / nm 3 Between about 5 and about 30 groups / nm 3 Between about 10 and about 20 groups / nm 3 It is between.

[0182] Typically, dendrimer-active agent conjugates have hydrodynamic volumes in the nanometer range. For example, in some embodiments, glucose dendrimer-active agent conjugates comprising one or more antidepressants and / or antipsychotics conjugated to a dendrimer have diameters of about 2 nm to about 100 nm or greater than 100 nm, up to 500 nm, depending on the generation of the dendrimer and the chemical composition and amount of active agent conjugated thereto. In some embodiments, dendrimer-active agent conjugates comprising one or more antidepressants and / or antipsychotics conjugated to a dendrimer have diameters effective to penetrate brain tissue and retain the active agents on the surface and / or within target nervous system cells and / or glial cells for a period of time sufficient for the active agents to bind to targeted receptors on the surface and / or within the target nervous system cells and / or glial cells. In some embodiments, dendrimer-active agent conjugates comprising one or more antidepressants and / or antipsychotics conjugated to a dendrimer have a diameter effective to be retained in the peripheral circulation and to be retained on the surface of and / or within target nervous system cells and / or glial cells (such as, for example, nervous system and / or glial cells of the gastrointestinal system) for a period of time sufficient for the active agent to bind to targeted receptors on the surface of and / or within the target nervous system cells and / or glial cells.

[0183] The dendrimer-active agent conjugate may be neutral, positively charged, or negatively charged. In some embodiments, the dendrimer-active agent conjugate is neutral. The presence of an antidepressant and / or antipsychotic derivative can affect the surface charge of the dendrimer-active agent conjugate. In some embodiments, the surface charge of a dendrimer conjugated to an antidepressant and / or antipsychotic 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 above ranges include all values ​​between -100 mV and 100 mV. In a preferred embodiment, the surface charge of the dendrimer-active agent conjugate is neutral or near neutral, ie, from about −10 mV to about 10 mV, inclusive.

[0184] An exemplary dendrimer-active agent conjugate is represented by formula (I): The dendrimer of the exemplary conjugate contains surface hydroxyl groups, one or more of which are conjugated to one or more active agents via one or more spacers, as shown in formula (I) below. [ka] wherein D can be a 1st to 10th generation or a 2nd to 10th generation dendrimer such as any one of those described above, for example, PAMAM (such as a hydroxyl-terminated PAMAM dendrimer) or a glucose-based dendrimer; L, at each occurrence, can be any suitable chemical moiety, preferably containing a triazole moiety; and Y is a bond, or a secondary amide (-CONH-), a tertiary amide (-CONR-), a sulfonamide (-S(O)-NR-), a secondary carbamate (-OCONH-; -NHCOO-), a tertiary carbamate (-OCONR-; -NRCOO-), a carbonate (-OC(O)-O-), a urea (-NHCONH-; -NRCONH-; -NHCONR-, -NRCONR-), a carbinol (-CHOH-, -CROH-), a disulfide group, a phosphodiester group. [ka] , a hydrazino group, a hydrazone, a hydrazide, an ester (-C(O)-O-), an ether (-O-), and an oligopeptide (e.g., a triglycyl peptide); R is an alkyl group, an aryl group, or a heterocyclic group; X, at each occurrence, can be an antidepressant and / or an antipsychotic; the functional group of X (such as an amino group, including a primary amino, secondary amino, or tertiary amino group, a carboxyl group; or a hydroxyl group) forms part of the linking group Y; n can be an integer from 1 to 100; and m can be an integer from 16 to 4096.

[0185] The oxygen atoms shown in formula (I) are derived from surface functional groups of the dendrimer, such as surface hydroxyl groups, which may or may not be part of a terminal sugar moiety / molecule (e.g., glucose). Although not depicted in formula (I), one or more hydroxyl groups of the dendrimer that are not conjugated to an active agent may be modified with one or more carbohydrates and / or polyalkylene glycols, such as PEG.

[0186] When administered to a subject in need thereof, the antidepressant and / or antipsychotic agent X of Formula (I) can bind to a target receptor on the surface of or inside a target cell. In some embodiments, when the antidepressant and / or antipsychotic agent X binds to the target receptor, the agent X remains conjugated to the dendrimer. In these embodiments, after binding, the agent X can be released from the dendrimer or can remain conjugated to the dendrimer as an intact dendrimer-active agent conjugate. In some embodiments, the antidepressant and / or antipsychotic agent X is released from the dendrimer in close proximity to the target receptor and then binds to the target receptor.

[0187] In some embodiments, L, at each occurrence, can be represented by -A'-L1-B'-L2-, where A' can be carbonyl (-C(O)-) or a bond (including single, double, and triple bonds, e.g., a single bond), B' can be a bond (including single, double, and triple bonds, e.g., 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, L1 and L2 may be a thiol, dithiol, thiol ether, polythioether, oligopeptide, polypeptide, oligo(alkylene glycol) or polyalkylene glycol, or L1 and L2 may independently be composed of combinations 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 -alkylene-triazole-di(alkylene glycol)-, -di(alkylene glycol)-triazole-alkylene-, -alkylene-triazole-oligo(alkylene glycol)-, -oligo(alkylene glycol)-triazole-alkylene-, -alkylene-triazole-poly(alkylene glycol)-, -poly(alkylene glycol)-triazole-alkylene-, -alkylene-triazole-ether-, -alkylene-triazole-alkylene-, -alkylene-amide-alkylene-, and combinations thereof.

[0188] In some embodiments, B' can be a bond (including single, double and triple bonds, eg, single bonds), an amide group, or a heterocyclic group such as a triazole group.

[0189] In some embodiments, L1 is a bond, C1-C 10alkylene, such as C1-C8 alkylene, C1-C6 alkylene, C1-C5 alkylene, C1-C4 alkylene or C1-C3 alkylene, or [ka] wherein p is an integer of 1 to 20, 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 or 2.

[0190] In some embodiments, L2 is a bond, C1-C 10 alkylene such as alkylene, C1-C8 alkylene, C1-C6 alkylene, C1-C5 alkylene, C1-C4 alkylene or C1-C3 alkylene; [ka] wherein p is an integer from 1 to 20, 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 or 2), an oligo- or poly-peptide such as triglycyl peptide, a thiol, or a dithiol, or L2 is comprised of a combination of two or more of alkylene, oligo- or poly-(alkylene glycol), oligo- or poly-peptide, thiol, and dithiol. For example, L2 can be [ka] wherein p, q, r, s, t, and u are independently integers from 0 to 10, 0 to 8, 0 to 6, 0 to 5, 0 to 4, 0 to 3, or 0 to 2, such as 0, 1, or 2, and G' is a thiol, dithiol, oligo-peptide (such as triglycyl peptide), or poly-peptide.

[0191] In some embodiments, Y is a linking group that is minimally cleavable in vivo. In some embodiments, Y is a linking group that is cleavable in vivo. In some embodiments, Y is an amide (-CONH-), ester (-C(O)-O-), ether (-O-), phosphodiester, or disulfide group.

[0192] In some embodiments, both L and Y are single bonds and D is conjugated directly to X (the active agent or analog thereof) through an ether linking group.

[0193] In some embodiments, D is a second generation PAMAM dendrimer, a third generation PAMAM dendrimer, a fourth generation PAMAM dendrimer, a fifth generation PAMAM dendrimer, a sixth generation PAMAM dendrimer, a first generation glucose dendrimer, a second generation glucose dendrimer, a third generation glucose dendrimer, a fourth generation glucose dendrimer, a fifth generation glucose dendrimer, or a sixth generation glucose dendrimer.

[0194] More specific exemplary dendrimer-active agent conjugates are shown in the Examples below. diagnostic agents

[0195] In some cases, the agent delivered to the target nervous system cells and / or glial cells or tissues by the dendrimer is a diagnostic agent. Examples of diagnostic agents that can be delivered to the brain by the glucose dendrimer conjugate include paramagnetic molecules, fluorescent compounds, magnetic molecules, and radionuclides, X-ray imaging agents, and contrast media. The dendrimer conjugate can contain an agent that is useful for determining the location of the administered composition. Agents useful for this purpose include fluorescent tags, radionuclides, and contrast agents.

[0196] Exemplary diagnostic agents include dyes, fluorescent dyes, near-infrared dyes, SPECT imaging agents, PET imaging agents, and radioisotopes. Representative dyes include carbocyanine, indocarbocyanine, oxacarbocyanine, thuicarbocyanine, and merocyanine, polymethine, coumarin, rhodamine, xanthene, fluorescein, boron-dipyrromethane (BODIPY), Cy5, Cy5.5, Cy7, VivoTag-680, VivoTag-S680, VivoTag-S750, AlexaFluor660, AlexaFluor680, AlexaFluor700, AlexaFluor750, AlexaFluor790, Dy677, Dy676, Dy682, Dy752, Dy780, DyLight547, Dylight647, HiLyte Fluor 647, HiLyte Fluor 680, HiLyte Fluor 750, IRDye 800CW, IRDye These include the 800RS, IRDye 700DX, ADS780WS, ADS830WS and ADS832WS.

[0197] Exemplary SPECT or PET imaging agents include chelators such as diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetraacetic acid (DOTA), diaminedithiols, activated mercaptoacetyl-glycyl-glycyl-glycine (MAG3) and hydrazidonicotinamide (HYNIC).

[0198] Exemplary isotopes include Tc-94m, Tc-99m, In-111, Ga-67, Ga-68, Gd3+, Y-86, Y-90, Lu-177, Re-186, Re-188, Cu-64, Cu-67, Co-55, Co-57, F-18, Sc-47, Ac-225, Bi-213, Bi-212, Pb-212, Sm-153, Ho-166, and Dy-166.

[0199] In an exemplary embodiment, the dendrimer composition comprises one or more radioisotopes suitable for positron emission tomography (PET) imaging. An exemplary positron-emitting radioisotope is carbon-11 ( 11 C), copper-64( 64 Cu), nitrogen-13( 13 N), oxygen-15( 15 O), gallium-68( 68 Ga) and fluorine-18( 18 F), for example, 2-deoxy-2- 18 F-fluoro-β-D-glucose ( 18 F-FDG).

[0200] In a further embodiment, a single dendrimer conjugate composition can simultaneously treat and / or diagnose a disease or condition at one or more locations in the body. E. Exemplary Dendrimer-Drug Conjugates

[0201] In a preferred embodiment, the dendrimer is conjugated to fluoxetine as shown in structures I and II below, where n is an integer from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. [ka]

[0202] In another embodiment, the dendrimer is conjugated to paroxetine as shown in structure III below. [ka]

[0203] In other embodiments, the dendrimer is conjugated to venlafaxine or a venlafaxine analog as shown in structures IV-VI below, where n is an integer from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. [ka]

[0204] In other embodiments, the dendrimer is conjugated to citalopram or a citalopram analog, as shown in structures VII and VIII below, where n is an integer from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. [ka] III. Methods of Making Dendrimers and Conjugates Thereof

[0205] Methods for synthesizing dendrimers and preparing dendrimer nanoparticles are also described. A. Methods for Making Dendrimers

[0206] Dendrimers can be prepared by various chemical reaction steps. Dendrimers are usually synthesized according to methods that allow control of their structure at each stage of construction. Dendritic structures are mostly synthesized by two main different methods: divergent or convergent.

[0207] In some embodiments, dendrimers are prepared using a divergent method, in which dendrimers are assembled from a multifunctional core that is extended outward through a series of reactions, typically the Michael reaction. This strategy involves coupling the multifunctional core moiety with monomer molecules bearing reactive and protecting groups, which results in the stepwise addition of generations around the core, followed by removal of the protecting groups. For example, PAMAM-NH2 dendrimers are first synthesized by coupling N-(2-aminoethyl)acrylamide monomers to an ammonia core.

[0208] In other embodiments, dendrimers are prepared using convergent methods, where dendrimers are built from small molecules that terminate on the surface of a sphere, and the reaction proceeds inward, building inward and finally attaching to the core.

[0209] Many other synthetic routes exist for the preparation of dendrimers, such as the orthogonal, accelerated, two-step convergent or hypercore approach, the hypermonomer or branched monomer approach, the double exponential, the orthogonal coupling or two-step approach, the two-monomer approach, and the AB2-CD2 approach.

[0210] In some embodiments, the dendrimer core, one or more branching units, one or more spacers, and / or one or more surface functional groups can be modified to allow conjugation to additional functional groups (such as branching units, spacers, surface functional groups), monomers, and / or drugs via click chemistry using one or more of copper-assisted azide-alkyne cycloaddition (CuAAC), Diels-Alder reaction, thiol-ene reaction, thiol-yne reaction, and azide-alkyne reaction (Arseneault M et al., Molecules. 2015 May 20;20(5):9263-94). In some embodiments, prefabricated dendrons are clicked onto high-density hydroxyl polymers. "Click chemistry" involves coupling two different moieties (e.g., a core group and a branching unit, or a branching unit and a surface functional group) via a 1,3-dipolar cycloaddition reaction between, for example, an alkyne moiety (or its equivalent) on the surface of a first moiety and an azide moiety (e.g., present in a triazine composition or its equivalent) or any reactive end group (e.g., a primary amine end group, a hydroxyl end group, a carboxylic acid end group, a thiol end group, etc.) on a second moiety. In some embodiments, one or more hydroxyl groups on the surface of a dendrimer (hydroxyl-terminated PAMAM dendrimer or glucose dendrimer) are modified to contain an alkyl group, and the drug is modified to contain an azide group. Alternatively, one or more hydroxyl groups on the surface of a dendrimer (hydroxyl-terminated PAMAM dendrimer or glucose dendrimer) are modified to contain an azide group, and the drug is modified to contain an alkyne group. The azide and alkyne then react via a 1,3-dipolar cycloaddition reaction to form the triazole moiety.

[0211] In some embodiments, dendrimer synthesis relies on one or more reactions such as thiol-ene click reaction, thiol-yne click reaction, CuAAC, Diels-Alder click reaction, azide-alkyne click reaction, Michael addition, epoxy ring-opening, esterification, silane chemistry, and combinations thereof.

[0212] In some embodiments, the method includes one or more protection and deprotection steps of functional groups (e.g., hydroxyl groups) on the central core, branching units, and / or therapeutic, prophylactic, or diagnostic agents to facilitate the addition of branching units to generate the desired dendrimer molecule, or the addition of the therapeutic, prophylactic, or diagnostic agent to generate the desired dendrimer conjugate. In the case of hydroxyl groups, the hydroxyl group may be protected by the formation of an ether, ester, or acetal. Other exemplary protecting groups include Boc and Fmoc.

[0213] Any existing dendritic platform can be used to create dendrimers with the desired functionality, i.e., a high density of surface hydroxyl groups, by conjugating higher hydroxyl-containing moieties such as 1-thio-glycerol or pentaerythritol. Exemplary dendritic platforms such as polyamidoamine (PAMAM), poly(propyleneimine) (PPI), poly-L-lysine, melamine, poly(etherhydroxylamine) (PEHAM), poly(esteramine) (PEA), and polyglycerol can be synthesized and explored.

[0214] Dendrimers can also be prepared by combining two or more dendrons. A dendron is a wedge-shaped section of a dendrimer that carries a reactive focal group. Numerous dendron scaffolds are commercially available. These dendrons have appeared in the first, second, third, fourth, fifth, and sixth generations, with 2, 4, 8, 16, 32, and 64 reactive groups, respectively. In certain embodiments, one type of drug is linked to one type of dendron, and a different type of drug is linked to another type of dendron. The two dendrons are then linked to form a dendrimer. The two dendrons can be linked via click chemistry, i.e., a 1,3-dipolar cycloaddition reaction, between an azide moiety on one dendron and an alkyne moiety on another dendron to form a triazole linker.

[0215] Exemplary methods of making dendrimers are described in detail in International Patent Publication Nos. WO2009 / 046446, WO2015168347, WO2016025745, WO2016025741, WO2019094952, and U.S. Pat. No. 8,889,101. 1. Method for preparing glucose dendrimers

[0216] In some embodiments, glucose-based dendrimers are prepared using a divergent method in which dendrimers are assembled from a multifunctional core that is extended outward through a series of reactions. This strategy involves coupling monomer molecules bearing reactive and protecting groups to the multifunctional core moiety, resulting in the stepwise addition of generations around the core, followed by removal of the protecting groups.

[0217] In some embodiments, glucose dendrimers are synthesized by coupling AB4 peracetylated β-D glucose-PEG4-azide monomers to a hexapropargylated core. In a preferred embodiment, the hypercore is prepared from dipentaerythritol, for example, by propargylating dipentaerythritol to obtain a hexapropargylated core. An exemplary scheme for preparing such glucose dendrimers is shown in Scheme I. [ka]

[0218] In some embodiments, the branching unit is a hypermonomer, i.e., AB n These are building blocks. Exemplary hypermonomers include the AB3, AB4, AB5, AB6, AB7, and AB8 building blocks. The hypermonomer strategy dramatically increases the number of available end groups. An exemplary hypermonomer is the orthogonal hypermonomer AB4, which contains one azide functional group and four allyl groups and is prepared by reacting dipentaerythritol, which has five allyl groups, with monotosylated triethylene glycol azide.

[0219] In some embodiments, the branching unit is a linear or branched polyethyleneglycerol, for example, as shown by Formula III. Other monomers include disaccharides and oligosaccharides, as well as saccharides such as fructose, lactose, and sucrose. a. Synthesis of AB4 building blocks

[0220] Some exemplary synthesis methods for hypermonomer AB4 are described below. In some embodiments, hypermonomer AB4 is based on a glucose molecule. In a preferred embodiment, hypermonomer AB4 is conjugated to polyethyleneglycerol, e.g., tetraethyleneglycol (PEG4). In one embodiment, hypermonomer AB4 is peracetylated β-D-glucopyranoside tetraethyleneglycol azide.

[0221] In some embodiments, the synthesis of glucose-OAc-TEG-OTs comprises the following steps: a solution of peracetylated β-D-glucopyranoside (10 g, 25.6 mmol) was dissolved in 50 mL of anhydrous dichloromethane (DCM), and then 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (6.2 g, 17.9 mmol) was added, and the reaction mixture was cooled to 0 °C. Boron trifluoride diethyl etherate (2.5 equivalents) was added, and the reaction was allowed to reach room temperature. The reaction was monitored by TLC and, after 5 h, quenched by adding saturated sodium bicarbonate solution at 0 °C. After stirring for 10 min, DCM (300 mL) was added, and the organic layer was washed three times with saturated sodium bicarbonate solution until foaming disappeared. The reaction mixture was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by combiflash® chromatography using an ethyl acetate / hexane (70:30) mixture as the eluent. The desired compound was obtained in 60% yield. The structure of Glucose-OAc-TEG-OTs is shown below: [ka]

[0222] In some embodiments, the synthesis of glucose-OAc-TEG-N3 involves the following steps: a solution of glucose-OAc-TEG-OTs (6 g, 8.8 mmol) is dissolved in 40 mL of anhydrous DMF, then sodium azide (2 equivalents) is added, and the reaction mixture is heated to 50° C. overnight. Upon completion, the reaction mixture is filtered and the DMF is evaporated. Once dry, the crude reaction mixture is passed through a combiflash® column using ethyl acetate:hexane (70:30) as the eluent. The structure of glucose-OAc-TEG-N3 is shown below: [ka]

[0223] In some embodiments, the synthesis of glucose-OH-TEG-N3 involves the following steps: dissolving peracetylated β-D-glucopyranoside tetraethylene glycol azide in anhydrous methanol and adding sodium methoxide to adjust the pH to about 8.5-9. The reaction is stirred overnight at room temperature, then diluted with methanol and adjusted to about pH 6-7 with Amberlist IR-120+. The reaction mixture is isolated by filtration, and the solvent is removed by rotary evaporation. The structure of glucose-OH-TEG-N3 is shown below. [ka] b. Synthesis of glucose dendrimers

[0224] In some embodiments, glucose dendrimers are synthesized by coupling AB4 peracetylated β-D-glucose-PEG-azide monomers to a hexapropargylated core. In a preferred embodiment, the hexapropargylated core is linked to the AB4 β-D-glucose-PEG-azide building block (2) via a click reaction to yield a first-generation dendrimer.

[0225] In some embodiments, the first-generation dendrimer D1-Glu6-OAc24 is prepared as follows: The hexapropargylated compound (0.5 g, 1 mmol) and the azide derivative (4.1 g, 7.4 mmol, 1.2 equivalents per acetylene) are suspended in a 1:1 mixture of DMF and water in a 20 mL microwave vial equipped with a magnetic stir bar. CuSO4·5H2O (5 mol% / acetylene, 75 mg) and sodium ascorbate (5 mol% / acetylene, 60 mg) dissolved in a minimum amount of water are added. The reaction is microwaved at 50 °C for 6 h. The reaction mixture is dialyzed against DMF followed by dialysis against water containing EDTA. The EDTA is further removed by extensive water dialysis. The product is lyophilized to afford D1-Glu6-OAc24. The structure of D1-Glu6-OAc24 is shown below. [ka]

[0226] In some embodiments, the first generation dendrimer D1-Glu6-OH 24 is prepared as follows: peracetylated first-generation glucose dendrimer (1 g, 0.26 mmol) is dissolved in anhydrous methanol and sodium methoxide is added to adjust the pH to approximately 8.5-9. The reaction is stirred overnight at room temperature, then diluted with methanol and the pH adjusted to approximately 6-7 with AMBERLIST® IR-120+. The reaction mixture is separated by filtration, the solvent removed by rotary evaporation, and then subjected to water dialysis. The structure of first-generation glucose dendrimer D1-Glu6-OH24 is shown below. [ka]

[0227] In some embodiments, first-generation glucose dendrimer D1-Glu6-OH24 was propargylated to give D1-acetylene 24 as follows: D1-GLu6-OH24 (2 g, 0.721 mmol) was dissolved in anhydrous dimethylformamide (DMF, 50 mL) by sonication. To this solution, sodium hydride [60% dispersion in mineral oil] (951 mg, 39.65 mmol) was slowly added in small portions with stirring at 0°C. The solution was stirred for an additional 15 minutes at 0°C. After this, propargyl bromide (3.85 mL, 34.608 mmol, 80% w / w solution in toluene) was added at 0°C, and stirring was continued for an additional 6 hours at room temperature. The reaction mixture was quenched with ice and water, filtered, and dialyzed against DMF, followed by water dialysis, to give D1-acetylene 24. The structure of D1-acetylene 24 is shown below. [ka]

[0228] In some embodiments, the first generation dendrimer D1-acetylene 24 is further reacted with AB4β-D-glucose-PEG4-azide to give a second generation dendrimer with 24 glucose molecules, containing 96 surface hydroxyl groups.

[0229] An exemplary second-generation dendrimer, D2-Glu24-OAc96, was prepared as follows: D1-acetylene dendrimer 24 (0.5 g, 0.13 mmol) and glucose-OAc-TEG-azide (2.2 g, 4 mmol) were suspended in a 1:1 mixture of DMF and water in a 20 mL microwave vial equipped with a magnetic stir bar. To this was added CuSO4·5H2O (5 mol% / acetylene, 5 mg) and sodium ascorbate (5 mol% / acetylene, 10 mg) dissolved in a minimal amount of water. The reaction was microwaved at 50 °C for 8 h. Upon completion, the reaction mixture was dialyzed against DMF followed by water dialysis containing EDTA. EDTA was further removed by extensive water dialysis. The product was lyophilized to yield D2-Glu24-OAc96.

[0230] In some embodiments, second-generation dendrimer D2-Glu24-OH96 is prepared as follows: peracetylated second-generation glucose dendrimer D2-Glu24-OH96 is dissolved in anhydrous methanol and sodium methoxide is added to adjust the pH to about 8.5-9.0. The reaction is stirred overnight at room temperature, then diluted with methanol and the pH adjusted to about 6-7 with AMBERLIST® IR-120+. The reaction mixture is filtered to remove the resin, and the filtrate is rotary evaporated, followed by water dialysis to give the product as an off-white solid.

[0231] The structure of the second generation glucose dendrimer D2-Glu24-OH96 is shown below. [ka]

[0232] In some embodiments, the second-generation dendrimer D2-Glu24-OH96 is propargylated at one or more terminal hydroxyl groups suitable for further conjugation to one or more therapeutic, prophylactic, or diagnostic agents. In some embodiments, one or more terminal hydroxyl groups of the second-generation dendrimer D2-Glu24-OH96 are propargylated as follows: D2-Glu24-OH96 (5b) (200 mg, 0.016 mmol) is dissolved in anhydrous dimethylformamide (DMF, 10 mL) by sonication. To this stirred solution, sodium hydride (60% dispersion in mineral oil) (22 mg, 0.934 mmol) is added slowly in small portions at 0° C. The solution is further stirred at 0° C. for 15 minutes. After this, propargyl bromide (18.0 μL, 80% w / w solution in toluene) is added at 0° C., and stirring is continued for an additional 6 hours at room temperature. The solvent is evaporated using a V10 evaporator system and the crude product is purified by passing through a PD10 SEPHADEX® G25M column. The aqueous solution is lyophilized to give the product as an off-white solid.

[0233] In some embodiments, one or more fluorescent dyes, such as infrared-fluorescent Cy5 dyes, are conjugated to the second-generation dendrimer D2-Glu24-OH96. In one embodiment, Cy5-D2-Glu24-OH96 (compound 7 in Figure 1B) is prepared as follows: Compound 6 (200 mg, 0.016 mmol) and Cy5 azide (20.7 mg, 0.02 mmol) are suspended in a 1:1 mixture of DMF and water in a 25 mL round-bottom flask equipped with a magnetic stir bar. To this, CuSO4·5H2O (5 mol% / acetylene, 0.3 mg) and sodium ascorbate (10 mol% / acetylene, 0.5 mg) dissolved in a minimum amount of water are added. The reaction is stirred at room temperature for 24 hours. Upon completion, the DMF is evaporated using a V10 column, and purification is performed using a PD10 Sephadex G25 M column. The aqueous solution is lyophilized to give the product as a blue solid.

[0234] In some embodiments, the total hydroxyl groups available for further conjugation to active agents, including therapeutic and / or diagnostic agents, are about 1-30, 2-20, or 5-10 of the total 96 hydroxyl groups available for an exemplary second generation dendrimer having 24 glucose molecules containing 96 surface hydroxyl groups. B. Methods of Making Dendrimer-Drug Conjugates

[0235] Methods for conjugating drugs to dendrimers are generally known in the art, for example, as described in U.S. Published Application Nos. US2011 / 0034422, US2012 / 0003155, and US2013 / 0136697.

[0236] In some embodiments, one or more drugs are covalently attached to the dendrimer. In some embodiments, the drugs are attached to the dendrimer via a spacer designed to be non-cleavable in vivo. In some embodiments, the drugs are attached to the dendrimer via a spacer designed to be cleavable in vivo. For example, the spacer can be designed to be cleaved by hydrolysis, enzymes, or a combination thereof to achieve sustained release of the drug in vivo. In some embodiments, both the chemical structure of the spacer and its point of attachment to the drug can be selected so that cleavage of the spacer releases either the drug or a suitable prodrug thereof. The chemical structure of the spacer can also be selected taking into account the desired release rate of the drug.

[0237] In some embodiments, the conjugation between the drug and the dendrimer is via one or more of a disulfide, ester, ether, phosphodiester, triglycyl peptide, hydrazine, amide, or aminoalkyl linking group. In some embodiments, the conjugation between the drug and the dendrimer is via a suitable spacer that results in an ester or amide bond between the drug and the dendrimer, depending on the desired release rate of the drug. In some cases, an ester or disulfide bond is introduced for a releasable form of the drug. In other cases, an amide or aminoalkyl bond is introduced for a non-releasable form of the drug.

[0238] The spacer generally contains one or more organic functional groups. Examples of suitable organic functional groups contained in the spacer include secondary amide (-CONH-), tertiary amide (-CONR-), sulfonamide (-S(O)2-NR-), secondary carbamate (-OCONH-; -NHCOO-), tertiary carbamate (-OCONR-; -NRCOO-), carbonate (-OC(O)-O-), urea (-NHCONH-; -NRCONH-; -NHCONR-, -NRCONR-), carbinol (-CHOH-, -CROH-), disulfide group, hydrazone, hydrazide, ether (-O-) and ester (-COO-, -CHOC-, CHROC-), where R is an alkyl group, an aryl group or a heterocyclic group. Generally, the one or more organic functional groups in the spacer are selected taking into account the desired release rate of the drug. Additionally, one or more organic functional groups can be selected to facilitate covalent conjugation of a drug to the dendrimer. In some embodiments, conjugation between the drug and the dendrimer is via a suitable spacer that results in a disulfide bridge between the drug and the dendrimer. In some embodiments, the dendrimer-active agent conjugate is capable of rapid release of the drug in vivo by a thiol exchange reaction under reducing conditions found in the body.

[0239] In certain embodiments, the spacer comprises one or more of the organic functional groups described above in combination with a linking group. The linking group may be composed of any collection of atoms, including oligomeric and polymeric chains, for example, where the total number of atoms in the linking group is between 3 and 200 atoms, between 3 and 150 atoms, between 3 and 100 atoms, or between 3 and 50 atoms. Examples of suitable linking groups include alkyl groups, heteroalkyl groups, alkylaryl groups, oligoethylene glycol chains and polyethylene glycol chains, and oligo(amino acid) chains and poly(amino acid) chains. Variations in the linking group provide further control over in vivo drug release. In embodiments in which the spacer comprises a linking group, one or more organic functional groups are typically used to link the linking group to both the anti-inflammatory agent and the dendrimer.

[0240] Reactions and strategies useful for covalently conjugating drugs to dendrimers are known in the art. See, for example, March, "Advanced Organic Chemistry," 5th Edition, 2001, Wiley-Interscience Publication, New York) and Hermanson, "Bioconjugate Techniques," 1996, Elsevier Academic Press, USA. The appropriate method for covalently conjugating a given drug involves functional group compatibility, protecting group strategy, and the presence of labile bonds, and can be selected taking into account the desired linking moiety, as well as the structure of the drug and dendrimer.

[0241] The amount of active agent (drug loading) in the dendrimer-active agent conjugate depends on numerous factors, including the choice of active agent, the structure and size of the dendrimer, and the tissue to be treated. In some embodiments, the one or more antidepressants and / or antipsychotics are conjugated to the dendrimer at a concentration of between about 0.01% and about 45% by weight (inclusive), between about 0.1% and about 30% by weight (inclusive), between about 0.1% and about 20% by weight (inclusive), between about 0.1% and about 10% by weight (inclusive), between about 1% and about 10% by weight (inclusive), between about 1% and about 5% by weight (inclusive), between about 3% and about 20% by weight (inclusive), or between about 3% and about 10% by weight (inclusive). However, the specific drug loading for any given active agent, dendrimer and targeting site can be determined by routine methods such as those described.

[0242] In some embodiments, drug / spacer conjugation occurs on about 1%, 2%, 3%, 4%, or 5% of the total number of available surface functional groups, such as hydroxyl groups, on the dendrimer prior to conjugation. In other embodiments, drug / spacer conjugation occurs on less than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of the total number of available surface functional groups on the dendrimer prior to conjugation with the active agent. In some embodiments, the dendrimer-active agent conjugate retains an effective amount of surface functional groups for targeting to target nervous system cells and / or glial cells while simultaneously being conjugated to an effective amount of drug for treating, preventing, and / or imaging a disease or disorder. In some embodiments, the dendrimer-active agent conjugate carries an amount of active agent effective to target the target nervous system cells and / or glial cells and to bind to a target receptor on or within the target nervous system cells and / or glial cells.

[0243] More specific methods for preparing exemplary dendrimer-active agent conjugates are described in the Examples below. IV. Pharmaceutical Preparations

[0244] Pharmaceutical compositions comprising the dendrimer-active agent conjugates can be formulated in a conventional manner using one or more physiologically acceptable carriers, optionally including additives and adjuvants that facilitate processing into preparations of the active compound that can be pharmaceutically used for oral, mucosal (intranasal, buccal, sublingual, vaginal, rectal or pulmonary), transdermal or injectable (intravenous, subcutaneous, intraperitoneal, intramuscular or intrathecal administration) administration.

[0245] Representative additives include aqueous buffers, wetting agents, viscosity modifiers, tonicity agents, stabilizers, and combinations thereof. Suitable pharmaceutically acceptable additives are preferably selected from generally recognized as safe (GRAS) substances and can be administered individually without causing undesired biological side effects or undesired interactions.

[0246] Generally, pharmaceutically acceptable salts of active substances can be prepared by reacting a drug in the form of a free acid or free base with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Pharmaceutically acceptable salts include drug salts derived from inorganic acids, organic acids, alkali metal salts, alkaline earth metal salts, and salts formed by the reaction of a drug with a suitable organic ligand (e.g., quaternary ammonium salts). A list of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704. Examples of ophthalmic drugs that are sometimes administered in the form of pharmaceutically acceptable salts include timolol maleate, brimonidine tartrate, and diclofenac sodium.

[0247] The compositions are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The phrase "dosage unit form" refers to a physically discrete unit of the conjugate appropriate for the patient being treated. However, it will be understood that the total number of single doses of the composition will be determined by the attending physician within the scope of sound medical judgment. The therapeutically effective dose can be initially estimated either in cell culture assays or animal models, usually mice, rabbits, dogs, or pigs, or can be extrapolated from human data. Animal models are also used to obtain a desirable concentration range and route of administration. Such information should then be useful for determining effective doses and routes for administration in humans. The therapeutic efficacy and toxicity of the conjugates can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for human use.

[0248] In certain embodiments, the composition is administered locally, for example, by direct injection at the site to be treated, or by an implant or pump. In some embodiments, the composition is injected, applied locally, or otherwise administered directly to the vasculature on the vascular tissue at or adjacent to the site of injury, surgery, or implantation. For example, in embodiments, the composition is applied locally to vascular tissue exposed during a surgical procedure. Typically, local administration results in an increased local concentration of the composition, which is higher than can be achieved by systemic administration.

[0249] Pharmaceutical compositions are described that are formulated for administration by parenteral (intramuscular, intraperitoneal, intravenous or subcutaneous injection) and enteral routes of administration, including administration to mucosal surfaces (nasal, buccal, sublingual, pulmonary, vaginal and rectal). A. Parenteral Administration

[0250] The dendrimer-active agent conjugate composition can be administered parenterally. The terms "parenteral administration" and "parenterally administered" are art-recognized terms and include modes of administration other than enteral and topical administration. Dendrimers can be administered orally, intranasally, subcutaneously, intraperitoneally, intravenously, intrathecally, or intramuscularly. For liquid formulations, pharmaceutically acceptable carriers can be, for example, aqueous or nonaqueous solutions, suspensions, emulsions, or oils. Parenteral vehicles (for subcutaneous, intravenous, intraarterial, or intramuscular injection) include, for example, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, and fixed oils. Examples of nonaqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include, for example, water, alcoholic / aqueous solutions, emulsions or suspensions, including cyclodextrins, saline, and buffered media. Dendrimers can also be administered in emulsion, for example, in water in oil.Examples of oils are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, fish liver oil, sesame oil, cottonseed oil, corn oil, olive, petrolatum and inorganic.The fatty acids suitable for use in parenteral formulations include, for example, oleic acid, stearic acid and isostearic acid.Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

[0251] Formulations suitable for parenteral administration can include aqueous and non-aqueous sterile suspensions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as suspending agents, solubilizers, thickeners, stabilizers, and preservatives. Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose). In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.

[0252] Injectable pharmaceutical carriers for injectable compositions are well known to those skilled in the art (see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Trissel, 15th ed., pages 622-630 (2009)). B. Enteral Administration

[0253] The dendrimer-active agent conjugate compositions may be administered enterally (oral, sublingual, vaginal, rectal, buccal, nasal, pulmonary, or transdermally). The carrier or diluent may be a solid carrier such as a capsule or tablet or diluent for solid formulations, a liquid carrier or diluent for liquid formulations, or a mixture thereof.

[0254] For liquid preparations, pharmaceutically acceptable carriers can be, for example, aqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.Aqueous carriers include, for example, water, alcoholic / aqueous solutions, cyclodextrins, emulsions or suspensions including saline and buffered media.

[0255] Examples of oils include those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, fish-liver oil, sesame oil, cottonseed oil, corn oil, olive, petrolatum, and inorganic. Fatty acids suitable for use in parenteral formulations include, for example, oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

[0256] Vehicles include, for example, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, and fixed oils. Formulations include, for example, aqueous and non-aqueous isotonic sterile injection solutions (which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient), and aqueous and non-aqueous sterile suspensions (which may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives). Vehicles may include, for example, fluid and nutrient supplements, electrolyte supplements (such as those based on Ringer's dextrose). In general, water, saline, aqueous dextrose, and related sugar solutions are preferred liquid carriers. They may also be formulated with proteins, fats, saccharides, and other ingredients of infant formula.

[0257] Oral preparations may be in the form of chewing gum, gel strips, tablets, capsules or lozenges. Encapsulating materials for preparing enteric-coated oral preparations include cellulose acetate phthalate, polyvinyl phthalate acetate, hydroxypropylmethylcellulose phthalate and methacrylic acid ester copolymers. Solid oral preparations such as capsules or tablets are preferred. Elixirs and syrups are also well-known oral preparations.

[0258] Formulations for administration to mucosal surfaces such as the nose, oral surfaces or lungs will usually contain pharmaceutically acceptable excipients, such as those used for parenteral administration, alone or in combination with various surfactants, penetration enhancers, etc.

[0259] The present compositions can also be made into aerosol formulations (i.e., they can be "nebulized") to be administered by inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and air. For administration by inhalation, the compounds are delivered in the form of an aerosol spray supply from a pressurized pack or nebulizer, using a suitable propellant.

[0260] In some embodiments, the dendrimer conjugates may increase the efficacy and duration of treatment, thereby reducing the need for repeat administration for weekly, monthly, 6-monthly, yearly, or other longer-term dosing regimens. Some embodiments may be incorporated into drug delivery systems (e.g., implants, pumps, patches, creams, etc.) to achieve controlled, sustained delivery in a manner that reduces compliance requirements and the potential for abuse. V. How to use

[0261] In preferred embodiments, the dendrimer compositions cross the central and peripheral nervous system barrier interface and selectively target specific cells and specific receptors on the cell surface to address various diseases, disorders, injuries, and conditions. The methods involve administering to a subject in need thereof an amount of the composition effective to increase the permeability of the antidepressant and / or antipsychotic agent across the central and peripheral nervous system barrier interface and / or to increase binding of the antidepressant and / or antipsychotic agent at specific receptors in specific cells, particularly serotonergic, noradrenergic, adrenergic, and dopaminergic receptors in cells in the central nervous system, peripheral nervous system, and / or peripheral circulation, such as nervous system cells, glial cells, cardiovascular cells, gastrointestinal cells, and immune cells. A. Treatment Method

[0262] The composition can be administered to treat, prevent, or manage the symptoms of various disorders, diseases, and conditions, including, but not limited to, anxiety disorders, mood disorders, eating disorders, personality disorders, stress disorders, and / or psychiatric disorders, as well as ADHD and individuals with ADHD symptoms. In some forms, when the dendrimer is conjugated to one or more antidepressants, the composition can be administered to treat one or more neurological disorders, such as mental health disorders, such as mood disorders, anxiety disorders, eating disorders, substance-related disorders, and post-traumatic disorders; degenerative disorders, such as Parkinson's disease and Alzheimer's disease; pain disorders, such as neuropathic pain, gastrointestinal disorders, and / or cardiovascular disorders. In some forms, when the dendrimer is conjugated to one or more antipsychotic drugs, the composition can be administered to treat psychosis occurring in bipolar disorder, schizophrenia, and / or degenerative disorders. In other embodiments, the dendrimer-antipsychotic conjugates may be administered to subjects in need of stabilizing mood, for example, in bipolar disorder, reducing anxiety in anxiety disorders, and reducing tics in Tourette's syndrome. In yet other embodiments, the dendrimers are conjugated to one or more antidepressants and / or antipsychotics to treat non-neuronal diseases, such as gastrointestinal and cardiovascular diseases.

[0263] Typically, an effective amount of a dendrimer complex comprising a combination of a dendrimer and one or more therapeutic, prophylactic and / or diagnostic active agents is administered to an individual in need thereof. The dendrimer also comprises a targeting agent, although, as demonstrated by the examples, these are not required for delivery to damaged tissue in the spinal cord, brain and related regions.

[0264] In some embodiments, the dendrimer complex comprises a drug bound to or conjugated to a dendrimer, which is capable of preferentially releasing the drug at the target receptor. The drug can be covalently bound or dispersed or encapsulated within the molecule. The amount of dendrimer complex administered to a subject is selected to deliver an amount effective to reduce, prevent, or otherwise alleviate one or more clinical or molecular symptoms of the disease or disorder being treated, compared to a control, for example, a subject treated with an active agent without a dendrimer. 1. Site-specific targeting

[0265] The present composition and method are designed to avoid the existing difficulties in selective drug delivery to the central nervous system and peripheral nervous system.The present composition and method can improve the bioavailability of drugs in the central nervous system and peripheral nervous system by one or more of the following: (i) increasing the density of drugs that pass through the brain barrier, particularly the blood-brain and blood-spinal fluid barrier; (ii) improving drug solubility; (iii) promoting target engagement, i.e., increasing site-specific binding; (iv) improving the pharmacokinetics of drugs; and (v) improving intracerebral distribution.For example, in some forms, the present composition and method can selectively deliver compounds to the peripheral nervous system, thereby increasing the possibility that the present composition can be used to selectively treat peripheral-specific diseases and disorders, including but not limited to neuropathic pain, local anesthesia, traumatic nerve injury, and hereditary and inflammatory neuropathy. a.Improved drug permeability through the barrier interface

[0266] The present dendrimer compositions and methods can improve the delivery of antidepressants and / or antipsychotics across one or more barrier interfaces in the brain and nervous system, particularly the blood-brain barrier (BBB), CSF-blood barrier, and blood-nerve barrier. These barrier interfaces normally protect neurons from blood-borne infectious agents and help maintain water homeostasis and a proper environment for neuronal function in the blood. Due to the clinical importance of antidepressants and antipsychotics, the present dendrimer compositions can be used to deliver antidepressants and / or antipsychotics with improved permeability across these barrier interfaces for site-specific targeting. i. Blood-brain barrier

[0267] The "blood-brain barrier" (BBB) ​​is a continuous endothelial membrane that, together with pericytes and other components of the neurovascular unit, restricts the entry of toxins, pathogens, and blood cells into the brain. However, the BBB also poses an obstacle to drug delivery to the central nervous system (CNS), in part because (1) delivery of drugs targeted to the brain via systemic routes can result in unacceptably high drug levels in the periphery, and (2) the complex interactions of cells and molecules that contribute to the structure and function of the BBB make it difficult to determine drug permeability across the BBB, drug distribution in the brain, and target engagement in the brain.

[0268] Brain microvascular endothelial cells, pericytes, astrocytes, tight junctions, neurons, and basement membrane structures physically stiffen brain capillaries at the BBB. Brain capillary endothelial cells lack fenestrae, limiting the diffusion of small molecules and proteins. Interendothelial junctions connect endothelial cells to form a continuous barrier, severely restricting the penetration of water-soluble substances. Pericytes, astrocytes, and basement membranes surround endothelial cells, ultimately forming the impermeable BBB. Furthermore, efflux transporters are located in brain capillary endothelial cells, further obstructing the entry of substances into the brain. BBB permeability is primarily controlled by interendothelial junctions, which are protein complexes including adherens junctions, tight junctions, and gap junctions. Adherens junctions primarily regulate the permeability of the endothelial barrier. Tight junctions play a key role in maintaining the permeability barrier between epithelial and endothelial cells, thereby controlling tissue homeostasis. Gap junctions, composed of six connexin molecules, direct electrical and chemical communication between endothelial cells. Finally, instead of having a static structure, the components of the BBB continuously adapt in response to various physiological changes in the brain. The dendrimer compositions and methods of the present application overcome the aforementioned challenges and are suitable for delivering antidepressants and / or antipsychotics across the blood-brain barrier by one or more of the transport mechanisms described above.

[0269] Molecules cross the BBB via the paracellular route (between adjacent cells) or the transcellular route (through cells). In the paracellular route, ions and solutes cross the BBB by passive diffusion, taking advantage of their concentration gradient. The transcellular route involves various mechanisms, such as passive diffusion, receptor-mediated transport, and transcytosis.

[0270] Physicochemical factors affecting BBB permeability include molecular weight, charge, lipid solubility, surface activity, and relative size of molecules. BBB permeability can also be affected by physiological factors such as efflux transporters, e.g., P-glycoprotein (P-gp), enzyme activity, plasma protein binding, and cerebral blood flow. Hydrophilic molecules, such as proteins and peptides, enter the brain via specific receptor- and saturable receptor-mediated transport mechanisms, such as glucose transporter-1 (GLUT-1), insulin transporter, and transferrin transporter. These endogenous transporters are expressed in the luminal and abluminal endothelial cell membranes. Among these transport mechanisms, receptor-mediated transcytosis has been extensively studied for delivering drugs to the brain. The dendrimer compositions and methods of the present application are suitable for delivering antidepressants and / or antipsychotics across the blood-brain barrier via one or more of the above-mentioned mechanistic pathways. ii. Blood-nerve barrier (BNB)

[0271] The blood-nerve barrier (BNB) defines a physiological space within which axons, Schwann cells, and other associated cells of peripheral nerves function, ensuring proper peripheral nerve function and maintaining homeostasis of the endoneurial environment. The BNB consists of endoneurial microvessels within nerve bundles and the surrounding perineurium. Tight junctions between endothelial cells and pericytes in the endoneurial vasculature isolate the endoneurial membrane from the blood, preventing uncontrolled leakage of molecules and ions from the circulatory system into peripheral nerves. Additionally, a diffusion barrier exists within the perineurium, formed by tight junctions between adjacent perineurial cells and the basement membrane surrounding each perineurial cell layer. Endoneurial capillaries and perineurial passages are strict barriers that isolate the endoneurial extracellular environment of peripheral nerves from both the epineurial perifascicular space and the systemic circulation, thus protecting the endoneurial microenvironment from dramatic concentration changes in the vascular space and other extracellular spaces.

[0272] For drug targets located in peripheral nerves, BNBs can be difficult to resolve because they can restrict or prevent drugs from reaching their sites of action, thus negatively affecting drug efficacy. Furthermore, the expression profile of transporters in peripheral nerves can be very different from that in the central nervous system. The dendrimer compositions of the present application can be used to improve the permeability of antidepressants and / or antipsychotics through BNBs, thereby improving the delivery of antidepressants and / or antipsychotics to peripheral nerve targets. iii. Blood-CSF barrier

[0273] The composition may be used to improve the delivery of antidepressants and / or antipsychotics to target sites through the blood-cerebrospinal fluid barrier (blood-CSF barrier) and ventricles. The choroid plexus is a vascular tissue found in all ventricles. The functional unit of the choroid plexus is composed of capillaries surrounded by a layer of differentiated ependymal epithelium. Unlike the capillaries that form the blood-brain barrier, choroid plexus capillaries are fenestrated and do not have tight junctions. Therefore, the endothelium does not form a barrier to the movement of small molecules. Instead, the blood-CSF barrier in the choroid plexus is formed by epithelial cells and the tight junctions that connect them. The other part of the blood-CSF barrier is the arachnoid membrane that surrounds the brain. The cells of this membrane are also connected by tight junctions.

[0274] The CSF space and brain structures adjacent to the CSF compartment are pathological targets of interest in CNS disorders. For example, the subarachnoid perivascular or periventricular space is an area where pathogenic lymphocytes, monocytes, and neutrophils accumulate in neuroinflammatory disorders such as multiple sclerosis and related experimental autoimmune encephalitis or viral-induced neuropathies (including neuroAIDS and CMV infection). Nests of potentially harmful antibody-producing B cells found in various CNS autoimmune diseases are thought to be primarily localized in the pia mater. Therefore, in some configurations, the dendrimer compositions can be used to deliver antidepressants and / or antipsychotics to areas of interest via the blood-CSF space connected to deep cervical lymph nodes to ameliorate or treat symptoms associated with neuroinflammatory disorders.

[0275] In some embodiments, the dendrimer compositions can be used to deliver antidepressants and / or antipsychotics to target sites to improve or treat symptoms and conditions associated with vascular degeneration. For example, cerebral amyloid angiopathy induces degenerative vascular changes driven by the deposition of amyloid beta (Aβ) peptide, cystatin c, transthyretin, or gelsolin around penetrating blood vessels. The deposits are accessible from the interconnected CSF / perivascular space.

[0276] In some embodiments, dendrimer compositions can be used to deliver antidepressants and / or antipsychotics to target sites to improve or treat symptoms and conditions associated with tumor development. For example, periventricular tumors, including myeloma, drug-resistant ependymomas, and leptomeningeal tumor metastases derived from peripheral primary tumors, all have direct contact with the CSF. As a result of the reduced efficacy of tight junctions, which allow contrast enhancement in magnetic resonance imaging, the blood-tumor barrier is often considered leaky. However, many antidepressants and / or antipsychotics are lipophilic and are prevented from crossing the BBB by multidrug resistance (MDR) efflux proteins that control the transcellular pathway. In some periventricular tumors, such as ependymomas, MDR proteins remain fully expressed in the blood-tumor barrier. Therefore, in some embodiments, dendrimer compositions can be used to utilize pharmacological pressure from the CSF to achieve therapeutic concentrations of antidepressants and / or antipsychotics in tumor tissue. b. Improved target-specific binding

[0277] The compositions can be used to target serotonin (5HT) receptors, e.g., 5HT-1A, 5HT-2B, 5HT-2A, 5HT-2B, 5HT-2C, 5HT-3, 5HT-4, one or more norepinephrine (NE) receptors, e.g., α 1A Adrenergic receptor, alpha 1B -adrenergic receptor, α 1D -adrenergic receptor, α 2A -adrenergic receptor, α 2B -adrenergic receptor, α 2CThe dendrimer compositions can be used to modulate one or more of the following transporters: GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, GLUT12, GLUT13, and GLUT14, thereby improving binding affinity and specificity to one or more receptors and delivering antidepressants and / or antipsychotics. i. Improved serotonin receptor binding

[0278] The present dendrimer compositions can improve binding to one or both serotonin receptors and modulate signal transduction in a cell- and tissue-specific manner.

[0279] In the central nervous system (CNS), serotonin is produced almost exclusively in neurons originating from the raphe nuclei located in the midline of the brainstem. These serotonin-producing neurons form the largest and most complex efferent system in the human brain. The most caudal raphe innervates the spinal cord, while the more rostral raphes, the dorsal and medial raphe nuclei, innervate most of the rest of the CNS through generalized projections. The vast majority of every cell in the brain is close to serotonergic fibers, and nearly all behavior and numerous other brain functions are regulated by serotonin.

[0280] Serotonin plays several roles in vascular biology, both within the CNS and throughout the body, ranging from regulating vascular resistance and blood pressure to hemostasis and platelet function. Serotonin causes vasoconstriction or vasodilation in various vascular beds, depending on the specific receptors expressed in each vessel wall and surrounding smooth muscle tissue. Thus, in some embodiments, dendrimer-antidepressant compositions can be used to activate 5-HT1B receptors in cerebral blood vessels, promoting vasodilation and providing analgesia in migraine states.

[0281] Platelets have large vesicular stores of serotonin but lack the enzyme to synthesize it. Instead, platelets take up serotonin from plasma via the serotonin transporter. Serotonin is then secreted by platelet dense granules during platelet activation, promoting platelet aggregation and vasoconstriction of surrounding blood vessels, thereby playing a role in promoting hemostasis. Intracellular serotonin also promotes platelet activation by covalently linking small G proteins via tissue transglutaminase. This modification constitutively activates G protein-dependent signaling pathways and stimulates platelet aggregation. Furthermore, serotonin is covalently crosslinked to various adhesion proteins and coagulation factors on the platelet cell surface, a process essential for the activation of small populations of platelets. Therefore, serotonin also acts through noncovalent interactions with membrane-bound receptors.

[0282] Serotonin regulates several different aspects of cardiac function, ranging from electrical conduction to valve closure and post-MI remodeling.Therefore, in some forms, dendrimer-SSRI compositions can be administered to reduce the risk of myocardial infarction.For example, in some forms, this composition can be used as a 5-HT4 antagonist to improve cardiac function and help prevent the pathological remodeling of congestive heart failure.In other forms, this composition can be used as a 5-HT2A antagonist to treat coronary spasm angina and ischemic heart disease, and / or as a 5-HT3 antagonist to treat post-MI pain. ii. Improved noradrenergic receptor binding

[0283] The present dendrimer compositions can improve binding to one or both noradrenergic receptors and modulate signal transduction in a cell- and tissue-specific manner.

[0284] Norepinephrine, also known as noradrenaline, is a brain neurotransmitter that plays an essential role in regulating arousal, attention, cognitive function, and stress response. Norepinephrine also functions peripherally as a hormone as part of the sympathetic nervous system in the "fight-or-flight" response. During states of stress or anxiety, norepinephrine and epinephrine are released and bind to adrenergic receptors throughout the body, exerting effects such as dilating the pupils and bronchioles, increasing heart rate and constricting blood vessels, increasing renin secretion from the kidneys, and inhibiting peristalsis. The noradrenergic system plays a role in the pathogenesis of some serious neuropsychiatric disorders and has become an important pharmacological target in a variety of neuropathological, neurological, and cardiopulmonary disorders.

[0285] The central noradrenergic system consists of two major ascending projections originating in the brainstem: the dorsal noradrenergic bundle (DNB) and the ventral noradrenergic bundle (VNB). The DNB originates from the A6 locus coeruleus, located in the dorsal pons, and is composed primarily of noradrenergic neurons. The DNB serves as the predominant site of norepinephrine production in the central nervous system. The DNB sends projections that exclusively innervate the cerebral cortex, hippocampus, and cerebellum, and has overlapping projections with those from the VNB to innervate regions of the amygdala, hypothalamus, and spinal cord. The VNB originates from nuclei in the pons and medulla and sends projections that innervate the amygdala, hypothalamus, and regions of the midbrain and medulla.

[0286] The sympathetic nervous system and neuroendocrine chromaffin cells (located in the adrenal medulla) are primarily responsible for the synthesis and exocytosis of norepinephrine and other catecholamines into the circulation. Hormones act on alpha- and beta-adrenergic receptors in smooth muscle cells and adipose tissue, located throughout the body.

[0287] After an action potential at the presynaptic terminal, voltage-gated calcium channels are stimulated, resulting in calcium influx from the extracellular space to the intracellular space. This influx causes norepinephrine (stored in vesicles) to bind to the cell membrane and be released into the synaptic cavity by exocytosis. Norepinephrine can then target and bind to three major receptors: alpha-1 (alpha-1), alpha-2, and beta receptors. These receptors are classified as G-protein-coupled receptors, which have either inhibitory or excitatory effects and have different binding affinities for norepinephrine.

[0288] Alpha-1 receptors are further subdivided into alpha-1a, alpha-1b, and alpha-1d receptors. These receptors are located postsynaptically in brain regions, including the locus coeruleus, olfactory bulb, cerebral cortex, dentate gyrus, amygdala, and thalamus. Alpha-1 receptors have a moderate binding affinity for norepinephrine and are coupled to the Gq protein signaling pathway. In this pathway, phospholipase C (PLC) is activated on the cell membrane to convert phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 is released into the cytosol and binds to transmembrane IP3 receptors located in the endoplasmic reticulum (ER), which function as calcium channels. Upon binding, the receptor undergoes a conformational change, resulting in calcium release from the ER into the cytosol. DAG persists in the cell membrane and functions to upregulate protein kinase C (PKC) and phosphorylate other proteins, the combined effects of which result in excitatory cellular effects.

[0289] Alpha-2 receptors are subdivided into alpha-2a, alpha-2b, and alpha-2c receptors. These receptors are located both presynaptically and postsynaptically in brain regions, including the locus coeruleus, amygdala, and hypothalamus. These receptors have the highest binding affinity for norepinephrine and are linked to the Gi / o protein signaling pathway. This pathway reduces cAMP levels, which in turn reduces adenylyl cyclase activity and produces inhibitory cellular effects. Presynaptic noradrenergic terminals contain alpha-2 autoreceptors that block further release of norepinephrine.

[0290] Beta receptors are subdivided into beta-1, beta-2, and beta-3 receptors. These receptors are present in various regions of the brain, with beta-1 and beta-2 receptors being most prevalent in cerebral lipids. These receptors have the lowest binding affinity for norepinephrine and are coupled to the G protein signaling pathway. In this pathway, elevated cAMP levels lead to the activation of protein kinase A (PKA), which then proceeds to phosphorylate other proteins within the cell, resulting in excitatory cellular effects. Beta-2 receptors are also coupled to the Gi protein signaling pathway. Beta-3 receptors are present in adipose tissue.

[0291] In the adrenal medulla, acetylcholine stimulates the release of adrenaline and noradrenaline. Acetylcholine binds to nicotinic acid receptors located on adrenal chromaffin cells, generating an action potential sustained by voltage-gated sodium and potassium channels. This action potential triggers calcium influx into the cytosol, leading to the binding of norepinephrine vesicles to the cell membrane and its release into the circulation, where it travels and binds to alpha and beta receptors on smooth muscle and adipocytes.

[0292] Norepinephrine can be broken down intracellularly or in the synaptic cleft by the enzymes monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT). MAO oxidizes norepinephrine, while COMT metabolizes the deaminated norepinephrine by O-methylation. MAO and COMT are found in adrenal chromaffin cells, while sympathetic nerves contain only MAO. COMT is found in all organs. The liver is responsible for the complete breakdown of norepinephrine to vanillylmandelic acid (VMA). B. The condition to be treated

[0293] The composition is suitable for treating one or more diseases, conditions, and injuries in the central and peripheral nervous systems. The composition can also be used to treat various diseases, disorders, and injuries, including mental health disorders, gastrointestinal disorders, and cardiovascular disorders, and / or other tissues in which nerves play a role in the disease or disorder. The composition and method are also suitable for prophylactic use. For example, the composition can be administered to a patient in need thereof to improve, treat, or prevent symptoms associated with various disorders, diseases, and conditions, including, but not limited to, anxiety disorders, mood disorders, eating disorders, ADHD, personality disorders, stress disorders, and / or psychiatric disorders. In some forms, when the dendrimer is conjugated to one or more antidepressants, the composition can be administered to treat one or more neurological disorders, such as mental health disorders, e.g., mood disorders, anxiety disorders, eating disorders, substance-related disorders, and post-traumatic disorders; degenerative disorders, e.g., Parkinson's disease and Alzheimer's disease; pain disorders, e.g., neuropathic pain, gastrointestinal disorders, and / or cardiovascular disorders. In some embodiments, when the dendrimer is conjugated to one or more antipsychotic drugs, the composition can be administered to treat psychosis occurring in bipolar disorder, schizophrenia, and / or degenerative disorders. In other embodiments, the composition can be administered to subjects who need to stabilize mood, for example, in bipolar disorder, reduce anxiety in anxiety disorders, and reduce tics in Tourette's syndrome. In still other embodiments, the dendrimer is conjugated to one or more antidepressants and / or antipsychotic drugs to treat non-neuronal diseases such as gastrointestinal disorders and cardiovascular disorders.

[0294] The dendrimer complexes are administered in dosage units effective to treat or alleviate conditions associated with pathological conditions in the central and peripheral nervous systems. For example, the dendrimer complexes are administered in dosage units effective to treat or alleviate conditions associated with pathological conditions affecting neurons, microglia, and / or astrocytes. Generally, by targeting these cells, the dendrimers specifically deliver agents to treat neuroinflammation.

[0295] In preferred embodiments, the compositions may comprise glucose or hydroxyl dendrimers having a diameter of 5 nm or less and may be conjugated to antidepressants, antipsychotics, or other agents that act by modulating monoaminergic neurotransmission to treat mental health and CNS disorders. In other preferred embodiments, the compositions may comprise glucose or hydroxyl dendrimers having a diameter of greater than 5 nm and may be conjugated to antidepressants, antipsychotics, or other agents that act by modulating monoaminergic neurotransmission to treat peripheral nervous system disorders. 1. Mental Health Disorders and Conditions

[0296] The compositions and methods are suitable for treating a variety of mental health disorders and conditions, including, but not limited to, affective or mood disorders, anxiety disorders, childhood disorders, eating disorders, personality disorders, schizophrenia and other psychotic disorders, and substance-related disorders. Affective or mood disorders

[0297] Affective or mood disorders are described by marked disruptions of emotion (severe low spirits called depression or severe elevated mood called hypomania or mania). These include bipolar disorder, cyclothymia, hypomania, major depressive disorder, severe mood dysregulation disorder, treatment-resistant depression, persistent depressive disorder, premenstrual dysphoric disorder, seasonal affective disorder, depression associated with a medical illness, and depression induced by substance use or medication.

[0298] In some forms, the compositions may be administered to a subject in need of treatment, prevention, or management of symptoms of major depressive disorder, including, but not limited to, persistent low mood or depression, anhedonia or decreased interest in pleasurable activities, feelings of guilt or worthlessness, loss of energy, poor concentration, changes in appetite, psychomotor retardation or agitation, sleep disturbances, and / or suicidal thoughts. b. Anxiety disorder

[0299] Anxiety disorders involve excessive fear or apprehension as opposed to normal feelings of tension or apprehension, and include generalized anxiety disorder, panic disorder, social anxiety disorder, and various phobia-related disorders.

[0300] Generalized anxiety disorder (GAD) usually involves persistent feelings of anxiety or fear, which can interfere with daily life. It is not the same as occasionally worrying about things or feeling anxious due to stressful life events. People living with GAD experience frequent anxiety for months, sometimes even years. The composition and method are suitable for treating one or more symptoms of GAD, including but not limited to restlessness, fatigue, difficulty concentrating, irritability, headache, muscle pain, stomach pain, or pain of unknown origin, excessive worry, and sleep problems, such as difficulty falling asleep or staying asleep.

[0301] In some embodiments, the composition may be administered to patients in need of treatment, prevention, or management of one or more symptoms associated with panic disorder.Panic disorder is an anxiety disorder characterized by unexpected, recurring episodes of intense fear accompanied by physical symptoms, which may include chest pain, palpitations, shortness of breath, dizziness or abdominal distress, or a sense of loss of control even when there is no obvious danger or trigger.Persons with panic disorder often worry about when their next attack will occur, and actively try to prevent future attacks by avoiding places, situations, or actions associated with panic attacks.Panic attacks may occur frequently, such as several times a day, or infrequently, such as several times a year.The composition and method are suitable for treating one or more symptoms of panic attacks, including, but not limited to, palpitations, excessive sweating, trembling or tingling, chest pain, and difficulty controlling emotions, such as feelings of impending doom and uncontrollable emotions.

[0302] Social anxiety disorder is an intense and persistent fear of being observed and judged by others.For people with social anxiety disorder, the fear of social situations can be so intense that it seems uncontrollable.For some people, this fear can prevent them from going to work, going to school or doing everyday things.The composition and method are suitable for treating one or more symptoms of social anxiety disorder, including but not limited to excessive blushing, sweating or trembling, palpitations, stomach pain, rigid body posture or speaking in an excessively low voice, and self-consciousness or fear of negative judgment.

[0303] Phobia is the strong fear or aversion to certain objects or situations.In some situations, feeling anxiety may be realistic, but the fear that phobia people feel is disproportionate to the actual danger caused by that situation or object.The composition and method are suitable for treating one or more symptoms of phobia, including but not limited to the irrational or excessive worry about encountering the object or situation of fear, the strong immediate anxiety when encountering the object or situation of fear, and the endurance of unavoidable objects and situations with strong anxiety. c. Eating disorders

[0304] Eating disorders are serious, often fatal, illnesses that involve severe disturbances in a person's eating behavior and related thoughts and emotions. Eating disorders involve preoccupations with food, weight, and body shape. Common eating disorders include anorexia nervosa, bulimia nervosa, and binge eating disorder.

[0305] Anorexia nervosa is a condition in which a person avoids food, severely restricts food, or eats only small amounts of certain foods. They may repeatedly weigh themselves. They may view themselves as overweight even when dangerously thin. There are two subtypes of anorexia nervosa: the restrictive subtype and the bulimic subtype. People with the restrictive subtype of anorexia nervosa severely restrict the amount and type of food they consume. People with the bulimic subtype of anorexia nervosa also severely restrict the amount and type of food they consume. In addition, they may have episodes of binge eating and vomiting, eating a large amount of food in a short period of time followed by vomiting or using laxatives or diuretics to expel the food. Symptoms of anorexia nervosa include, but are not limited to, thinning of bones (osteopenia or osteoporosis), mild anemia, and muscle wasting and weakness, brittle hair and nails, dry, yellowish skin, thin hair growth (vellus hair) all over the body, severe constipation, low blood pressure, slowed breathing and pulse rate, damage to the structure and function of the heart, brain damage, multiple organ failure, a drop in internal body temperature, feeling constantly cold, lethargy, sluggishness or constant fatigue, and infertility.

[0306] Bulimia nervosa is a condition in which a person has repeated and frequent episodes of eating abnormally large amounts of food and feels unable to control these episodes. This binge eating is followed by behaviors to counteract the binge eating, such as compulsive vomiting, excessive use of laxatives or diuretics, fasting, excessive exercise, or a combination of these behaviors. People with bulimia nervosa may be slightly underweight, normal weight, or overweight. Symptoms of bulimia nervosa include chronic inflammation and pain in the throat, swelling of the salivary glands in the neck and jaw area, worn tooth enamel and increased tooth sensitivity and tooth decay as a result of exposure to stomach acid, acid reflux and other gastrointestinal problems, intestinal discomfort and irritation due to laxative abuse, severe dehydration due to fluid expulsion, and electrolyte imbalances (too low or too high levels of sodium, calcium, potassium, and other minerals) that can lead to stroke or heart attack. d. Schizophrenia

[0307] The compositions and methods are suitable for treating symptoms associated with schizophrenia.

[0308] Schizophrenia is characterized by persistent delusions (i.e., a person has a fixed belief that something is true, despite evidence to the contrary); persistent hallucinations (i.e., a person can hear, smell, see, touch, or feel things that are not present); experiences of influence, control, or passivity (i.e., experiences that one's feelings, impulses, actions, or thoughts are not generated by oneself but are placed in or extracted from one's mind by others, or that one's thoughts are being spread around to others); disorganized thinking (this is often observed as disorganized or unrelated speech); highly disorganized behavior (e.g., a person does things that seem strange or purposeless, or has unpredictable or inappropriate emotional reactions that interfere with the person's ability to organize their behavior); "negative symptoms" (such as very limited speech, restricted experience and expression of emotions, inability to experience interest or pleasure, and social withdrawal); and / or significant impairment in the way one perceives reality and changes in behavior associated with extreme agitation or slowed movements, or maintaining abnormal postures.

[0309] Antipsychotic drugs are the mainstay of pharmacological treatment for schizophrenia. Therefore, the composition is suitable for treating one or more of the above-mentioned positive symptoms, negative symptoms, cognitive symptoms, confusion symptoms and mood symptoms in a subject in need thereof. 2. Neurological and neurodegenerative diseases

[0310] The compositions and methods are suitable for treating symptoms associated with neurological and neurodegenerative diseases.

[0311] Neurodegenerative diseases are chronic, progressive disorders of the nervous system that affect neurological and behavioral functions and involve biochemical changes that result in distinct histopathological and clinical syndromes (Hardy H, et al., Science. 1998;282:1075-9). Abnormal proteins that resist cellular degradation accumulate within cells. The pattern of neuronal loss is selective, in the sense that one group is affected while others remain intact. In many cases, there is no clear precipitating event for the disease. Diseases traditionally described as neurodegenerative include Alzheimer's disease, Huntington's disease, and Parkinson's disease.

[0312] Neuroinflammation, mediated by activated microglia and astrocytes, is a major hallmark of various neurological disorders and represents a potential therapeutic target (Hagberg, H et al., Annals of Neurology 2012, 71, 444; Vargas, DL et al., Annals of Neurology 2005, 57, 67; and Pardo, CA et al., International Review of Psychiatry 2005, 17, 485). Several scientific reports suggest that targeting these cells early in the disease process can reduce neuroinflammation, potentially delaying disease onset and providing a longer therapeutic window for treatment (Dommergues, MA et al., Neuroscience 2003, 121, 619; Perry, VH et al., Nat Rev Neurol 2010, 6, 193; Kannan, S et al., Sci. Transl. Med. 2012, 4, 130ra46; and Block, ML et al., Nat Rev Neurosci 2007, 8, 57). Delivering therapeutic agents across the blood-brain barrier (BBB) ​​is challenging. Neuroinflammation causes disruption of the BBB. BBB damage in neuroinflammatory disorders can be exploited to transport drug-loaded nanoparticles through the brain (Stolp, HB et al., Cardiovascular Psychiatry and Neurology 2011, 2011, 10; and Ahishali, B et al., International Journal of Neuroscience 2005, 115, 151).

[0313] The present compositions and methods can also be used to deliver active agents for treating neurological or neurodegenerative diseases, or neurological or neurodegenerative disorders, or central nervous system disorders.In a preferred embodiment, the present compositions and methods are effective for treating and / or improving neuroinflammation associated with neurological or neurodegenerative diseases, or neurological or neurodegenerative disorders, or central nervous system disorders, or peripheral symptoms caused by neurological or neurodegenerative diseases, or neurological or neurodegenerative disorders.The present methods generally include administering an effective amount of the composition to a subject to improve cognition or reduce cognitive decline, improve cognitive function or reduce cognitive decline, improve memory or reduce memory decline, improve learning skills or learning ability, or reduce decline in learning skills or learning ability, or a combination thereof.

[0314] Neurodegeneration refers to the progressive loss of neuron structure or function, including neuron death.For example, the present compositions and methods can be used to treat the subject with diseases or disorders such as Parkinson's disease (PD) and PD-related disorders, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and other dementia, multiple sclerosis (MS), post-encephalitic dementia, cancer and chemotherapy-related cognitive impairment and dementia, and depression-induced dementia and pseudodementia. 3.Pain

[0315] The present compositions and methods are suitable for treating neuropathic and / or non-neuropathic pain associated with various disorders, such as complex regional pain syndrome, peripheral neuropathy, multiple sclerosis, and sciatica. For example, tricyclic antidepressants (TCAs) are effective in treating neuropathic (chronic) nerve pain. Chronic nerve pain, also known as neuropathic pain, is caused by nerve damage or other problems involving the nerves and often does not respond to standard painkillers, such as paracetamol. In some forms, the present compositions can be used to treat chronic pain cases that do not involve nerves (non-neuropathic pain). For example, the present dendrimer compositions can be complexed with TCAs, SSRIs, and / or serotonin-noradrenaline reuptake inhibitors (SNRIs) and used to treat chronic non-neuropathic pain. Conditions causing non-neuropathic pain that may benefit from treatment with the compositions include, but are not limited to, fibromyalgia, chronic back pain, and chronic neck pain. 4. Gastrointestinal disorders

[0316] The compositions and methods are suitable for treating gastrointestinal disorders and / or digestive disorders.

[0317] Functional gastrointestinal (GI) disorders and motility disorders are the most common GI disorders in the general population. Functional GI disorders are disorders of gastrointestinal-brain interaction. They are a group of disorders classified by GI symptoms related to any combination of changes in central nervous system (CNS) processing, such as motility disorders, visceral hypersensitivity, altered mucosal and immune function, altered intestinal microflora, and difficulty in the brain's ability to regulate pain signals from the GI tract. The term "functional" generally applies to disorders in which the body's normal activity is impaired regarding bowel movements, intestinal nerve sensitivity, or the way the brain controls some of these functions. In some forms, the composition can be administered to treat bowel disorders and / or abdominal pain, such as irritable bowel syndrome (IBS), functional abdominal bloating / distention, constipation, diarrhea, and / or opioid-induced constipation. In the case of IBS, a person's perception and interpretation of these activities may be abnormal (abnormal perception). In some forms, the compositions may be administered to treat centrally mediated disorders of gastrointestinal pain, such as central abdominal pain syndrome (CAPS) and / or narcotic bowel syndrome (NBS) / opioid-induced GI hyperalgesia. 5. Irritable bowel syndrome

[0318] IBS is characterized by abnormal changes in intestinal muscle movement (dysmotility), increased sensations caused by intestinal activity (visceral hypersensitivity), and brain-gastrointestinal dysfunction, particularly the brain's difficulty controlling pain signals from the GI tract. Instead of normal digestive muscle activity (motility), IBS patients may experience cramps and spasms. Motility that is too fast can result in diarrhea, while motility that is too slow can result in constipation. These two conditions can also cause abdominal discomfort or pain in IBS patients. Motility abnormalities can also be accompanied by abdominal cramps, belching, urgency, or other unpleasant GI symptoms.

[0319] In patients with IBS, the nerve sensitivity of the GI tract may also be increased. This can occur after a gastrointestinal infection or surgery that causes damage to the nerves in the intestines. This results in a lowered threshold for experiencing intestinal sensations, leading to abdominal discomfort or pain. In patients with visceral hypersensitivity, even ingesting a small amount of food can stretch the intestines and cause discomfort.

[0320] When nerve impulses from the gastrointestinal tract reach the brain, they may be perceived as more or less severe based on the regulatory activity of the brain-gastrointestinal axis. Pain or discomfort signals travel from the intestines to the brain. The brain can "turn down" pain by sending signals that block nerve impulses originating in the GI tract. In patients with IBS, this ability to turn down pain is impaired. Furthermore, pain can be more severe if an individual is experiencing psychological distress. Often, this can occur due to stress in life or even the stress and frustration of GI symptoms. Such brain-gastrointestinal dysfunction can be treated with either psychological treatment or antidepressants, or a combination of both.

[0321] Therefore, dendrimer-antidepressant compositions can be used as effective analgesics (pain-relieving drugs) for treating the symptoms of IBS and other functional GI disorders.In some forms, dendrimer-antidepressant compositions are effective in treating abdominal pain and relieving other IBS symptoms, such as diarrhea, constipation, bloating, nausea, or urgency.For example, dendrimer-antidepressant conjugates can be useful for regulating abnormal bowel function, such as diarrhea and constipation, and other IBS symptoms.In other forms, dendrimer-antidepressant conjugates can contain tricyclic antidepressants (TCAs), such as amitriptyline (Elavil), imipramine (Tofranil), desipramine (Norpramin), and nortriptyline (Pamelor), to treat diarrhea.In yet another example, dendrimer-antidepressant conjugates can contain serotonin reuptake inhibitors (SSRIs) to treat constipation. In exemplary embodiments, the dendrimer-antidepressant conjugates may also be useful for other problems such as anxiety and depression that are often associated with chronic pain disorders. 6. Sleep disorders

[0322] The compositions and methods are suitable for treating or managing symptoms associated with sleep disorders and / or sleep disturbances, including, but not limited to, insomnia, restless legs syndrome, narcolepsy, and sleep apnea.

[0323] In some embodiments, the compositions and methods are also suitable for treating symptoms associated with narcolepsy. Narcolepsy is a rapid-onset rapid eye movement (REM) sleep disorder characterized by excessive daytime sleepiness (EDS), frequent uncontrollable sleep attacks, and sleep fragmentation, and may be accompanied by cataplexy, sleep paralysis, and hypnagogic hallucinations. Two types exist: narcolepsy type 1 (formerly known as narcolepsy with cataplexy) and narcolepsy type 2 (formerly known as narcolepsy without cataplexy). In some embodiments, the compositions and methods can be administered to patients in need thereof to treat or manage one or more symptoms of cataplexy, including seizures (especially cataplexy), periodic limb paralysis, cardiogenic syncope, orthostatic syncope, neurogenic syncope, and / or psychotic symptoms. In some embodiments, the compositions and methods can be administered to patients in need thereof to treat or manage excessive daytime sleepiness in narcolepsy patients. In some forms, the compositions and methods can be administered to a patient in need thereof to treat or manage depression and / or anxiety symptoms in a patient with narcolepsy. 7. Neurodevelopmental disorders and attention deficit disorder

[0324] The compositions and methods are suitable for treating or managing symptoms associated with attention deficit disorders, such as attention deficit hyperactivity disorder, autism spectrum disorder, Tourette's syndrome, sensory integration disorder, auditory processing disorder, and other specific learning disorders.

[0325] In some embodiments, the composition can be administered to a patient in need thereof to treat or manage symptoms associated with developmental disorders, such as autism spectrum disorder. Autism spectrum disorder (ASD) encompasses a spectrum of neurodevelopmental disorders. This spectrum is characterized by repetitive patterns of behavior, interests, activities, and problems in social interactions. ASD is a complex neurodevelopmental disorder characterized by behavioral and psychological problems in children. These children have minimal adaptive abilities, and become distressed when their surrounding environment changes. Symptoms are present from early childhood and affect daily functioning. Children with ASD have a higher rate of comorbid language disorders, intellectual disabilities, and epilepsy than the general population.

[0326] In some forms, the composition can be administered to patients in need of treatment or management of symptoms related to attention deficit / hyperactivity disorder (ADHD).ADHD is one of the most common neurodevelopmental disorders, usually first diagnosed in childhood and often persists into adulthood. Individuals with ADHD may have problems paying attention, controlling impulsive behavior (may act without thinking about the consequences), or become overly active.ADHD symptoms include, but are not limited to, inattention, such as confusion, problems concentrating on tasks, constant daydreaming, and not paying attention when spoken to directly; impulsivity, such as making snap decisions without thinking about potential harm or long-term consequences, often acting quickly to obtain immediate benefits, and frequently interrupting others; and hyperactivity, such as squirming, fidgeting, hitting, talking, and constant movement, especially in inappropriate situations.

[0327] Tourette's syndrome, also known as Tourette's disorder, is a common neurodevelopmental disorder affecting up to 1% of the population. Tourette's syndrome is characterized by multiple motor and vocal tics and begins in childhood. In some forms, the composition may be administered to patients in need thereof to treat or manage symptoms associated with Tourette's syndrome, including, but not limited to, simple tics, such as sudden, short, repetitive movements involving a limited number of muscle groups, e.g., eye blinking and other eye movements, grimacing, shrugging, and head or shoulder jerks, repeated throat clearing, sniffing, barking, or moaning, and / or complex tics, such as discrete, coordinated movement patterns involving several muscle groups, e.g., head twisting, shrugging, and simultaneously grimacing, sniffing or touching an object, jumping, jumping up and down, bending or twisting, repeating one's own words or phrases, repeating the words or phrases of others (called echolalia), or, more rarely, using vulgar, obscene, or foul language (called coprolalia). C. Dosage and Effective Amount

[0328] In some in vivo procedures, the dendrimer complex is administered to a subject in a therapeutically effective amount. The term "effective amount" or "therapeutically effective amount" refers to a dosage sufficient to treat, inhibit, or alleviate one or more symptoms of the disorder being treated, or to achieve other desired pharmacological and / or physiological effect. The exact dosage will vary according to various factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder, and the treatment being performed.

[0329] Generally, the dosage of the composition may be about 0.001 to about 100 mg / kg, about 0.01 to about 100 mg / kg, about 0.1 mg to about 10 mg / kg, or about 0.5 mg to about 5 mg / kg of body weight of the subject to be treated. The subject is typically a mammal, most preferably a human.

[0330] For example, the dendrimer conjugate composition may be in an amount effective to deliver one or more active agents to cells at or near the site of inflammation, particularly inflammation of the central nervous system or inflammation of the eye. Thus, in some embodiments, the dendrimer conjugate composition comprising one or more active agents is in an amount effective to ameliorate inflammation in a subject. In preferred embodiments, an effective amount of the dendrimer conjugate composition does not induce significant cytotoxicity in cells of a subject compared to an untreated control subject. Preferably, the amount of the dendrimer conjugate composition is effective to prevent or reduce inflammation and / or further associated symptoms of a disease or disorder in a subject compared to an untreated control.

[0331] Generally, the timing and frequency of administration will be adjusted to balance the efficacy of a given treatment or diagnostic schedule with the side effects of a given delivery system. Exemplary administration frequencies include continuous infusion, single administration, and multiple administrations, such as hourly, daily, or weekly administration.

[0332] In some embodiments, the dosage is administered to a human once, twice, or three times daily, or every other day, every two days, every three days, every four days, every five days, or every six days. In some embodiments, the dosage is administered about once or twice every week, every two weeks, or every three weeks. In some embodiments, the dosage is administered about once or twice every month, every two months, every three months, every four months, every five months, or every six months.

[0333] It will be understood by those skilled in the art that the dosage regimen can be of any length of time sufficient to treat the disorder in the subject. The term "long-term" means that the length of time of the dosage regimen can be hours, days, weeks, months, or possibly years.

[0334] In some embodiments, the regimen includes one or more cycles of treatment followed by a rest period (e.g., drug-free). The treatment round may be, for example, a round of administration as discussed above. Similarly, the rest period may be 1, 2, 3, 4, 5, 6, or 7 days; or 1, 2, 3, 4 weeks, or 1, 2, 3, 4, 5, or 6 months.

[0335] The dendrimer complexes may be administered in combination with one or more additional therapeutically active agents known to be capable of treating the conditions or diseases discussed above. D. Control

[0336] The effect of the dendrimer conjugate composition can be compared to a control. Suitable controls are known in the art and include, for example, untreated cells or an untreated subject. In some embodiments, the control is an untreated tissue derived from a treated or untreated subject. Preferably, the control cells or tissue are derived from the same tissue as the treated cells or tissue. In some embodiments, the untreated control subject suffers from or is at risk of suffering from the same disease or condition as the treated subject. E. Combination Therapy

[0337] The dendrimer complex composition can be administered alone or in combination with one or more additional active agents as part of a therapeutic or preventative treatment regimen, including other antidepressants or psychedelic agents, cannabinoids, or psychedelics. The dendrimer complex composition can be administered on the same day as the second active agent, or on a different day. For example, a composition containing the dendrimer complex composition can be administered on day 1, day 2, day 3, or day 4, or a combination thereof.

[0338] The terms "combination" or "combined" are used to refer to either simultaneous, parallel, or sequential administration of two or more agents. Thus, combinations can be administered simultaneously (e.g., as an admixture), separately but in parallel (e.g., through separate intravenous lines to the same subject), or sequentially (e.g., one of the compounds or agents is administered first, followed by the second). VI. Kit

[0339] The composition can be packaged in a kit.The kit can include a single-dose or multiple-dose composition, comprising one or more antidepressants and antipsychotics associated with or conjugated to a dendrimer (for example, one or more hydroxyl-terminated PAMAM dendrimers or glucose dendrimers described in the examples), and instructions for administering the composition.Specifically, the instructions instruct to administer an effective amount of the dendrimer composition to an individual with a specific disease / disorder that is indicated.The composition can be formulated as described above with reference to a specific treatment method, and can be packaged in any convenient manner.

[0340] The present invention will be further understood by reference to the following non-limiting examples. [Example]

[0341] Example 1 Synthesis of hydroxyl-polyamidoamine (PAMAM-OH) dendrimers conjugated to antipsychotic / antidepressant drugs Conjugation of PAMAM-OH to one or more antipsychotic or antidepressant drugs is described below. Selective serotonin reuptake inhibitor (SSRI) drugs are used as exemplary drugs. Exemplary SSRIs include fluoxetine (PROZAC®), paroxetine (PAXIL®), venlafaxine, citalopram (CELEXA®), and the like.

[0342] The synthesis of PAMAM-OH-SSRI conjugates is achieved using a combination of linking chemistries and linkers (both cleavable and non-cleavable). Briefly, the surface hydroxyl groups of PAMAM-OH are modified with a linker to provide complementary groups on the surface that can further react with complementary groups on the drug-linker. Meanwhile, the drug is modified with a linker that provides a complementary functional group for reaction with the dendrimer-linker. The linker on the drug is attached by a cleavable or non-cleavable linking group. Examples of cleavable linking groups include esterase-sensitive ester bonds, glutathione-sensitive disulfide bonds, phosphatase-sensitive phosphodiester bonds, lysosomal-releasable triglycyl peptide linkers (CX), and acid-cleavable hydrazine linking groups. Examples of non-cleavable linking groups include ether, aminoalkyl, or amide bonds. The linker may be an amino acid, peptide, polyethylene glycol (n = 2-15), or a hydrocarbon chain. 1. Synthesis of Hydroxyl-Terminated PAMAM Dendrimer-Fluoxetine (PROZAC®) Conjugates Using Non-Cleavable Linkers

[0343] PAMAM dendrimer-fluoxetine (Prozac) conjugates bearing non-cleavable linking groups were prepared according to the reactions illustrated in Figures 1A and 1B, which are schematic diagrams showing exemplary synthetic routes for conjugating fluoxetine to dendrimers using click chemistry. 2. Synthesis of Hydroxyl-Terminated PAMAM Dendrimer-Paroxetine (PAXIL®) Conjugates Using Non-Cleavable Linkers

[0344] PAMAM dendrimer-paroxetine (Paxil) conjugates bearing non-cleavable linking groups were prepared according to the reactions illustrated in Figures 2A and 2B, which are schematic diagrams showing exemplary synthetic routes for conjugating paroxetine to dendrimers using click chemistry. 3. Synthesis of Hydroxyl-Terminated PAMAM Dendrimer-Venlafaxine Conjugates Using Enzymatically Cleavable Linkers

[0345] PAMAM dendrimer-venlafaxine conjugates bearing enzymatically cleavable ester linkers were prepared according to the reactions illustrated in Figures 3A and 3B, which are schematic diagrams showing exemplary synthetic routes for conjugating venlafaxine to dendrimers using click chemistry. 4. Synthesis of Hydroxyl-Terminated PAMAM Dendrimer-Venlafaxine Analogue Conjugates Using Non-Cleavable Linking Groups

[0346] PAMAM dendrimer-venlafaxine analog conjugates bearing non-cleavable amide linkers were prepared according to the reactions illustrated in Figures 4A and 4B, which are schematic diagrams showing exemplary synthetic routes for conjugating venlafaxine analogs to dendrimers using click chemistry. 5. Synthesis of Hydroxyl-Terminated PAMAM Dendrimer-Citalopram (CELEXA®) Analog Conjugates Using Non-Cleavable Linkers

[0347] PAMAM dendrimer-citalopram (Celexa) conjugates bearing non-cleavable amide linkers were prepared according to the reactions illustrated in Figures 5A and 5B, which are schematic diagrams showing exemplary synthetic routes for conjugating citalopram to dendrimers using click chemistry. Example 2 Synthesis of glucose dendrimers (GD) conjugated to antipsychotic / antidepressant drugs

[0348] Conjugation of glucose dendrimers (GDs) to one or more antipsychotic or antidepressant drugs is described below. Selective serotonin reuptake inhibitor (SSRI) drugs are used as exemplary drugs. Exemplary SSRIs include fluoxetine (PROZAC®), paroxetine (PAXIL®), venlafaxine, citalopram (CELEXA®), and the like.

[0349] The synthesis of GD-SSRI conjugates is achieved using a combination of various linking chemistries and linkers (both cleavable and non-cleavable). Briefly, the surface hydroxyl groups of GD are modified with a linker to provide complementary surface groups that can further react with complementary groups on the drug-linker. Meanwhile, the drug is modified with a linker that provides a complementary functional group for reaction with the dendrimer-linker. The linker on the drug is attached via a cleavable or non-cleavable linking group. Examples of cleavable linking groups include esterase-sensitive ester bonds, glutathione-sensitive disulfide bonds, phosphatase-sensitive phosphodiester bonds, lysosomal-releasable triglycyl peptide linkers (CX), and acid-cleavable hydrazine linking groups. Examples of non-cleavable linking groups include ether or amide bonds. The linker can be an amino acid, peptide, polyethylene glycol (n = 2-15), or a hydrocarbon chain. 1. Synthesis of Glucose Dendrimer-Fluoxetine (PROZAC®) Conjugates Using Non-Cleavable Linkers

[0350] Glucose dendrimer-fluoxetine conjugates with non-cleavable linking groups were prepared according to the reactions illustrated in Figure 6. The synthesis of fluoxetine azide is shown in Figure 1A. The synthesis of glucose dendrimer and fluoxetine conjugates is achieved by partially modifying the OH groups of the glucose dendrimer with complementary groups on the surface of the glucose dendrimer, which are then reacted with an azide-containing complementary linker linked to fluoxetine to generate the glucose dendrimer-fluoxetine conjugate (Figure 6). 2. Synthesis of Glucose Dendrimer-Paroxetine (PAXIL®) Conjugates Using Non-Cleavable Linkers

[0351] Glucose dendrimer-paroxetine conjugates with non-cleavable linking groups were prepared according to the reactions illustrated in Figure 7. The synthesis of paroxetine-azide is shown in Figure 2A. The synthesis of glucose dendrimer and paroxetine conjugates is achieved by partially modifying the OH groups of the glucose dendrimer with complementary groups on the surface of the glucose dendrimer, which are then reacted with an azide-containing complementary linker linked to paroxetine to generate the glucose dendrimer-paroxetine conjugate (Figure 7). 3. Synthesis of glucose dendrimer-venlafaxine conjugates using enzymatically cleavable linking groups

[0352] Glucose dendrimer-venlafaxine conjugates with enzymatically cleavable ester linking groups were prepared according to the reactions illustrated in Figure 8. Venlafaxine was first modified with an azide, as shown in Figure 3A. An exemplary synthetic route for glucose dendrimer and venlafaxine conjugates is shown in Figure 8. 4. Synthesis of glucose dendrimer-venlafaxine analogue conjugates using non-cleavable linking groups

[0353] Glucose dendrimer-venlafaxine conjugates with non-cleavable amide linkers were prepared according to the reactions illustrated in Figure 9. Venlafaxine was first modified with an azide, as shown in Figure 4A. An exemplary synthetic route for glucose dendrimer and venlafaxine conjugates is shown in Figure 9. 5. Synthesis of glucose dendrimer-citalopram analogue conjugates using non-cleavable linking groups

[0354] Glucose dendrimer-citalopram analog conjugates with non-cleavable linking groups were prepared according to the reactions illustrated in Figure 10. The citalopram analog was first modified with an azide, as shown in Figure 5A. An exemplary synthetic route for glucose dendrimer and citalopram analog conjugates is shown in Figure 10.

[0355] Unless otherwise stated, reactions were carried out in flame-dried glassware under a positive nitrogen pressure using dry solvents. Commercial-grade reagents and anhydrous solvents were purchased from chemical suppliers and used without further purification. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl), N,N-diisopropylethylamine (DIPEA), 4-(dimethylamino)pyridine (DMAP), trifluoroacetic acid (TFA), anhydrous dichloromethane (DCM), and N,N'-dimethylformamide (DMF) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Cyanine 5 (Cy5)-mono-NHS ester was obtained from

[0356] The solvents were purchased from Amersham Bioscience-GE Healthcare. The deuterated solvents dimethyl sulfoxide (DMSO-d), water (DO), and chloroform (CDCl) were purchased from Cambridge Isotope Laboratories Inc. (Andover, MA). Ethylenediamine-core polyamidoamine (PAMAM) dendrimer, generation 4.0, hydroxy surface (G4-OH; diagnostic grade; consisting of 64 hydroxyl end groups), methanol solution (13.75% w / w) was purchased from Dendritech Inc. (Midland, MI, USA). Dialysis membranes were purchased from Spectrum Laboratories Inc. (Rancho Dominguez, CA, USA). Hu308, tryptamine, 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexanol, nor-ketamine, 5-hydroxytryptamine, psilocybin analogs, psilocyn analogs and cannabidiol drugs were purchased from Cayman Chemicals. Synthesis of hydroxyl-PAMAM dendrimer-drug conjugates

[0357] The PAMAM-G4-OH (D4-OH) dendrimer, consisting of approximately 64 terminal hydroxyl groups, was used in the synthesis. After each synthesis step, the product was purified by dialysis in DMF for 24 hours to remove small molecular weight impurities, followed by water dialysis to remove the DMF. 1 H NMR (in DMSO-d6 and DO) and HPLC analysis were used to confirm the formation and purity of the intermediates and final products. Monofunctional D4-OH was functionalized with alkyne groups by treatment with 5-hexynoic acid under standard esterification conditions using EDC.HCl and 4-DMAP in DMF at room temperature for 36 hours to yield the D-hexyne bifunctional dendrimer. The number of alkyne groups on the dendrimer surface was selected to maintain approximately 10-15 to maintain the overall aqueous solubility of the conjugate. The crude product was dialyzed against ultrapure water for 24 hours using a 1 kDa membrane to remove low molecular weight impurities by selective diffusion through the semipermeable dialysis membrane. 1H NMR and HPLC analysis were used to confirm product formation and purity of intermediates and final products. Synthesis of D-hexyne

[0358] A solution of PAMAM G4-OH 1 (10.00 g, 0.7 mmol) in DMF (50 mL) was treated with 5-hexynoic acid (1.40 g, 12.6 mmol) and DMAP (2.41 g, 12.6 mmol) and stirred for 5 minutes at room temperature. EDC.HCl (1.54 g, 12.6 mmol) was then added portionwise to the reaction mixture over 5 minutes. The reaction mixture was stirred at room temperature for 36 hours. The crude product was transferred to cellulose dialysis tubing with a 1 kD MW cutoff and dialyzed against DMF for 12 hours and then against water for 24 hours. The aqueous layer was frozen and lyophilized to afford D-hexyne as a hygroscopic white solid (75% yield). 1 H NMR (500 MHz, DMSO-d6) 8.21-7.57 (m, internal amide H), 4.71 (s, GABA amide H, 50H), 4.01 (t, 22-24 CH2), 3.5-2.1 (m, dendrimer CH2) 1.71-1.59 (m, 22-24 CH2). HPLC C18 retention time 4 minutes: purity approximately 99%. Synthesis of dendrimer-drug conjugates

[0359] A solution of D-hexyne and drug-azide in DMF (5 mL) was treated with copper sulfate pentahydrate (CuSO4.5H2O) and sodium ascorbate in water. The reaction mixture was stirred and heated at 50 °C for 10 h in a microwave synthesizer. Upon completion, the reaction mixture was dialyzed against DMF in 1 KDa cutoff cellulose dialysis tubing. EDTA (50 μL, 0.5 M) solution was added to the solution to remove copper by chelation. DMF dialysis was followed by water dialysis overnight. Drug loading was calculated by proton integration comparing the peaks corresponding to the dendrimer and drug. G2-glucose dendrimer (GD2)-drug conjugate

[0360] The second-generation glucose dendrimer (GD2) consists of 24 glucose molecules (96 surface hydroxyl groups) used for conjugation. Glucose dendrimers are primarily made up of a central core of di-pentaerythritol and glucose moieties consisting of one or more branching units of monosaccharide glucose molecules. Unlike hydroxyl-terminated PAMAM dendrimers, glucose dendrimers are primarily taken up by injured neurons and have been found to specifically target hyperexcitable neurons in both culture and in vivo mouse models. Synthesis and characterization of glucose dendrimer (GD2)

[0361] GD synthesis began by reacting the hexapropargylated core with AB4, a β-D-glucose-PEG-azide building block, via a click reaction to yield the first-generation glucose dendrimer (GD1). Propargylation of the OH groups on GD1 yielded GD1-acetylene 24, which was reacted with β-D-glucose-PEG-azide to yield the second-generation GD2 with 24 glucose moieties, resulting in 96 surface hydroxyl groups. Furthermore, a Cy5 fluorescent tag was attached onto GD2 via propargylation of approximately 2–3 hydroxyl groups to yield an alkyne-containing GD2 dendrimer. GD intermediates and final products were purified using dialysis. 1 The physicochemical properties of the GD2 dendrimer were also evaluated (Table 2). [Table 2] Synthesis and characterization of GD2-drug conjugates

[0362] Norketamine, tryptamine, venlafaxine, and Hu308 drugs were conjugated to GD2-hexynoic acid dendrimers using a click chemistry strategy. The linker-attached drug moieties were conjugated to glucose dendrimers using a Cu(I)-catalyzed click (CuAAC) reaction in the presence of catalytic amounts of CuSO4.5HO and sodium ascorbate to yield the GD2-drug conjugates. Trace amounts of copper were removed by dialysis against ethylenediaminetetraacetic acid (EDTA). The final GD2-drug conjugates were characterized by NMR and HPLC. Figure 14A is a schematic diagram of the synthesis of a PAMAM dendrimer-norketamine conjugate. Figure 14B is a schematic diagram of the synthesis of a glucose dendrimer-norketamine conjugate.

[0363] Characterization of dendrimer-drug conjugates with venlafaxine and fluoxetine shows that the conjugates are pure and dramatically more water-soluble than the free drugs, >200-fold and >2900-fold, respectively. This improved solubility allows for formulation in saline without the need for relatively toxic formulations. [Table 3-1] [Table 3-2] [Table 4] Example 4 Binding assay of dendrimer-ketamine conjugates Materials and Methods Human serotonin 5-HT2A receptor (agonist radioligand):

[0364] Objective: To evaluate the affinity of compounds for the human 5-HT2A receptor in transfected HEK-293 cells as determined in a radioligand binding assay.

[0365] Experimental protocol: Cell membrane homogenates (30 μg of protein) are incubated with 0.1 nM [125I]DOI in the absence or presence of test compounds in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 10 μM pargyline, and 0.1% ascorbic acid at 22°C for 60 min.

[0366] Non-specific binding is determined in the presence of 1 μM DOI.

[0367] After incubation, samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked in 0.3% PEI using a 96-sample cell harvester (Unifilter, Packard) and rinsed several times with ice-cold 50 mM Tris-HCl. The filters were then dried and the radioactivity was counted in a scintillation counter (Topcount, Packard) using scintillation cocktail (Microscint 0, Packard).

[0368] Results are expressed as percent inhibition of control radioligand specific binding.

[0369] The standard reference compound is DOI, which is tested in each experiment at several concentrations to obtain a competition curve from which the IC50 of DOI is calculated.

[0370] See Bryant, et al. (1996), A novel class of 5-HT2A receptor antagonist: aryl aminoguanidines, Life Sci., 15: 1259. Assay for the human opioid GPCR cell-based antagonist cAMP delta (DOP):

[0371] Objective: To evaluate the efficacy (IC50) and potency (maximal response) of compounds against the human delta (DOP) receptor in stably transfected CHO-K1 cells. The assay principle is a cAMP cell-based assay.

[0372] Experimental protocol: Cells were seeded into white-walled 384-well microplates in a total volume of 20 μL and incubated overnight at 37° C. Before testing the cells, the plate culture medium was replaced with 10 μL of assay buffer (HBSS + 10 mM HEPES).

[0373] Briefly, intermediate dilutions of sample stock solutions were made to generate 4X samples in assay buffer. 5 μL of 4X sample was added to cells and incubated at 37°C for 30 minutes. 5 μL of 4X EC80 in 4X forskolin reagent was added and cells were incubated at 37°C for 30 minutes. The final assay vehicle concentration was 1%. Results are expressed as percent inhibition of control ligand.

[0374] General information [Table 6]

[0375] TA1 Human Trace Amine GPCR Cell-Based Agonist cAMP Assay

[0376] Objective: To assess compound efficacy (EC50) and potency (maximal response) against the human TA1 receptor in stably transfected CHO-K1 cells as determined in a GPCR cell-based cAMP assay.

[0377] Experimental protocol: Prior to testing, cells were seeded into white-walled 384-well microplates in a total volume of 20 μL and incubated overnight at 37°C.

[0378] Prior to testing the cells, the plating medium was replaced with 15 μL of assay buffer (HBSS + 10 mM HEPES). Briefly, intermediate dilutions of sample stock solutions were made to generate 4X samples in assay buffer. 5 μL of 4X was added to the cells and incubated at 37°C for 30 minutes. The final assay vehicle concentration was 1%.

[0379] Results are expressed as percent efficacy relative to the maximal response of the control ligand. General information [Table 7]

[0380] result [Table 5]

[0381] Figure 15A is a graph of the NMDAR1A / 2B antagonist assay for glucose dendrimer-ketamine (IC50 = 4.54 μM), hydroxyl dendrimer-ketamine (IC50 > 100), and norketamine (IC50 = 6.96 μM). Figure 15B is the % binding efficacy of log concentration (micromolar) of compound in a D2L human dopamine GPCR cell-based agonist cAMP assay. Norketamine (filled circles), glucose dendrimer-ketamine EC50 = 13.08 μmolar (open circles), and hydroxyl dendrimer-ketamine EC50 = 4.263 μmolar (triangles). Figure 15C is the % efficacy of log concentration (micromolar) of ketamine in a TA1 human trace amine GPCR cell-based agonist cAMP assay. Norketamine (closed circles), glucose dendrimer-ketamine EC50 = 13.08 micromolar (open circles) and hydroxyl dendrimer-ketamine EC50 = 4.263 micromolar (triangles).

[0382] Significant efficacy data have been obtained with a clinically important drug, a derivative of ketamine (norketamine), which has been tested for depression and addiction. Hydroxyl dendrimer-drugs target these receptors in microglia / macrophages, while glucose dendrimer-drugs target these receptors in both neurons and microglia.

[0383] The conjugate may be active with or without drug release. Binding affinity measures the activity of the intact conjugate. Typically, psychedelic drug conjugates are prepared in a non-release form (e.g., tryptamine, psilocin, psilocybin, ketamine) and are intended to be active in the intact form. This allows the intact conjugate to be released through the kidney without toxicity due to drug release. Alternatively, the intact conjugate can be designed to be released via an analog.

[0384] Both GD-ketamine and HD-ketamine exhibit unique effects that may be beneficial for neuropsychiatric conditions. Both dendrimer-ketamine conjugates exhibit stronger binding to opiate μ, opiate k, and sigma 2 receptors than nor-ketamine, indicating that dendrimer conjugation provides a positive benefit for binding to these receptors. Norketamine does not bind to opioid μ receptors (Ki of 53 μM for GD-ket and 40 μM for HD-ket). The Ki for norketamine against opioid k is 381 μM, which is approximately four-fold better than GD-ket (Ki = 82 μM) and approximately seven-fold better than HD-ket (Ki = 556 μM). The antidepressant effects of ketamine are thought to be mediated by opioid k receptors, and dendrimer conjugation increases its affinity for these receptors.

[0385] Improved binding to sigma 2 receptors based on dendrimer conjugation has also been observed. The greater the binding ability of HD ketamine to sigma 2 receptors, the greater the neuroprotective effect. The mechanism of neuroprotection may be related to increased NGF and BDNF production. Activation of sigma 2 receptors may also be beneficial for neuropsychiatric conditions such as schizophrenia and psychosis. Reduced anxiety and increased antidepressant effects may be observed with sigma 2 receptor targeting. Ketamine binds to sigma 2 receptors at mM concentrations (Pergolizi, 2023; Bonaventura, 2021).

[0386] Binding to the dopamine 2 receptor is only observed with dendrimer-conjugated ketamine. Free norketamine does not appear to bind to the dopamine 2 receptor. Similarly, ketamine also shows no affinity for the dopamine 2 receptor. The dopaminergic effects of ketamine are thought to be indirect. However, glucose dendrimer-ketamine has an RC50 of 13.07 μM at the D2 receptor, while hydroxyl dendrimer-ketamine has an RC50 of 4.3 μM, demonstrating its greater potency. Ketamine's antidepressant and neuroprotective effects are largely mediated by these receptors and dopamine receptors. Ketamine, norketamine, and ketamine metabolites do not appear to have a direct effect on dopamine receptors and do not bind to them. The enhanced activity observed at the D2 receptor in functional assays indicates that dendrimer-ketamine is more potent than an antidepressant.

[0387] GD-ketamine and HD-ketamine exhibit distinct characteristics. Conjugation with hydroxyl dendrimers (HD) compared to glucose dendrimers (GD) appears to alter ketamine's function, which is highly expected. While HD-ketamine does not demonstrate blockage of NMDAR1A / 2B ion channels, GD-ketamine demonstrates that the type of dendrimer conjugated to ketamine is important for the functional differences between them. GD-ketamine also exhibits agonist activity at the 5HT1A receptor, which is not observed in the case of HD-ketamine.

[0388] These results indicate that dendrimer conjugation produces unexpected advantages over free drug for receptor binding and that they depend on dendrimer structure. The microglial targeting of hydroxyl dendrimers and the additional neuronal targeting of glucose dendrimers yields unexpected results with clinical significance.

[0389] The conjugates are targeted to specific receptors on whatever cells they are present on. This includes neurons, microglia, macrophages, and other cells. These receptors can be found anywhere in the brain. Examples include serotonin receptors such as 5HT1A, 5HT2A, and NMDA. Serotonin receptors can also be found on microglia. The compounds bind to and act on these receptors. The "intrinsic cellular targeting" of these dendrimers (hydroxyl dendrimers—microglia / macrophages and glucose dendrimers—to neurons) is somewhat secondary to the action on the specific receptors targeted by the compositions. Important receptors include serotonin receptors [5HT1A, 5HT2A (agonist, antagonist, reverse, or inverse agonist)] and NMDA receptors. In many cases, binding to specific receptors and not binding to other receptors using dendrimers can increase binding potency and reduce the side effects of these drugs.

[0390] Combined with the cell targeting capabilities of glucose dendrimers (e.g., against injured neurons (primary), microglia / macrophages (secondary), or hydroxyl dendrimers (microglia / macrophages)), dendrimer conjugation has demonstrated improved aqueous solubility of >5-200 fold, offering the distinct advantages of modifiable linkages, improved targeting selectivity, ease of formulation and delivery, and reduced side effects.

[0391] Using tryptamine as an example, the binding affinity of drugs conjugated to these dendrimers was shown to have unexpected properties.

[0392] Both hydroxyl and GD dendrimers have OH surface groups. When tryptamine was conjugated to these dendrimers using the same linking chemistry, very different affinities were observed for serotonin and other receptors. The conjugates exhibited lower affinities than the free drug in cell-based binding assays (an indicator of in vivo efficacy). Lower affinity may allow for less robust binding and may modulate the drug's undesirably strong effects on the receptor. Second, the hydroxyl dendrimer conjugate was not active, whereas the glucose dendrimer conjugate was. This was unexpected and may be due to differences in the internal structure of the glucose and hydroxyl dendrimers. The drug may fold within the hydrophobic core of the hydroxyl dendrimer but open outward in the hydrophilic interior of the glucose dendrimer. Example 5 Treatment of Animal Models of Rett Syndrome with Ketamine and Ketamine-Dendrimer Conjugates

[0393] Rett syndrome (RTT) is a genetic neurodevelopmental disorder affecting females, occurring in 1 in 10,000–15,000 live births. Affected females develop normally for 6–18 months but then lose voluntary movement, including speech and manual dexterity. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2, which encodes a protein that binds to methylation sites in genomic DNA, resulting in gene silencing. The symptoms, progression, and severity of Rett syndrome can vary dramatically from person to person. A wide range of disorders can potentially be associated with Rett syndrome. Symptoms generally appear gradual. RTT is usually characterized by a period of normal postnatal growth followed by regression of speech and hand movements, gait abnormalities, irregular hand movements, and slowed head growth. Other diagnostic criteria for RTT include irregular breathing, gastrointestinal and musculoskeletal disorders, seizures, poor sleep, decreased response to physical pain, and behavioral problems.

[0394] Ketamine is a well-established anesthetic that produces "dissociative anesthesia," exerting both central and peripheral effects, including hypnosis, analgesia, and sympathetic activity, leading to hypertension and tachycardia. The primary mechanism is thought to be its role as an antagonist at N-methyl-d-aspartate (NMDA) receptors. Unlike SSRIs and SNRIs, which only have a delayed effect on depression control, this can result in rapid action and response, as observed in the treatment of treatment-resistant depression, MDD, and suicidal ideation. Ketamine is also effective as a treatment for chronic pain, again due to its effect on NMDAR inhibition. However, its increased dopamine release and its role in ketamine also exert neuroprotective effects through non-NMDAR-mediated mechanisms, such as increased BDNF and mTOR. Ketamine also exerts effects on opioid receptors, increasing dopamine. These effects are beneficial for chronic pain, treatment-resistant depression, MDD, and treatment-resistant epilepsy / seizures.

[0395] However, ketamine has several short-term and long-term side effects. At high doses, ketamine can cause respiratory control and systemic side effects such as increased heart rate, high blood pressure, hyperthermia, loss of coordination, dizziness, nausea, vomiting, sensory-perceptual alternation disorders, and a high incidence of auditory and visual hallucinations. More than half of patients treated with ketamine develop and manifest themselves after the effects of ketamine wear off, a phenomenon characterized by euphoria, vivid dreams, hallucinations, illusions, body image and object distortions, and delirium, which can be extremely upsetting and lead to self-harm. Some of these symptoms correlate with those of schizophrenia. Long-term use of ketamine can result in memory impairment and impaired executive function. Ketamine is also addictive, resulting in tolerance and withdrawal and dependence. Due to these significant side effects, ketamine can only be administered in a controlled environment.

[0396] Ketamine has been shown to be effective in a mouse model of Rett syndrome when delivered IP at a large dose of 8 mg / kg daily for 40 days (total dose of 320 mg / kg), improving survival by 50% at postnatal day 80 (Patrizi et al., 2016). Materials and Methods

[0397] The dendrimer conjugates were prepared as described above.

[0398] As reported by Guy et al., Mecp2 null mutant mice develop neurological symptoms mimicking Rett syndrome. Nat Genet. 2001 Mar;27(3):322-6. doi: 10.1038 / 85899. PMID: 11242117. Both Mecp2 null mutant mice and mice lacking Mecp2 in the brain develop severe neurological symptoms at approximately 6 weeks of age.

[0399] Patrizi A, et al. Chronic Administration of the N-Methyl-D-Aspartate Receptor Antagonist Ketamine Improves Rett Syndrome Phenotype. Biol Psychiatry. 2016 May 1;79(9):755-764. doi: 10.1016 / j.biopsych.2015.08.018. Epub 2015 Aug 24. PMID: 26410354; PMCID: PMC7410367 reported a systematic randomized preclinical study of chronic administration of low-dose (8 mg / kg, i.p.) NMDAR antagonist ketamine in Mecp2 null mice, initiated either early at disease onset or after the development of the RTT phenotype. Mice were treated with 8 mg ketamine / kg / day ip from days 15 to 55 or from days 30 to 55 (total dose of 320 mg / kg for 40 days or 200 mg / kg for 25 days). Treatment from day 30 was ineffective, while treatment from day 15 showed some efficacy at a total dose of 320 mg / kg. Experimental paradigm for MECP2 knockout ("KO") mice:

[0400] Treated from 28 days of age (4 weeks old, symptomatic). Untreated animals die around 55-60 days.

[0401] Mice were treated with ketamine or dendrimer-conjugated ketamine, and controls included wild-type, saline-treated, and saline-treated knockout.

[0402] Animals were treated ip twice weekly at 2.5 mg / kg / dose, with a total dose at the time of evaluation (60 days of age) of approximately 22.5 mg / kg.

[0403] Dendrimer ketamine was tested in a Rett syndrome mouse model at a dose of 2.5 mg / kg (ketamine) IP every other week for 8 weeks (total dose of ketamine 40 mg / kg).

[0404] Four-week-old Mecp2 knockout (KO) mice were randomly treated with saline or 2.5 mg / kg i.p. ketamine or D-ketamine (WT-saline, KO-saline, KO-ketamine, KO-D-ketamine groups) every other week for 8 weeks. Neurobehavioral assessments were performed weekly by recording a composite neurobehavioral score (NBS), which includes assessments of mobility, gait, paw grip, tremor, and respiration, each on a 0-3 scale; higher scores indicate worse phenotypes. The D-ketamine-treated group showed a slowing of disease phenotype progression, accompanied by better neurobehavioral scores after treatment, whereas untreated KO mice did not. [Table 8]

[0405] Open field test: Long-term behavioral changes in saline (WT), ketamine, and D-ketamine groups compared to KO-saline at 8.5 weeks of treatment. Motor function was assessed by recording mice in an open field arena (10.5 inches × 19 inches × 8 inches). Mice were recorded in the same room where they were housed to avoid stress and variability in the testing procedure. Each mouse was placed in a clean open field arena and allowed to explore for 10 minutes, and activity was recorded. Animals were placed in the same open field, facing the long wall and 5 cm apart. result

[0406] Animal survival, neurobehavioral score and activity (total distance traveled, speed and time spent in the corner) were assessed.

[0407] Figures 13A and 13B are graphs of the composite neurobehavioral score (Figure 13A) and postnatal survival probability (Figure 13B) of wild-type, knockout saline (control) versus knockout mice treated with dendrimer-ketamine conjugates. Figure 13C is a graph of the composite neurobehavioral score. Figure 13D is a graph of distance traveled (m).

[0408] The dendrimer conjugated with ketamine provides increased efficacy and increased binding to NMDAR without associated side effects.The dose used is significantly lower than that of free ketamine, which reduces side effects.This is tested in a mouse model of Rett syndrome as proof of concept, because Rett syndrome is a disease that increases glutamate production and increases NMDAR expression / activation.

[0409] A significant improvement in survival was observed with D-ketamine compared to untreated and free ketamine-treated animals, with 100% survival up to 90 days of age. Previously published data by others in a similar model showed only 50% survival after treatment with 320 mg / kg ketamine (an 8-fold higher dose).

[0410] A significant improvement in motor function was observed with D-ketamine, with behavior similar to that of normal healthy controls.

[0411] During a 10-minute period in the open field, a significant difference was observed in the total distance traveled by WT compared to KO mice. Significant improvements were also observed in motor function, expressed as an increase in total distance traveled, by D-ketamine-treated KO in the open field test. Significant improvements were observed in maximum speed and time spent in the corner with D-ketamine compared to the KO saline group.

[0412] The video shows a dramatic improvement in phenotype, with D-ketamine-treated KO mice approaching healthy mice.

Claims

1. A composition comprising a dendrimer, preferably a hydroxyl-terminated dendrimer, a sugar-terminated dendrimer, and / or a sugar-based dendrimer, which is covalently conjugated to at least one antidepressant and / or antipsychotic compound, wherein the psychedelic and hallucinogenic agents are not ketamine, methoxetamine, derivatives of ketamine, cannabinoids, ibogaine, or derivatives of cannabinoids or ibogaine.

2. The composition according to claim 1, wherein the covalent conjugation is a covalent linkage between the modified or unmodified surface group or internal group of the dendrimer, which includes an amide, ester, disulfide, ether, or phosphate linking group.

3. The composition according to claim 1, wherein the covalent bond between the dendrimer and the antidepressant and / or antipsychotic compound is cleaved after administration.

4. The composition according to claim 1, wherein the dendrimer is a first to tenth generation (such as the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth generation) glucose dendrimer or polyamidoamine (PAMAM) dendrimer, and preferably, between 40% and 100% of the surface groups are hydroxylated or conjugated to a monosaccharide.

5. The composition according to claim 1, wherein the dendrimer is a glucose dendrimer, preferably a first-generation, second-generation, or third-generation glucose dendrimer.

6. The composition according to claim 1, wherein the dendrimer is a second to seventh generation PAMAM dendrimer modified with a sugar moiety, and the sugar group is selected from the group consisting of glucose, galactose, mannose, and fructose.

7. The composition according to claim 1, wherein the dendrimer is a dendritic polymer, and optionally a superbranched polymer.

8. The composition according to claim 1, wherein the dendrimer is a second to tenth generation PAMAM dendrimer (such as a hydroxyl-terminated PAMAM dendrimer), and preferably more than 40% of the functional groups are in the form of hydroxyl (OH) groups or monosaccharide groups.

9. The composition according to claim 1, wherein the dendrimer is a glucose dendrimer made from a glucose building block and optionally an ethylene glycol building block, having more than 10 surface glucose moieties.

10. The composition according to claim 1, wherein the dendrimer is a galactose dendrimer made from a galactose building block and optionally an ethylene glycol building block, having more than 10 surface sugar moieties.

11. The composition according to claim 1, wherein the dendrimer is a sugar dendrimer made from a sugar building block and optionally an ethylene glycol building block having more than 10 surface sugar moieties, and optionally the sugar building block is mannose or galactose.

12. The composition according to claim 1, wherein the compound is a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), an antipsychotic, an atypical antipsychotic, a tricyclic antidepressant (TCA), a monoamine oxidase inhibitor (MAOI), a benzodiazepine, a beta-blocker (BB), and an anticonvulsant.

13. The composition according to claim 12, wherein the antidepressant is a serotonin receptor antagonist preferably selected from the group consisting of citalopram, escitalopram, fluoxetine, paroxetine, paxiparoxetine, virazodone, sertraline, fluvoxamine, or analogs or derivatives thereof.

14. The composition according to claim 12, wherein the antidepressant is a serotonin and norepinephrine receptor antagonist preferably selected from the group consisting of imipramine, nortriptyline, amitriptyline, doxepin, desipramine, duloxetine, venlafaxine, desvenlafaxine, levomirunacipran, or their analogs or derivatives.

15. The composition according to claim 12, wherein the antidepressant is an MAO-A and / or MAO-B receptor antagonist, and the antidepressant is selected from the group consisting of tranylcypromine, phenelzine, isocarboxazide, and selegiline.

16. The composition according to claim 12, wherein the antidepressant alters the excitation of neurons, and preferably the antidepressant is ganaxolone, minaxolone, zulanolone, or an analog or derivative thereof.

17. The composition according to claim 12, wherein the antidepressant is norepinephrine and a dopamine receptor antagonist, and preferably the antidepressant is bupropion and / or mirtazapine, their analogs or derivatives.

18. The composition according to claim 12, wherein the antipsychotic compound is a typical antipsychotic and / or atypical antipsychotic, preferably the antipsychotic is quetiapine, haloperidol, risperidone, olanzapine, clozapine, or an analog or derivative thereof.

19. The composition according to claim 12, wherein the compound is selected from the group consisting of methylphenidate, amphetamine, atomoxetine, clonidine, guanfacine, biloxazine, or their analogs or derivatives.

20. The composition according to claim 1, wherein the dendrimer-antidepressant and / or antipsychotic composition has at least a 10-fold increase in drug solubility compared to a free antidepressant and / or antipsychotic, or the dendrimer-antidepressant and / or antipsychotic composition reduces the onset of action compared to a free antidepressant and / or antipsychotic.

21. The composition according to claim 1, wherein the dendrimer-antidepressant and / or antipsychotic composition shortens the time to the onset of drug action by 50% or more.

22. The composition according to claim 1, wherein the dendrimer-antidepressant and / or antipsychotic composition reduces the side effects of the free drug.

23. The composition according to claim 1, wherein the dendrimer-antidepressant and / or antipsychotic conjugate further comprises a pharmaceutically acceptable additive.

24. The composition according to any one of claims 1 to 23, comprising a high-order next-generation dendrimer, preferably a third, fourth, fifth, or sixth-order PAMAM dendrimer (such as a hydroxyl-terminated PAMAM dendrimer), a first, second, third, or higher-order glucose dendrimer, or functionalized with PEG, wherein the conjugate is restricted to peripheral circulation.

25. The composition according to any one of claims 1 to 23, wherein the at least one antidepressant and / or antipsychotic compound is conjugated to the dendrimer via a spacer comprising a hydrocarbon (such as alkylene), a diethylene glycol moiety, an oligoethylene glycol chain, a triazole moiety, or a combination thereof, and preferably the spacer comprises a triazole moiety.

26. A composition according to any one of claims 1 to 23, characterized in that the composition is administered to an individual in need thereof, preferably by mucosal administration, enteral administration or injection, preferably by a route selected from the group consisting of intranasal, intravenous, oral, sublingual, subcutaneous, inhalation, transdermal, intraperitoneal or intrathecal.

27. The composition according to claim 26 for preventing or treating depression such as major depressive disorder, treatment-resistant depression and postpartum depression, post-traumatic stress disorder, panic disorder, social anxiety disorder, anorexia nervosa, suicidal ideation, obsessive-compulsive disorder, ADHD or its symptoms, premenstrual dysphoric disorder, anorexia, substance abuse disorder, epilepsy, bipolar disorder, autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, cluster headache, migraine, seizures, fibromyalgia, narcolepsy, obesity, Alzheimer's disease, Tourette syndrome, pain such as neuropathic pain and chronic pain, phobias, and cardiovascular disease, The composition is characterized in that it contains the dendrimer conjugated to or formulated with a therapeutic agent such as a selective serotonin reuptake inhibitor (SSRI), serotonin and norepinephrine reuptake inhibitor (SNRI), norepinephrine-dopamine reuptake inhibitor (NDRI), tricyclic antidepressant (TCA), monoamine oxidase inhibitor (MAOI), benzodiazepine, neurosteroid, antipsychotic, atypical antipsychotic, or other GABA modulator, or analogs thereof, and the composition is delivered by oral, subcutaneous, transdermal, intranasal, intramuscular, intravenous or intrathecal route.

28. The composition according to claim 27, characterized in that administration of the composition treats neuroinflammatory mental health disorders by modulating the activation of receptors in microglial cells.

29. The composition according to claim 27, characterized in that administration of the composition treats mental health disorders by modulating the activation of neuronal receptors.

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