EP4577245A1 - Compositions de dendrimères pour l'administration ciblée d'agents thérapeutiques psychédéliques - Google Patents

Compositions de dendrimères pour l'administration ciblée d'agents thérapeutiques psychédéliques

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Publication number
EP4577245A1
EP4577245A1 EP23772729.2A EP23772729A EP4577245A1 EP 4577245 A1 EP4577245 A1 EP 4577245A1 EP 23772729 A EP23772729 A EP 23772729A EP 4577245 A1 EP4577245 A1 EP 4577245A1
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EP
European Patent Office
Prior art keywords
dendrimer
dendrimers
glucose
composition
ketamine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23772729.2A
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German (de)
English (en)
Inventor
Kannan Rangaramanujam
Sujatha Kannan
Kunal PARIKH
Anjali Sharma
Wathsala LIYANAGE
Preeti VYAS
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Johns Hopkins University
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Johns Hopkins University
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Application filed by Johns Hopkins University filed Critical Johns Hopkins University
Publication of EP4577245A1 publication Critical patent/EP4577245A1/fr
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/595—Polyamides, e.g. nylon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • Psychedelic drugs such as AyA'-DMT/DMT (AfiV- dimethyltryptamine), 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), LSD (lysergic acid diethylamide), MDMA (3,4- methylenedioxymethamphetamine) and psilocybin have had significant value as an entheogen in spiritual, religious (shamanic) and sociocultural rituals in Central and South American cultures for thousands of years.
  • Psychedelic and hallucinogenic drugs such as plant-derived indoleamines (e g., N,N-dimethyltryptamine (DMT), 5-methoxy-DMT (5- MeO-DMT), psilocybin, 4-hydroxy-DMT (psilocin, the active metabolite of psilocybin)), phenylalkylamines (e.g., mescaline and synthetic ‘amphetamines’ such as 2,5-dimethoxy-4-iodoamphetamine (DOI) and 2,5- dimethoxy-4-bromoamphetamine (DOB)), mianserin and semi-synthetic ergolines (e.g., LSD), have shown significant therapeutic potential for treatment of several mental health and neurological disorders (e.g., depression, treatment resistant depression, suicidal ideation, autism, bi-polar disorder, anxiety, drug dependence, substance abuse disorders, post- traumatic stress disorder, obesity, headaches, pain,
  • 5-HT2A is a type of serotonin receptor which is thought to mediate brain plasticity, and is found with high density in areas of the cortex involved in high-level cortical processing (prefrontal cortical regions: cingulate cortex and posterior cingulate cortex).
  • cingulate cortex prefrontal cortical regions
  • posterior cingulate cortex posterior cortical regions
  • Psychedelics have limited access into these critical regions of the brain, and specifically to brain cells and immune cells which are involved in disease processes. Collectively, these issues limit the applicability, efficacy, and translational potential of this class of drugs, and prevent them from realizing their broad therapeutic potential.
  • the group of hallucinogens and dendrimer compositions formulated herein include active ingredients such as: (i) psychedelics, group of serotonergic, typically Schedule I, agonists such as psilocybin, lysergic acid, mescaline; (ii) entactogens, Schedule I monoamine releasers and reuptake inhibitors known to evoke a sense of emotional openness and connection such as 3,4-methylenedioxy-methamphetamine (MDMA), and 3,4- methylenedioxyamphetamine (MDA); (iii) dissociatives, glutamatergic NMDA antagonists such as ketamine, dextromethorphan (DXM) and nitrous oxide; (iv) atypical hallucinogens, with diverse mechanisms such as A 9 - tetrahydrocannabinol (THC) and ibogaine.
  • active ingredients such as: (i) psychedelics, group of serotonergic, typically
  • Dendrimer conjugate compositions that can deliver drugs to receptors on specific cells (neuronal cells, glial cells, macrophages), including targets on their surface and inside them, have been developed. These formulations can enhance the effectiveness of these drugs through superior binding to target receptors, enabling lower doses, leading to new mechanistic insights, reducing side effects, improving solubility, formulation, PK and other aspects of the use of these drugs, opening new clinical avenues of use.
  • Formulations are based on conjugates of the drugs to dendrimers, especially PAMAM (such as G3, G4, G5, and G6 hydroxyl-terminated PAMAM dendrimers) and glucose dendrimers (such as Gl, G2, and G3 glucose dendrimers).
  • PAMAM such as G3, G4, G5, and G6 hydroxyl-terminated PAMAM dendrimers
  • glucose dendrimers such as Gl, G2, and G3 glucose dendrimers.
  • the dendrimers provide enhanced solubility, uptake into the brain and other specific cell types, and selectivity of uptake and receptor binding.
  • FIG. 1A and IB are schematics showing an exemplary synthetic route for dendrimer-psilocin with cleavable ester linkage using click chemistry.
  • Psilocin is first conjugated to a linker with an azide moiety via an ester linkage (FIG. 1A), followed by conjugation to a dendrimer modified with surface alkyne groups via azide-alkyne click reactions (FIG. IB).
  • FIGs. 2A and 2B are schematics showing an exemplary synthetic route for dendrimer-psilocin analog with non-cleavable amide linkage using click chemistry.
  • Psilocin analog is first conjugated to a linker with an azide moiety via an amide linkage (FIG. 2A), followed by conjugation to a dendrimer modified with surface alkyne groups via azide-alkyne click reactions (FIG. 2B).
  • FIGs. 3A and 3B are schematics showing an exemplary synthetic route for dendrimer-ketamine with non-cleavable amino-alkyl linkage using copper-catalyzed alkyne azide click chemistry.
  • Ketamine hydrochloride (1) is first modified with an alkyne (FIG. 3A), followed by conjugation to a dendrimer modified with surface azide groups via azide-alkyne click reactions (FIG. 3B).
  • FIGs. 4A and 4B are schematics showing an exemplary synthetic route for dendrimer-DMT analog with non-cleavable amide linkage using copper-catalyzed alkyne azide click chemistry.
  • N,N dimethyl tryptamine analog (DMT analog) is first conjugated to a linker with an azide moiety via an amide linkage (FIG. 4A), followed by conjugation to a dendrimer modified with surface alkyne groups via azide-alkyne click reactions (FIG. 4B).
  • FIGs. 5A and 5B are schematics of the synthesis of dendrimer-DMT with a non-cleavable amino-alkyl linkage.
  • FIGs. 5A shows DMT drug modified with an alkyne group.
  • FIG. 5B shows conjugation to a dendrimer modified with surface azide groups via azide-alkyne click reactions.
  • FIGs. 6A and 6B are schematics of the dendrimer-lysergic acid diethylamide (dendrimer-LSD) with a non-cleavable amino-alkyl linkage.
  • FIG. 6A show's LSD modified with an alkyne group.
  • FIG. 6B shows conjugation to a dendrimer modified with surface azide groups via azide- alkyne click reactions.
  • FIG. 7 is a schematic of the stepwise synthetic route for the synthesis of glucose dendrimer-psilocin conjugate with a cleavable ester linkage.
  • FIG. 8 is a schematic of the stepwise synthetic route for the synthesis of glucose dendrimer-psilocin analog conjugate with a non-cleavable amide linkage.
  • FIG. 9 is a schematic of the stepwise synthetic route for the synthesis of glucose dendrimer-ketamine conjugate with a non-cleavable amino-alkyl linkage.
  • FIG. 10 is a schematic of the stepwise synthetic route for the synthesis of glucose dendrimer N,N dimethyl tryptamine analog (DMT analog) conjugate with a non-cleavable amide linkage.
  • DMT analog glucose dendrimer N,N dimethyl tryptamine analog
  • FIG. 11 is a schematic of the stepwise synthetic route for the synthesis of glucose dendrimer-DMT analog conjugate with a non-cleavable amino-alkyl linkage.
  • FIG. 12 is a schematic of the stepwise synthetic route for the synthesis of glucose dendnmer-lysergic acid diethylamide (LSD) conjugate with a non-cleavable amino-alkyl linkage.
  • LSD glucose dendnmer-lysergic acid diethylamide
  • FIG. 13 is a schematic overview of the main pharmacological targets of LSD, psilocybin, DMT, MDMA, and ketamine, the signaling cascades involved, hormonal modulation, as well as main behavioral outcomes following their administration in both animals and humans.
  • FIG. 14A is a schematic of the synthesis of a PAMAM dendrimer- norketamine conjugate.
  • FIG. 14B is a schematic of the synthesis of a Glucose dendrimer-norketamine conjugate.
  • FIG. 15B is the % binding efficacy of the log concentration of compound in micromolar in a D2L human dopamine GPCR cell based agonist cAMP assay.
  • Norketamine solid circle
  • glucose dendrimer-ketamine EC50 13 08 micromolar (open circle)
  • hydroxyl dendrimer-ketamine EC50 4.263 micromolar (triangle).
  • FIG. 15B is the % binding efficacy of the
  • 15C is the % efficacy of the log concentration of ketamine in micromolar in the TAI human trace amine GPCR cell based agonist cAMP assay.
  • Norketamine solid circle
  • glucose dendrimer-ketamine EC50 13.08 micromolar
  • hydroxyl dendrimer-ketamine EC50 4.263 micromolar (triangle).
  • FIG. 16A and 16B are graphs of wild type, knock out saline (controls) versus knockout mice treated with dendrimer-ketamine conjuate composite neurobehavior score of (FIG. 16A) and probability of survival over post natal day (FIG. 16B).
  • FIG. 16C is a graph of the distance traveled (m);
  • FIG. 16D is a graph of the speed at which the mice traveled;
  • FIG. 16E is a graph of the time spent in comers.
  • hallucinogen refers to a group of chemically heterogeneous compounds, all with the ability to induce altered states of consciousness (ASC) characterized by profound alterations in mood, thought processes, perception, and experience of the self and environment otherwise rarely experienced except in dreams, contemplative and religious exaltation, and acute psychoses. Not all hallucinogenic compounds reliably produce visual and auditory hallucinations. Therefore, hallucinogens may also be referred to as psychotomimetic (psychosis-mimicking), psycholytic (psycheloosening), or psychedelic (mind-manifesting), reflecting the widely different attitudes and intentions with which these substances have been approached.
  • ASC altered states of consciousness
  • psychedelics refer to a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness. This causes specific psychological, visual, and auditory changes, and often a substantially altered state of consciousness. Psychedelic states are often compared to meditative, psychodynamic or transcendental types of alterations of mind.
  • the “classical” psychedelics, the psychedelics wi th the largest scientific and cultural influence, are mescaline, LSD, psilocybin, and DMT
  • psychedelic drugs fall into one of the three families of chemical compounds: tryptamines, phenethylamines, or lysergamides and many tend to act via serotonin 2A receptor agonism.
  • tryptamines When compounds bind to serotonin 5-HT2A receptors, they modulate the activity of key circuits in the brain involved with sensory perception and cognition, however, the exact nature of how psychedelics induce changes in perception and cognition via the 5-HT2A receptor is still unknown, although reduction in default mode network activity and increased functional connectivity between regions in the brain as a result may be one of the most relevant pharmacological mechanisms underpinning the psychedelic experience, particularly ego death.
  • active agent or “biologically active agent” are used interchangeably to refer to a chemical or biological compound that induces a desired pharmacological and/or physiological effect, which may be prophylactic, therapeutic, or diagnostic. These may be a nucleic acid, a nucleic acid analog, a small molecule having a molecular weight less than 2 kD, more typically less than 1 kD, a peptidomimetic, a protein or peptide, carbohydrate or sugar, lipid, or a combination thereof.
  • the terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of agents, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, and analogs.
  • therapeutic agent refers to an agent that can be administered to treat one or more symptoms of a disease or disorder.
  • diagnostic agent generally refers to an agent that can be administered to reveal, pinpoint, and define the localization of a pathological process.
  • the diagnostic agents can label target cells that allow subsequent detection or imaging of these labeled target cells
  • “Analog” as relates to a given compound refers to another compound that is structurally similar, functionally similar, or both, to the specified compound.
  • Structural similarity can be determined using any criterion known in the art, such as the Tanimoto coefficient that provides a quantitative measure of similarity between two compounds based on their molecular descriptors.
  • the molecular descriptors are 2D properties such as fingerprints, topological indices, and maximum common substructures, or 3D properties such as overall shape, and molecular fields. Tanimoto coefficients range between zero and one, inclusive, for dissimilar and identical pairs of molecules, respectively.
  • a compound can be considered an analog of a specified compound, if it has a Tanimoto coefficient with the specified compound between 0.5 and 1.0, inclusive, preferably between 0.7 and 1.0, inclusive, most preferably between 0.85 and 1.0, inclusive.
  • a compound is functionally similar to a specified compound, if it induces the same pharmacological effect, physiological effect, or both, as the specified compound.
  • “Analog” can also refer to a modification including, but not limited to, hydrolysis, reduction, or oxidation products, of the compounds. Hydrolysis, reduction, and oxidation reactions are known in the art.
  • terapéuticaally effective amount refers to an amount of the therapeutic agent that, when incorporated into and/or onto dendrimers, produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition.
  • One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation.
  • the term “effective amount” refers to an amount of a therapeutic agent or prophylactic agent to reduce or diminish the symptoms of one or more diseases.
  • inhibitor or “reduce” in the context of inhibition, mean to reduce, or decrease in activity and quantity. This can be a complete inhibition or reduction in activity or quantity, or a partial inhibition or reduction. Inhibition or reduction can be compared to a control or to a standard level. Inhibition can be 5, 10, 25, 50, 75, 80, 85, 90, 95, 99, or 100%.
  • dendrimer compositions including one or more inhibitors may inhibit or reduce the activity and/or quantity of diseased neurons by about 10%, 20%, 30%, 40%, 50%, 75%, 85%, 90%, 95%, or 99% from the activity and/or quantity of the same cells in equivalent tissues of subjects that did not receive, or were not treated with the dendrimer compositions.
  • the inhibition and reduction are compared at levels of mRNAs, proteins, cells, tissues, and organs. For example, an inhibition and reduction in the rate of neural loss, in the rate of decrease of brain weight, or in the rate of decrease of hippocampal volume, as compared to an untreated control subject.
  • treating mean to ameliorate, reduce or otherwise stop a disease, disorder or condition from occurring or progressing in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress: and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition.
  • Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.
  • Desirable effects of treatment include decreasing the rate of disease progression, ameliorating, or palliating the disease state, and remission or improved prognosis.
  • an individual is successfully “treated” if one or more symptoms associated with depression are mitigated or eliminated, including, but are not limited to, reducing the level of anxiety, agitation, or restlessness, improving feelings of sadness, tearfulness, emptiness or hopelessness, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease.
  • phrases “pharmaceutically acceptable” or “biocompatible” refers to compositions, polymers, and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier refers to pharmaceutically acceptable materials, compositions, or vehicles, such as a liquid or solid filler, diluent, solvent, or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient.
  • biodegradable generally refers to a material that will degrade or erode under physiologic conditions to smaller units or chemical species that are capable of being metabolized, eliminated, or excreted in vivo.
  • the degradation time is a function of composition and morphology.
  • dendrimer includes, but is not limited to, a molecular architecture with an interior core, interior layers, or “generations” of repeating units regularly attached to this initiator core, and an exterior surface of terminal groups attached to the outermost generation.
  • a molecule may be functionalized by the introduction of a molecule that makes the molecule a strong nucleophile or strong electrophile.
  • targeting moiety refers to a moiety that localizes to or away from a specific location.
  • the moiety may be, for example, a protein, nucleic acid, nucleic acid analog, carbohydrate, or small molecule.
  • the location may be a tissue, a particular cell type, a subcellular compartment, or a molecule such as a receptor.
  • Prolonged residence time refers to an increase in the time required for an agent to be cleared from a patient’s body, or organ or tissue of that patent.
  • “prolonged residence time” refers to an agent that is cleared with a half-life that is 10%, 20%, 50% or 75% longer than a standard of comparison such as a comparable agent without conjugation to a delivery vehicle such as a dendrimer.
  • “prolonged residence time” refers to an agent that is cleared with a half-life of 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, or 10000 times longer than a standard of comparison such as a comparable agent without a dendrimer that specifically target specific cell types.
  • incorporated and “encapsulated” refer to incorporating, formulating, or otherwise including an agent into and/or onto a composition that allows for release, such as sustained release, of such agent in the desired application.
  • the agent or other material can be incorporated into a dendrimer, by binding to one or more surface functional groups of such dendrimer (by covalent, ionic, or other binding interaction), by physical admixture, by enveloping the agent within the dendritic structure, and/or by encapsulating the agent inside the dendritic structure.
  • central nervous system includes the brain and spinal cord.
  • peripheral nervous system refers to the nerves other than in the brain and spinal cord.
  • “Sugar-terminated,” as relates to dendrimers, refers to dendrimers that contain a sugar moiety (such as a saccharide moiety)on their surface and not in their core.
  • a sugar moiety such as a saccharide moiety
  • compositions of dendrimers conjugated or complexed with one or more hallucinogens and/or dissociative compounds for preventing and/or treating symptoms associated with one or more psychological, cognitive, behavioral, mood disorders, and/or non-neurological disorder, in a subject in need thereof, have been developed.
  • compositions are particularly suited for treating and/or ameliorating one or more symptoms of mental health and neurological disorders (e.g., depression (major depressive disorder, treatment-resistant depression, post-partum depression), suicidal ideation, autism, bi-polar disorder, anxiety, drug dependence, substance abuse disorders, post-traumatic stress disorder, obesity, headaches, cluster headaches, migraines, epilepsy, pain, fibromyalgia, obsessive compulsive disorder, anorexia nervosa, inflammation, Alzheimer’s, attention- deficit/hyperactivity disorder, narcolepsy, Tourete’s syndrome).
  • dendrimers are glucose dendrimers or hydroxyl terminated dendrimers such as hydroxyl terminated PAMAM or sugar modified dendrimers.
  • Exemplary psychedelics include psilocin, ketamine (//-ketamine. S- ketamine, (7AS')-kelamine). norketamine, ketamine analogues, ketamine metabolites, N,N dimethyl tryptamine (DMT), 4-acetoxy-N,N-dimethyl tryptamine, 5-methoxy DMT, 5-chloro DMT, lysergide (LSD), 3,4- methylenedioxymethamphetamine (MDMA), psilocybin, ibogaine, mescaline, mianserin and norbaeocystin.
  • DMT N,N dimethyl tryptamine
  • LSD lysergide
  • MDMA 3,4- methylenedioxymethamphetamine
  • psilocybin ibogaine, mescaline, mianserin and norbaeocystin.
  • the hallucinogens and/or their derivatives bind to a receptor on the surface of the target cells and/or a receptor inside the target cells.
  • target cells include, but not limited to, brain cells such as microglia, astrocytes, and/or neurons, for example, those within the site of pathology in the brain or the CNS; cells in the peripheral nervous system, such as peripheral neurons, glia, and/or their supporting cells, e.g., enteric cells, cardiovascular cells, and immune system cells.
  • the microglia and/or astrocytes to which the hallucinogens and/or their derivatives are delivered may be activated or inactive microglia and/or astrocytes.
  • Classic/serotonergic psychedelic compounds also display immunomodulatory properties, and therefore have applications in autoimmune disorders.
  • the hallucinogens and/or their derivatives of the dendrimer-active agent conjugate binds to a target receptor on the surface of the target cell or inside the target cell.
  • the agent when hallucinogens and/or their derivatives binds to the target receptor, the agent remains conjugated to the dendrimer.
  • the agent may be released from the dendrimer or remain conjugated to the dendrimer as an intact dendrimer-active agent conjugate.
  • the hallucinogens and/or their derivatives are released from the dendrimer at close proximity to the target receptor and then binds to the target receptor on the target neural and/or glial cell.
  • Dendrimers are three-dimensional, hyperbranched, monodispersed, globular and polyvalent macromolecules including surface end groups (Tomalia, D. A., et al., Biochemical Society Transactions, 35, 61 (2007); and Sharma, A., et al., ACS Macro Letters, 3, 1079 (2014)).
  • dendrimer includes, but is not limited to, a molecular architecture with an interior core (“GO”) and layers (or “generations”) of repeating units which are attached to and extend from this interior core, each layer having one or more branching points, and an exterior surface of terminal groups attached to the outermost generation.
  • GO interior core
  • generations layers of repeating units which are attached to and extend from this interior core, each layer having one or more branching points, and an exterior surface of terminal groups attached to the outermost generation.
  • dendrimers have regular dendrimeric or “starburst” molecular structures.
  • the dendrimers have a diameter between about 1 nm and about 60 nm, more preferably between about 1 nm and about 50 nm, between about 1 nm and about 40 nm, between about 1 nm and about 30 nm, between about 1 nm and about 20 nm, between about 1 nm and about 10 nm, or between about 1 nm and about 5 nm.
  • the diameter is between about 1 nm to about 2 nm.
  • the preferred size of the dendrimers for crossing the blood brain barrier (“BBB”) is less than 5 nm, whereas those for not crossing the BBB and staying in the peripheral circulation are greater than 5nm.
  • the dendrimers have a diameter effective to penetrate BBB and to be retained close to or within target neural and/or glial cells for delivery of the agents conjugated thereto. In some embodiments, the dendrimers have a diameter effective to penetrate a BBB and to be internalized into target neural and/or glial cells for delivery of the agents conjugated thereto, such as for example, neurons, oligodendrocytes, astrocytes, microglial, and neuroglial support cells.
  • the dendrimers have a diameter effective to penetrate a barrier interface, such as a blood nerve barrier (“BNB”), and to be internalized into neural and/or glial cells of the peripheral nervous system for delivery of the agents conjugated thereto such as for example, neurons, Schwann cells, satellite cells, and neuroglial support cells.
  • BNB blood nerve barrier
  • the dendrimers have a diameter effective to be retained in the peripheral circulation for delivery of the agents conjugated thereto to target cells of the peripheral nervous system e.g., enteric neurons and glia.
  • dendrimer conjugates A major benefit of the use of dendrimer conjugates is the ability of the dendrimer to enhance the binding of the psychedelic drug to its target receptor on target cells, for example, binding of compounds to the serotogenic receptors on neurons in the affected areas of the brain.
  • dendrimers have a molecular weight between about 500 Daltons and about 100,000 Daltons inclusive, between about 500 Daltons and about 50,000 Daltons inclusive, or between about 1,000 Daltons and about 20,000 Daltons inclusive. Dendrimer sizes of less than 30,000 Da are preferred for transport across the BBB, and sizes of greater than 50,000 Da are preferred for confinement to the periphery.
  • the dendrimers have a hypercore (e.g., dipentaerythritol) and one or more monosaccharide branching units.
  • the monosaccharide branching units are conjugated to the core or the pnor layer of monomers via linkers such as polyethylene glycol chains.
  • the hypercore is dipentaerythritol and the monosaccharide branching unit is glucose-based branching unit such as shown in Structures II-IV.
  • the dendrimers are made entirely of glucose building blocks.
  • PAMAM dendrimers modified by sugar may also work, but dendrimers made of sugars, especially glucose, are most preferred.
  • Particularly preferred glucose dendrimers are G1 to G3 glucose dendrimers, such as Gl, G2, and/or G3 glucose dendrimers.
  • Suitable dendnmers scaffolds for use in the conjugates include, but are not limited to, poly(amidoamine), also known as PAMAM, or STARBURSTTM dendrimers; polypropylamine (POP AM), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), aromatic polyether dendrimers, dendrimer of a sugar (e.g., glucose, galactose, mannose, fructose, etc ), and copolymers thereof, such as a copolymer of a sugar and an alkylene glycol (e.g., a dendrimer formed by glucose and ethylene glycol building blocks).
  • POP AM polypropylamine
  • POP AM polyethylenimine
  • polylysine polylysine
  • polyester e.g., iptycene
  • aliphatic poly(ether) aliphatic poly(ether)
  • aromatic polyether dendrimers
  • the dendrimers can have a plurality of surface functional groups, such as carboxylic, amine, hydroxyl, and/or acetamide.
  • surface functional groups and “terminal groups” are used interchangeably herein.
  • the dendrimers have surface hydroxyl groups.
  • one or more of these surface functional groups are further modified with other molecules, such as further modified with a sugar (e.g., glucose, galactose, mannose, fructose, etc.) and/or a polyalkylene glycol, for example, polyethylene glycol, and thus have sugar molecules and/or polyalkylene glycols as terminal moieties/molecules.
  • a sugar e.g., glucose, galactose, mannose, fructose, etc.
  • polyalkylene glycol for example, polyethylene glycol
  • Dendrimers can be any generation including, but not limited to, generation 1 , generation 2, generation 3, generation 4, generation 5, generation 6, generation 7, generation 8, generation 9, or generation 10.
  • the dendrimers are PAMAM dendrimers used as a platform and modified with functional groups for increased number of surface hydroxyl groups.
  • Preferred PAMAM dendrimers include hydroxylated PAMAM dendrimers, particularly G3 to G6 hydroxyl-terminated PAMAM dendrimers, such as G3, G4, G5, and G6 hydroxyl-terminated PAMAM dendrimers.
  • the dendrimer-active agent conjugates can be confined to the peripheral circulation and specifically target a particular tissue region and/or cell type, such as peripheral neural cells, glial cells and/or their supporting cells e.g., enteric neurons and glia, by using higher generation dendrimer (such as generation 4, 5, or 6 PAMAM dendrimer, generation 2, 3, or higher glucose-based dendrimers). Additionally, or alternatively, the dendrimer-active agent conjugates can be confined to the peripheral circulation by appropriate functionalization of the dendrimer (such as PEGylation).
  • the dendrimers can specifically target a particular tissue region and/or cell type of the central nervous system (CNS), the peripheral nervous system (PNS), and/or the periphery, such as neurons and gha of the CNS, and/or neurons and glia of the PNS by using dendrimers of a certain generation, such as PAMAM dendrimers and/or glucose dendrimers of generation 2 (G2), G3, G4, and G5.
  • CNS central nervous system
  • PNS peripheral nervous system
  • G2 glucose dendrimers of generation 2
  • the branching units include monosaccharides.
  • the monosaccharide branching units are conjugated to the core or the prior layer of monomers via linkers such as polyethylene glycol chains.
  • the monosaccharide branching units are glucose-based branching units.
  • the branching units can include PEG and/or alkyl chain linkers between different dendrimer generations.
  • the glucose layers are connected via PEG linkers and triazole rings.
  • the branching units are the same for each generation of dendrimers generated from the core. Therefore, for example, the branching units are glucose-based branching units for generating generation 1 dendrimers, for generating generation 2 dendrimers, and for generating generation 3 dendrimers.
  • the dendrimers have a hypercore such as dipentaerythritol and one or more monosaccharide branching units.
  • the hypercore is dipentaerythntol and the monosaccharide branching unit is glucose-based branching unit.
  • spacer molecules can also be alkyl (CH2)n-hydrocarbon-like units.
  • dendrimers synthesized using glucose building blocks with a surface made predominantly of glucose moieties, specifically targets cells including injured neurons, ganglion cells, and other neuronal cells in the brain, the eye, and/or in peripheral nervous system.
  • the glucose-based dendrimer selectively targets or is enriched inside target neural and/or glial cells.
  • the glucose-based dendrimer selectively targets or enriches the surface of target neural and/or glial cells.
  • the glucose-based dendrimer selectively targets or is enriched inside target neuronal cells and on the surface of the target neural and/or glial cells.
  • the glucose-based dendrimer selectively targets or is enriched inside and/or on the surface of injured, diseased, and/or hyperactive neurons and/or glial cells.
  • the dendrimers include an effective number of sugar molecules and terminal groups, for example, glucose and/or hy droxyl groups, for targeting to one or more neurons and/or glia of the CNS, PNS, and/or the eye.
  • the terminal hydroxyl groups of these dendrimers may be part of terminal glucose molecules or extra hydroxyl groups that are not part of the glucose molecules, or a combination thereof. In some embodiments, all the terminal hydroxyl groups are part of the terminal glucose molecules.
  • the number of sugar molecules on the termination of dendrimer is determined by the generation number.
  • dendrimers are made of glucose and oligoethylene glycol building blocks. Exemplary glucose dendrimers are shown in Structures V and VII.
  • glucose dendrimers include a generation 1 glucose dendrimer having 24 hydroxyl (-OH) end groups, a generation 2 glucose dendrimer having 96 hydroxyl (-OH) end groups, a generation 3 glucose dendrimer having 396 hydroxyl (-OH) end groups, and generation 4 glucose dendrimer having 1584 hydroxyl (-OH) end groups.
  • the glucose dendrimer is a generation 2 glucose-based dendrimer that has 24 glucose molecules at the periphery and 6 embedded glucose molecules in the backbone held together by PEG segments.
  • Dendrimer compositions that can selectively accumulate inside neurons, particularly in the nucleus of injured and/or hyperactive neurons, referred to as “glucose dendrimers” also accumulate at a high level inside activated microglia. However, compared to hydroxyl dendrimers which primarily accumulate in microglia, these dendrimers primarily go to neurons.
  • Glucose dendrimers are described in U.S.S.N. 63/327,610 “Dendrimer Compositions for Targeted Delivery of Therapeutics to Neurons” by The Johns Hopkins University, inventors Kannan Rangaramanujam, Rishi Sharma, Anjali Sharma, Sujatha Kannan, Nimath Sah, Mira Sachdeva, and Siva P. Kambhampati filed April 5, 2022.
  • Glucose dendrimers include (a) a central core, (b) one or more branching units, wherein the branching units are monosaccharide glucose- based branching units, optionally with a linker conjugated thereto; and optionally (c) one or more therapeutic, prophylactic and/or diagnostic agents.
  • the one or more branching units are conjugated to the central core, and the surface groups of the dendrimer are monosaccharide glucose molecules.
  • the central core is dipentaerythritol, or a hexa-propargylated derivative thereof.
  • the branching unit is conjugated to the central core via a linker such as a hydrocarbon or an oligoethylene glycol chain.
  • the branching units are
  • the glucose dendrimer is a generation 1, generation 2, generation 3, generation 4, generation 5, or generation 6 dendrimer.
  • the dendrimer is a generation 1 dendrimer having the following structure:
  • the dendrimer is a generation 2 dendrimer having the following structure:
  • the one or more therapeutic agents, prophylactic agents, and/or diagnostic agents are encapsulated, associated, and/or conjugated in the dendrimer, at a concentration of between about 0.01% to about 30%, preferably about 1% to about 20%, more preferably about 5% to about 20% by weight.
  • the dendrimers may also be conjugated to one or more diagnostic agents such as fluorescent dyes, near infra-red dyes, SPECT imaging agents, PET imaging agents, and radioisotopes.
  • the dendrimer and the agent(s) are conjugated via one or more linkers or coupling agents such as one or more hydrocarbon or oligoethylene glycol chains.
  • linkages are disulfide, ester, ether, thioester, and amide linkages.
  • dendrimers are prepared using methods in which the dendrimer is assembled from a multifunctional core, which is extended outward by a series of reactions.
  • a multifunctional core moiety allows stepwise addition of branching units (i.e., generations) around the core.
  • Exemplary chemical structures suitable as core moieties include dipentaerythritol, pentaerythritol, 2-(aminomethyl)-2-(hydroxymethyl) propane- 1,3 -diol, 2-ethyl-2-(hydroxymethyl) propane-1, 3-diol, 3, 3', 3", 3"'- silanetetrayltetrakis (propane- 1 -thiol), 3,3-divinylpenta-l,4-diene, 3, 3', 3"- nitrilotripropionic acid, 3,3',3"-nitrilotris(N-(2-aminoethyl)propanamide), 3,3',3",3"'-(ethane-l,2-diylbis(azanetriyl)) tetrapropanamide, 3- (carboxymethyl)-3-hydroxypentanedioic acid, 2,2'-((2,2-bis((2- hydroxy ethoxy
  • the core moiety is chitosan.
  • azide-modified chitosan, or alkyne-modified chitosan are suitable for conjugating to branching units using click chemistry.
  • the central core is dipentaerythritol or a hexa-propargylated derivative thereof.
  • the core moiety is ethylenediamine, or tetra(ethylene oxide). In some embodiments, the core moiety is dipentaerythritol. Exemplary chemical structures suitable for use as core moieties are shown in Table 1 below. Table 1. Structural representation of various building blocks (cores, branching units, surface functional groups, monomers) for the synthesis of dendrimers.
  • Exemplary chemical structures suitable as branching units include monosaccharides.
  • the monosaccharide branching units are conjugated to the core or the prior layer of monomers via linkers such as polyethylene glycol chains.
  • the monosaccharide branching units are glucose-based branching units.
  • Exemplary glucose-based branching units are show n in Structures II-IV. These are spacer molecules, so can also be alkyl (CH2)n - hydrocarbon-like units.
  • the branching units are the PEG or alkyl chain linkers between different dendrimer generations, for example, the glucose layers are connected via PEG linkers and triazole rings.
  • the branching units are the same for each generation of dendrimers generated from the core. Therefore, in one embodiment, the branching units are glucose-based branching units for generating generation 1 dendnmers as shown in Structures V-VII.
  • the branching units are hyper-monomers i.e., ABn building blocks.
  • exemplary hyper-monomers include AB4, AB5, AB6, AB7, AB8 building blocks.
  • Hyper-monomer strategy drastically increases the number of available end groups.
  • An exemplary AB4 hypermonomer is peracetylated P-D-Glucopyranoside tetraethylene glycol azide as shown in Structure III.
  • the branching units of the dendrimers are formed by dipentaerythritol. pentaerythritol, 2-(aminomethyl)-2-(hydroxymethyl) propane-1, 3-diol, 2- ethyl-2-(hydroxymethyl) propane-1, 3-diol, 3,3',3",3"'-silanetetrayltetrakis (propane- 1 -thiol), 3,3-divinylpenta-l,4-diene, 3,3',3"-nitrilotripropionic acid, 3,3',3"-nitrilotris(N-(2-aminoethyl)propanamide), 3,3',3",3” , -(ethane-l,2- diylbis(azanetriyl)) tetrapropanamide, 3-(carboxymethyl)-3-
  • branching units of the dendrimers include, but are not limited to, sugar moieties, such as glucose, galactose, mannose, and fructose, and alkylene glycol, such as ethylene glycol, and combinations thereof.
  • the branching unit is chitosan.
  • azide- modified chitosan, or alkyne-modified chitosan are suitable for conjugating to the core moiety or additional same or different branching units using click chemistry.
  • the branching unit is methyl acrylate or ethylenediamine, or a combination thereof.
  • the branching unit is polyethylene glycerol linear or branched.
  • 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.
  • the surface functional groups are hydroxyl groups, for example those of PAMAM dendrimers, of generation 2 OEG dendrimer as shown in Structure I, or of the terminal glucose of dendrimers prepared with glucose-based branching units as shown in Structures V and VII.
  • desired surface functional groups can be modified or added via one of the conjugation methods for the core and branching unit.
  • Exemplary surface functional groups include hydroxyl end groups, amine end groups, carboxylic acid end groups, acetamide end group, and thiol end groups, and combinations thereof.
  • the dendrimers include an effective number of terminal glucose and/or hydroxyl groups for targeting to one or more neurons and/or glia of the CNS, the PNS, and/or the eye. In some embodiments, the dendrimers include an effective number of terminal glucose and/or hydroxyl groups for targeting to one or more non-neural and/or non-glial cells such as gastrointestinal cells, cardiovascular cells, and/or immune system cells.
  • dendrimers are made of glucose and oligoethylene glycol building blocks. Exemplary generation 1 glucose dendrimer is shown in Structure VI, and generation 2 glucose dendrimers is shown in Structure VIII.
  • the dendrimers have a plurality of surface functional groups, such as hydroxyl (-OH) groups, amine groups, acetamide groups, and/or carboxyl groups on the periphery of the dendrimers (also referred to herein as surface functional groups or peripheral functional groups).
  • surface functional groups such as hydroxyl (-OH) groups, amine groups, acetamide groups, and/or carboxyl groups on the periphery of the dendrimers (also referred to herein as surface functional groups or peripheral functional groups).
  • the surface density of such peripheral functional groups is at least 1 group/nm 2 (number of the surface functional groups/surface area in nm 2 ).
  • the surface density of the surface functional groups, such as hydroxyl groups is more than 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 OH groups/nm 2 , such as at least 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50 OH groups/nm 2 .
  • the volumetric density of surface functional groups, such as hydroxyl groups is between about 1 and about 50 groups/nm 3 , between about 5 and about 30 groups/nm 3 , or between about 10 and about 20 groups/nm 3 .
  • the surface density of the surface functional groups is between about 1 and about 50, preferably 5-20 group/nm 2 (number of surface functional groups/surface area in nm 2 ), while each surface functional moiety has a molecular weight of between about 100 Da and about 10 kDa, preferably between about 100 Da and 1000 Da.
  • the amount of the surface functional groups, such as any one of those described above, e.g., hydroxyl groups, of the dendrimer is at least 30%, at least 40%, at least 50%, more than 40%, more than 50%, or in a range from more than 30% to 100%. %. In preferred embodiments, the amount of surface hydroxyl groups of the dendrimer is preferably more than 35%.
  • one or more of the surface functional groups, such as any one of those described above, on the periphery of the dendrimers are further modified by conjugating with one or more carbohydrate molecules and/or more or more polyalkylene glycols, such as polyethylene glycols.
  • the surface density of the terminal carbohydrate moieties/molecules and/or polyalkylene glycols can have any of the ranges described above for hydroxyl groups. Hydroxyl-terminated PAMAM dendrimers, PAMAM dendrimer modified on the surface with sugar moi eties (with >10% of surface groups modified by sugars, especially by glucose, and glucose dendrimers (where the dendrimers are made of glucose building blocks are preferred).
  • constructs with a total molecular weight of ⁇ 30,000 Da are preferred.
  • constructs with a total molecular weight of >50,000 Da are preferred.
  • the terminal hydroxyl groups of these dendrimers may be part of the terminal sugar moieties/molecules or extra hydroxyl groups that are not part of the sugar moieties/molecules, or a combination thereof. In some embodiments, all of the terminal hydroxyl groups are part of the terminal sugar moieties/molecules.
  • the dendrimers include a plurality of hydroxyl groups.
  • Some exemplary high-density hydroxyl groups-containing dendrimers include commercially available polyester dendritic polymer such as hyperbranched 2,2-Bis(hydroxyl-methyl)propionic acid polyester polymer (for example, hyperbranched bis-MP polyester-64-hydroxyl, generation 4), dendritic poly glycerols.
  • the hydroxyl terminated dendrimers include hydroxyl-terminated PAMAM dendrimers, particularly G3 to G6 hydroxyl-terminated PAMAM dendrimers, such as G3, G4, G5, and G6 hydroxyl-terminated PAMAM dendrimers.
  • the high-density hydroxyl groups-containing dendrimers are oligo ethylene glycol (OEG)-like dendrimers.
  • OEG oligo ethylene glycol
  • D2-OH-60 generation 2 OEG dendrimer
  • Highly dense polyol dendrimer at very low generation in minimum reaction steps can be achieved by using an orthogonal hypermonomer and hypercore strategy, for example as described in WO2019094952.
  • the dendrimer backbone has non- cleavable polyether bonds throughout the structure to avoid the disintegration of dendrimer in vivo and to allow the elimination of such dendrimers as a single entity from the body (non-biodegradable).
  • the dendrimers have a plurality of hydroxyl (-OH) groups on the periphery of the dendrimers Tn some embodiments, the surface density of hydroxyl (-OH) groups is at least 1 OH group/nm 2 (number of surface hydroxyl groups/surface area in nm 2 ). For example, in some embodiments, the surface density of hydroxyl groups, per nm 2 , is more than 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 OH groups/nm 2 , such as at least 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50 OH groups/nm 2 .
  • the volumetric density of hydroxyl groups is between about 1 and about 50 groups/nm 3 , between about 5 and about 30 groups/nm 3 , or between about 10 and about 20 groups/nm 3 .
  • the surface density of hydroxyl (-0H) groups is between about 1 and about 50, or between 5 and 20 OH group/nm 2 (number of surface hydroxyl groups/surface area in nm 2 ) while having a molecular weight of between about 100 Da and about 1000 Da.
  • the amount of the surface hydroxyl groups of the dendrimer is preferably greater than 35%, at least 40%, at least 50%, more than 40%, more than 50%, or in a range from more than 40% to 100.
  • the dendrimers may have a fraction of the hydroxyl groups exposed on the outer surface, with the others in the interior core of the dendrimers.
  • the dendrimer specifically targets a particular tissue region and/or cell types following administration into the body. In some embodiments, the dendrimer specifically targets a particular tissue region and/or cell type without a targeting moiety. In some embodiments, the dendrimers include an effective number of hydroxyl groups for targeting CNS cells and/or PNS cells, such as microglial, astrocytes, and/or neurons associated with a disease, disorder, or injury of the central nervous system or the peripheral nervous system. In some embodiments, the dendrimer specifically targets a particular tissue region and/or cell type without a targeting moiety and the active agent conjugated thereto bind directly to a receptor on the surface and/or interior of target neural and/or glial cells.
  • Unmodified PAMAM dendrimers with hydroxyl end groups do not enrich in the neurons of brain and/or retinal ganglion cells (RGCs) in the eye as much as the glucose dendrimers.
  • the glucose dendrimers with terminal glucose monosaccharide and a high density of hydroxyl functional groups effectively target the neurons in a generation dependent manner.
  • Generation 2 (G2), and G3 and G4 should be efficacious.
  • G5 and above are more difficult to use.
  • the dendrimers include an effective number of terminal glucose and/or hydroxyl groups for targeting to one or more neurons of the CNS, or the eye.
  • the hydroxyl groups on the dendrimer surface are part of glucose molecules. There are no extra hydroxyls in addition to the glucose molecules on the surface. The number of sugar molecules on the surface is determined by the generation number. All generations are expected to target neurons.
  • glucose dendrimers include a generation 1 glucose dendrimer having 24 hydroxyl (-OH) end groups, a generation 2 glucose dendrimer having 96 hydroxyl (-OH) end groups, a generation 3 glucose dendrimer having 396 hydroxyl (-OH) end groups, and generation 4 glucose dendrimer having 1584 hydroxyl (-OH) end groups.
  • the glucose dendrimer is a generation 2 glucose based dendrimer that has 24 glucose molecules at the periphery and 6 embedded glucose molecules in the backbone held together by PEG segments.
  • the dendrimers contain one or more carbohydrate molecules at the termination. These terminal carbohydrate molecules can be prepared by conjugating one or more surface functional groups of a dendrimers, such as amine groups, carboxyl groups, or hydroxyl groups, with one or more carbohydrate molecules.
  • the dendrimers prior to carbohydrate conjugation, are hydroxyl-terminated dendrimers such as hydroxyl-terminated PAMAM dendrimers and one or more of the hydroxyl groups are conjugated with one or more carbohydrate molecules.
  • hydroxyl-terminated dendrimers modified with surface glucose molecules selectively target central and/or peripheral neural and/or glial cells in vitro and in vivo; and/or selectively accumulate on the surface and/or within these targets, such that the active agent(s) conjugated thereto bind to one or more receptors on/in the target neural and/or glial cells.
  • hydroxyl-terminated dendrimers modified with surface glucose molecules selectively target gastrointestinal cells, cardiovascular cells, and/or immune system cells in vitro and in vivo; and/or selectively accumulate on the surface and/or within these targets, such that the active agent(s) conjugated thereto bind to one or more receptors on/in the target gastrointestinal cells, cardiovascular cells, and/or immune system cells.
  • the carbohydrate moieties used to modify one or more surface functional groups of the dendrimers are monosaccharides.
  • Exemplary monosaccharides suitable for modifying the dendrimers include glucose, glucosamine, galactose, mannose, fructose, dehydroascorbic acid, urate, myo-inositol.
  • the dendrimers are conjugated to glucose and thus contain glucose as terminal moieties/molecules.
  • hydroxyl-terminated dendrimers are modified with one or more glucose moieties to the dendrimer (“D-Glu”).
  • D-Glu glucose moieties to the dendrimer
  • the dendrimers are conjugated to galactose.
  • the dendrimers are conjugated to mannose.
  • the dendrimers are conjugated to fructose.
  • the dendrimers are conjugated to one or more monosaccharides other than glucose, such as galactose, mannose, and/or fructose.
  • the carbohydrate moieties are oligosaccharides which terminate in one or more monosaccharides including glucose, glucosamine, mannose, fructose, thus exposing these sugar moieties on the surface for binding.
  • the glucose or hydroxyl-terminated PAMAM dendrimers, or carbohydrate-functionalized dendrimers are conjugated to one or more active agents that have affinity to and are suitable for binding directly or indirectly, one or more of serotonin (5HT) receptors e.g., 5HT-1 A, 5HT-2B, 5HT-2A, 5HT-2B, 5HT-2C, 5HT-3, 5HT-4, 5HT-6, and 5HT-7 receptors.
  • 5HT serotonin
  • the dendrimers are conjugated to one or more carbohydrates moieties that have affinity to and are suitable for binding one or more norepinephrine (NE) receptors e.g., oax-adrenergic receptor, ct2B-adrenergic receptor, ouc-adrenergic receptor, and/or - adrenergic receptor.
  • NE norepinephrine
  • the dendrimers are conjugated to one or more carbohydrates moieties that have affinity to and are suitable for binding directly or indirectly, dopamine DI and D2 receptors.
  • the dendrimers are conjugated to one or more carbohydrates moieties that have affinity to and are suitable for binding one or more monoamine transporters e.g., vesicular monoamine transporter 2 (VMAT2), serotonin reuptake transporter (SERT), the noradrenaline transporter (NAT), the dopamine transporter (DAT).
  • VMAT2 vesicular monoamine transporter 2
  • SERT serotonin reuptake transporter
  • NAT noradrenaline transporter
  • DAT dopamine transporter
  • the dendrimers are conjugated to one or more carbohydrates moieties that have affinity to and are suitable for binding one or more of AMPA receptors, NMDA receptors, EGFR1 receptors, EGFR2 receptors, histamine (Hl) receptors, GABA receptors, and trace amine-associated receptor 1 (TAAR1).
  • the dendrimers are conjugated to one or more active agents that have affinity to and are suitable for transport via one or more of GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, GLUT12, GLUT13, and GLUT 14.
  • the dendrimers are conjugated to one or more glucose and/or glucosamine moieties.
  • the dendrimers contain carbohydrate moieties which enable transport of the active agent to target cells/receptors, wherein the activity at the target cell or receptor is driven by the active agent.
  • the carbohydrates and glucose moieties enable better drug targeting to cells and/or receptors of interest.
  • the dendrimers are conjugated to one or more glucose and/or glucosamine moieties.
  • the dendrimers are conjugated to one or more oligosaccharides terminating in glucose and/or glucosamine moieties, i.e., glucose and/or glucosamine moieties are exposed on the surface of the dendrimer conjugates suitable for binding to one or more of the GLUTs, 5HT receptors, NE receptors, DA receptors and/or transporters.
  • FIG. 13 is a schematic overview of the main pharmacological targets of LSD, psilocybin, DMT, MDMA, and ketamine, the signaling cascades involved, hormonal modulation, as well as main behavioral outcomes following their administration in both animals and humans.
  • the dendrimers have a plurality of carbohydrate moieties/molecules such as monosaccharides, e.g, glucose, on the periphery of the dendrimers.
  • the surface density of carbohydrate molecules such as monosaccharides, e.g., glucose is at least 1 carbohydrate molecule/nm 2 (number of surface carbohydrate groups/surface area in nm 2 ).
  • the surface density of carbohydrate molecules, per nm 2 is more than 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 OH groups/nm 2 , such as at least 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50 OH groups/nm 2 .
  • surface density of carbohydrate molecules, per nm 2 is more than 10.
  • the volumetric density of surface carbohydrate molecules is between about 1 and about 50 groups/nm 3 , between about 5 and about 30 groups/nm 3 , or between about 10 and about 20 groups/nm 3 .
  • the surface density of carbohydrate molecules is between about 1 and about 50, between about 5 and about 20, per nm 2 (number of surface carbohydrate molecules/surface area in nm 2 ) while each carbohydrate moiety having a molecular weight of between about 100 Da and about 1000 Da.
  • the terminal hydroxyl groups may be part of the terminal sugar moieties/molecules or extra hydroxyl groups that are not modified with sugar moieties/molecules and thus are not part of the sugar moieties/molecules, or a combination thereof.
  • carbohydrate molecules such as monosaccharides, e.g., glucose
  • carbohydrate molecules are present in an amount by weight that is between about 1% and 40% of the total weight of the glycosylated dendrimer, for example, between about 2% and 20%, between about 5% and 15%, or between 9 % and 12 % of the total weight of the glycosylated dendrimer.
  • the carbohydrate moieties are present in an amount that is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the total weight of the glycosylated dendrimer following conjugation.
  • conjugation of carbohydrate molecules through one or more surface functional groups occurs via about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25% of the total available surface functional groups, preferably hydroxyl groups, of the dendrimers prior to the conjugation.
  • the conjugation of carbohydrate molecules occurs on less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40% of total available surface functional groups of the dendrimers prior to the conjugation.
  • the dendrimers contain one or more polyalkylene glycols at the termination. These terminal polyalkylene glycols can be prepared by conjugating one or more of surface functional groups of the dendrimers, such as hydroxyl groups, with a polyalk lene glycol, such as PEG.
  • the dendrimers, prior to conjugation are hydroxyl-terminated dendrimers such as hydroxyl-terminated PAMAM dendrimers and at least a portion of the surface hydroxyl groups are conjugated with PEG.
  • the dendrimers have a plurality of poly alkylene glycols such as PEG, on the periphery of the dendrimers.
  • the surface density of polyalkylene glycols such as PEG is at least 1 polyalkylene glycol/nm 2 (number of surface polyalkylene glycol/surface area in nm 2 ).
  • the surface density of polyalkylene glycols, per nm 2 is more than 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 polyalkylene glycol/nm 2 , such as at least 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50 polyalkylene glycol/nm 2 .
  • surface density of polyalkylene glycols, per nm 2 is more than 10.
  • the volumetric density of surface polyalkylene glycols is between about 1 and about 50 groups/nm 3 , between about 5 and about 30 groups/nm 3 , or between about 10 and about 20 groups/nm 3 .
  • the surface density of polyalkylene glycols such as PEG is between about 1 and about 50, between about 5 and about 20, per nm 2 (number of surface poly alkylene glycols/ surface area in nm 2 ) while having a molecular weight of between about 100 Da and about 1000 Da.
  • the polyalkylene glycol molecules such as PEG can be present in an amount by weight that is between about 1 % and 40% of the total weight of the pegylated dendrimer, for example, between about 2% and 20%, between about 5% and 15%, or between 9 % and 12 % of the total weight of the pegylated dendrimer.
  • the polyalkylene glycol molecules such as PEG are present in an amount that is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the total weight of the pegylated dendrimer following conjugation.
  • Exemplary hallucinogens that can be conjugated to the dendrimer compositions include but are not limited to a range of drug classes including but not limited to classical psychedelics, dissociatives, and deliriants.
  • the hallucinogens and their derivatives typically bind to one or more receptors, thereby modulating signaling in neurotransmitter signaling in the central nervous system and peripheral nervous system.
  • Hallucinogens typically inhibit reuptake of neurotransmitters, particularly serotonin, dopamine, and noradrenaline, through selective receptors thereby increasing the concentration of these specific neurotransmitters in the synaptic cleft.
  • partial antagonism, functional selectivity and inverse agonism all play important roles in determining the cellular response to specific neurotransmitter receptor ligands.
  • the dendrimers are conjugated to one or more psychedelic hallucinogens such as psilocin, ketamine (A-ketamine, S- ketamine, ( Aj-ketamine). norketamine, ketamine analogues, ketamine metabolites, N,N dimethyl tryptamine (DMT), 4-acetoxy-N,N- dimethyltryptamine, 5-methoxy DMT, 5-chloro DMT, LSD, 3,4- methylenedioxymethamphetamine (MDMA), psilocybin, ibogaine, mescaline, norbaeocystin, 2C compounds (synthetic psychedelic drugs which belong to a group of designer agents similar in structure to Ecstasy and MDMA), NBOMes (N-benzylmethoxy derivatives of the 2C family hallucinogens - 4-Iodo-2,5-dimethoxy-N-(2 -methoxy
  • the psychedelic hallucinogens functionalized, for example with ester, disulfide, phosphodiester, triglycyl peptide, hydrazine, amide, ether, and amino alkyl linkage, optionally with one or more spacers/linkers, for ease of conjugation with the dendrimers and/or for desired release kinetics.
  • compositions may include a dendrimer complexed to one or more classical psychedelics.
  • Classic or serotoninergic psychedelic compounds are so called mainly because they interact with the serotonergic system and most of them derive from plants or are semisynthetic compounds.
  • the classical psychedelics share part of the chemical structure with the endogenous neurotransmitter serotonin (5-HT) — in particular, the indole scaffold.
  • 5-HT neurotransmitter serotonin
  • mescaline do not possess an indole but are still considered serotonergic psychedelics.
  • the classical psychedelics exert their effects via serotonin 2A receptor (5HT-2A) agonism.
  • the classical psychedelic conjugated to the dendrimer composition may be one or more semisynthetic ergoline LSD, plant-derived tryptamines, and/or phenethylamines.
  • exemplary serotonergic hallucinogens include indolamines, such as psilocybin and LSD, and phenylethylamines, such as mescaline and 2,5-dimethoxy-4-iodoamphetamine (DOI).
  • the classical psychedelic conjugated to the dendrimer composition may be one or more tryptamines.
  • Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan.
  • the chemical structure is defined by an indole — a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the first one being the heterocyclic nitrogen). Tryptamine activates trace amine-associated receptors expressed in the brain, and regulates the activity of dopaminergic, serotonergic, and glutamatergic systems.
  • symbiotic bacteria convert dietary tryptophan to tryptamine, which activates 5-HT4 receptors and regulates gastrointestinal motility.
  • Exemplary psychedelic tryptamines that may be conjugated to the dendrimer include DMT, etryptamine, N,N-diethyltryptamine (DET), Psilocin and psilocybin, and their derivatives. i. Psilocybin
  • N,N-Dimethyltryptamine N,N-Dimethyltryptamine (DMT) N,N-Dimethyltryptamine (DMT or N,N-DMT) is a substituted tryptamine and which is both a derivative and a structural analog of tryptamine.
  • DMT has a rapid onset, intense effects, and a relatively short duration of action.
  • DMT binds to the following serotonin receptors: 5-HT1 A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7.
  • DMT acts as an agonist at 5-HT1 A, 5-HT2A and 5-HT2C, with strong binding affinity for the 5-HT2B receptor.
  • DMT also has affinity for the dopamine DI, al -adrenergic, a2-adrenergic, imidazoline- 1, and ol receptors. It has also been shown in vitro to be a substrate for the cell-surface serotonin transporter (SERT) expressed in platelets, and the vesicular monoamine transporter 2 (VMAT2). Most of DMT's psychedelic effects can be attributed to a functionally selective activation of the 5-HT2A receptor.
  • SERT cell-surface serotonin transporter
  • VMAT2 vesicular monoamine transporter
  • the dendrimer composition may be conjugated to one or more lysergamides.
  • Amides of lysergic acid are collectively known as lysergamides and include a number of compounds with potent agonist and/or antagonist activity at various serotonin and dopamine receptors.
  • Exemplary lysergamides include but are not limited to d-lysergic acid amide (or d- lysergamide; LSA or LAA), Lysergic acid diethylamide (LSD), ergometrine, DAM-57, ergotamine, Methergine, Methysergide, Amesergide, 2-Bromo- LSD, LSD-Pip, 12-methoxy-LSD, 1P-LSD, 1B-LSD, 1V-LSD, IcP-LSD, 13-fluoro-LSD, and 14-hydroxy-LSD.
  • the lysergamide conjugated to the dendrimer composition is Lysergic acid diethylamide (LSD) or an LSD derivative.
  • LSD is an LSD is a semisynthetic ergosterol that can be derived by the naturally occurring ergot alkaloid lysergic acid, which is contained in the rye parasite Claviceps purpurea
  • the mechanism by which LSD works is mainly mediated by activation of serotonin receptors (namely 5HT2A receptors or 5hydroxytryptamine 2A receptor, 5-HT2AR) with modulation of the 5HT2C and 5HT1A receptors.
  • serotonin receptors namely 5HT2A receptors or 5hydroxytryptamine 2A receptor, 5-HT2AR
  • 5-HT2AR 5hydroxytryptamine 2A receptor
  • LSD reduces brain activity in the right middle temporal gyrus, superior/middle/inferior frontal gyrus, anterior cingulate cortex, and the left superior frontal and postcentral gyrus and cerebellum. Activation of the right hemisphere, alters thalamic functioning, and increases activity in the paralimbic structures and the frontal cortex; leading to the formation of induced visual imageries. Structure of LSD
  • the dendrimer composition may be conjugated to one or more phenethylamins.
  • Phenethylamine is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. Phenethylamine is produced from the amino acid L- phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation.
  • Phenethylamine releases norepinephrine and dopamine, induces acetylcholine release via glutamate mediated mechanisms, and binds to trace amine-associated receptor 1 (TAAR1) as an agonist.
  • TAAR1 trace amine-associated receptor 1
  • Exemplary phenethylamines that can be conjugated to the dendrimer compositions include mescaline and MDMA. i. Mescaline
  • Mescaline or mescalin (3,4,5-trimethoxyphenethylamine) is a naturally occurring psychedelic protoalkaloid of the substituted phenethylamine class andis the active component of psychedelic cacti such as peyote (Lophophora wilhamsii) and wachuma (Echinopsis pachanoi. also known as San Pedro).
  • Mescaline is biosynthesized from tyrosine which, in turn, is derived from phenylalanine by the enzyme phenylalanine hydroxylase.
  • mescaline is a 5HT2A/2C agonist and one of the most selectively serotonergic psychedelics.
  • Mescaline is also binds and modulates the activity of noradrenergic receptors al and a2A as well as the TAAR1 receptor.
  • the dendrimer composition can be complexed with mescaline in an amount effective to provide between about 300 and about 500 mg. In some forms, the dendrimer composition can be complexed with mescaline in an amount effective to provide a hallucinogenic effect for about 6 hours to about 8 hours.
  • the dendrimer compositions may include one or more entactogens.
  • Entactogens are Schedule I monoamine releasers and reuptake inhibitors known to evoke a sense of emotional openness and connection such as 3,4- methylenedioxymethamphetamine (MDMA) and 3,4- methylenedioxyamphetamine (MDA).
  • MDMA 3,4- methylenedioxymethamphetamine
  • MDA 3,4- methylenedioxyamphetamine
  • entactogens that may be conjugated to the dendrimers include but are not limited to 3,4- methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxy-N-ethyl- amphetamine (MDEA), 3, 4-Methylenedi oxy amphetamine (MDA), 3,4- Methylenedioxy-N-hydroxyamphetamine (MDOH), 1 ,3-Benzodioxolyl-N- methylbutanamine (MBDB), 6-APB, methylone, mephedrone, GBL, aMT, MDAI and related compounds.
  • MDMA 3,4- methylenedioxymethamphetamine
  • MDEA 3,4-methylenedioxy-N-ethyl- amphetamine
  • MDA 3,4- Methylenedioxy-N-hydroxyamphetamine
  • MDOH 1, ,3-Benzodioxolyl-N- methylbutanamine
  • 6-APB 6-APB, methylone, mep
  • the dendrimer composition may be complexed with MDMA.
  • MDMA increases the amount of serotonin in the synaptic clefts of serotonergic neurons by inhibiting its uptake into neurons and by directly releasing it from the neurons. The released serotonin binds to various serotonin receptors and activates them in excess, the primary mechanism through which MDMA causes intoxication. MDMA also induces significant norepinephrine release.
  • Extracellular MDMA binds to presynaptic serotonin (SERT), norepinephrine (NET) and dopamine transporters (DAT) as a reuptake inhibitor, so that they uptake less of their namesake monoamine neurotransmitters.
  • SERT serotonin
  • NET norepinephrine
  • DAT dopamine transporters
  • Intracellular MDMA binds to VMAT2-proteins on synaptic vesicles as an inhibitor. Each VMAT2 transports cytosolic monoamines into the vesicle by dissipating proton gradient across the vesicular membrane. Thus, VMAT2 inhibition results in more free cytosolic monoamines like serotonin in the case of serotonergic neurons. These monoamines can then be released via monoamine transporters, which have been reversed by MDMA. Intracellular MDMA can also bind to monoamine oxidase A (MAO-A) as an inhibitor, and thus prevent it from breaking down cytosolic serotonin.
  • MAO-A monoamine oxidase A
  • arylcyclohexamines also known as arylcyclohexylamines
  • Arylcyclohexamines are a group of compounds that contain a cyclohexamine unit with an aryl moiety , typically a phenyl ring, attached to the same atom to which the amine group is linked. They all exhibit dissociative effects due to their antagonism of N-methyl-d-aspartate (NMDA) receptors.
  • NMDA N-methyl-d-aspartate
  • the dendrimer compositions may be conjugated to ketamine (R- ketamine, S-ketamine, (/AS')-kelamine).
  • ketamine analogues ketamine metabolites, 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone or analogs thereof, such as KEA-1010, methoxetamine, norketamine, and 2- Fluorodeschloroketamine.
  • D can be a generation 1 to generation 10 or generation 2 to generation 10 dendrimer, such as any one of those described above, for example, PAMAM (such as hydroxyl-terminated PAMAM dendrimer) or a glucose-based dendrimer; each occurrence of L can be any suitable chemical moiety, preferably containing a triazole moiety; Y can be a bond or a linkage selected from secondary amides (-CONH-), tertiary' amides (-CONR-), sulfonamide (-S(O)2-NR-), secondary carbamates (-OCONH-; -NHCOO-), tertiary carbamates (-OCONR-; -NRCOO-), carbonate (-O-C(O)-O-), ureas (-NHCONH-; -NRCONH-; -NHCONR-, -NRCONR-), carbinols (-CHOH-, -
  • X can be a antidepressant and/or antipsychotic agent, wherein a functional group of X (such as an amino group including primary amino, secondary' amino, or tertiary amino group; a carboxylic group; or a hydroxyl group) forms a portion of linkage Y; n can be an integer from 1 to 100; and m can be an integer from 16 to 4096.
  • the dendrimer can be PAMAM (such as hydroxyl-terminated PAMAM) or a glucose dendrimer, which is 100% hydroxyl, m and n depend on the size of the dendrimer D, n should be such that the weight percent of the drug in the total conjugate is 5-20%. This range is also appropriate for binding and internalization.
  • PAMAM such as hydroxyl-terminated PAMAM
  • glucose dendrimer which is 100% hydroxyl
  • m and n depend on the size of the dendrimer D
  • n should be such that the weight percent of the drug in the total conjugate is 5-20%. This range is also appropriate for binding and internalization.
  • the oxygen atom shown in Formula (I) is from the surface functional group of the dendrimer, such as a surface hydroxyl group, where the surface hydroxyl group may or may not be part of a terminal sugar moiety/molecule (e.g., glucose).
  • a surface hydroxyl group may or may not be part of a terminal sugar moiety/molecule (e.g., glucose).
  • one or more hydroxyl groups of the dendrimer that are not conjugated to active agents may be modified with one or more carbohydrates and/or polyalkylene glycols, such as PEG.
  • the antidepressant and/or antipsychotic agent X of Formula (I) can bind to a target receptor on the surface of the target cell or inside the target cell.
  • the agent X when the antidepressant and/or antipsychotic agent X binds to the target receptor, the agent X remains conjugated to the dendrimer.
  • the agent X following binding, the agent X may be released from the dendrimer or remain conjugated to the dendrimer as an intact dendrimeractive agent conjugate.
  • the antidepressant and/or antipsychotic agent X is released from the dendrimer at close proximity to the target receptor and then binds to the target receptor.
  • each occurrence of L can be represented by - A -LI-B -L2-, wherein A’ can be a carbonyl (-C(O)-) or a bond (including single, double, and triple bonds, for example a single bond); B’ can be a bond (including single, double, and triple bonds, for example a single bond), an amide, an ester, an ether, a thiol, a dithiol, an aryl, a heteroaryl, a polyaryl, a heteropolyaryl, or a heterocyclic; and LI and L2 can be independently a bond, an alkylene, a heteroalkylene, an aryl, an aralkyl, an ether, a polyether, a thiol, a dithiol, a thiolether, a polythioether, an oligopeptide, a polypeptide, an oligo(alkylene glycol), or a poly alkylene glyco
  • Ll-B’-L2- together form a chemical moiety selected from an -alkylene-triazole-di(alkylene glycol)-, a -di(alkylene glycol)-triazole-alkylene-, -alkylene-triazole-oligo(alkylene glycol)-, an - oligo(alkylene glycol)-triazole-alkylene-, an -alkylene-triazole-poly(alkylene glycol)-, -poly(alkylene glycol)-triazole-alkylene-, an -alkyl ene-triazole- ether-, an -alkylene-triazole-alkylene-, an -alkylene-amide-alkylene-, and combinations thereof.
  • B’ can be a bond (including single, double, and triple bonds, for example a single bond), an amide group, or a heterocyclic group, such as a triazole group.
  • L2 can be a bond; an alkylene, such as a Ci- C10 alkylene, a Ci-Cs alkylene, a Ci-Ce alkylene, a C1-C5 alkylene, a C1-C4 alkylene, or a C1-C3 alkylene; an oligo- or poly-(alkylene glycol), such as where p is an integer from 1 to 20, from 1 to 18, from 1 to 16, from 1 to 14, from 1 to 12, from 1 to 10, from 1 to 8, from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, or 1 or 2; an oligo- or poly -peptide, such as a triglycyl peptide; a thiol; or a dithiol; or L2 is composed of a combination of two or more of alkylene, oligo- or poly-(alkylene glycol), oligo- or poly -peptide, thiols, and dithiols.
  • Y is a linkage that is minimally cleavable in vivo. In some embodiments, Y is a linkage that is cleavable in vivo. In some embodiments, Y is an amide (-CONH-), an ester (-C(O)-O-), an ether (-O-), a phosphodiester, or a disulfide group.
  • L and Y are both a single bond, and D is directly conjugated to X (an active agent or analog thereol) via an ether linkage.
  • D is a generation 2 PAMAM dendrimer, a generation 3 PAMAM dendrimer, a generation 4 PAMAM dendrimer, a generation 5 PAMAM dendrimer, a generation 6 PAMAM dendrimer, a generation 1 glucose dendrimer, a generation 2 glucose dendrimer, a generation 3 glucose dendrimer, a generation 4 glucose dendrimer, a generation 5 glucose dendrimer, or a generation 6 glucose dendrimer. More specific exemplary dendrimer-active agent conjugates are shown in the Examples below.
  • the dendrimer is conjugated to psilocin, or a psilocin analog as shown in Structures A-D below.
  • GD-Psilocin analog Structure D GD-Psilocin n is an integer from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • the dendrimer is conjugated to ketamine, or a ketamine analog as shown in Structures E and F below.
  • the dendrimer is conjugated to
  • the dendrimer is conjugated to LSD, or a
  • Dendrimers also can be prepared by combining two or more dendrons.
  • Dendrons are wedge-shaped sections of dendrimers with reactive focal point functional groups.
  • Many dendron scaffolds are commercially available. They come in 1, 2, 3, 4, 5, and 6th generations with, respectively, 2, 4, 8, 16, 32, and 64 reactive groups.
  • one type of agents is linked to one type of dendron and a different type of agent is linked to another ty pe of dendron.
  • the two dendrons are then connected 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 alkyne moiety on another to form a triazole linker.
  • generation one dendrimer Dl-acetylene24 is further reacted with AEU P-D-glucose-PEG4-azide to provide generation 2 dendrimer with 24 glucose molecules containing 96 surface hydroxyl groups
  • D2-Glu24-Oac96 is prepared according to the following: Dl-acetylene dendrimer24 (0.5g, 0. 13 mmoles) and glucose-Oac-TEG-azide (2.2g, 4mmoles) are suspended in a 1 : 1 mixture of DMF and water in a 20 mL microwave vial equipped with a magnetic stir bar. To this C11SO4 5H2O (5mol%/acetylene, 5mg) and sodium ascorbate (5mol%/acetylene, lOmg) dissolved in the minimum amount of water are added. The reaction is irradiated in a microwave at 50 °C for 8 h. Upon completion, the reaction mixture is dialyzed against DMF followed by water dialysis containing EDTA. The EDTA is further removed by extensive water dialysis. The product is lyophilized to obtain D2-Glu24-Oac96.
  • generation two dendrimer D2-G1U24-OH96 is prepared according to the following: the peracetylated generation 2 glucose dendrimer D2-G1U24-OH96 is dissolved in anhydrous methanol and sodium methoxide is added to adjust the pH around 8.5-9.0. The reaction is stirred overnight at room temperature, then diluted with methanol and pH is adjusted with AMBERLIST® IR-120+ around 6-7. The reaction mixture is filtered to remove the resin and the filtrate is evaporated by rotary evaporation followed by water dialysis to obtain the product as off-white solid.
  • generation two dendrimer D2-G1U24-OH96 is propargylated at one or more terminal hydroxyl groups suitable for further conjugation to one or more therapeutic, prophylactic or diagnostic agents.
  • one or more terminal hydroxyl groups of generation two dendrimer D2-Glu24-OH96 is propargy lated according to the following: D2- Glu24-OH96 (5b) (200 mg, 0.016 mmol) is dissolved in anhydrous dimethylformamide (DMF, 10 mb) by sonication. To this stirring solution, sodium hydride [60% dispersion in mineral oil] (22 mg, 0.934 mmol) is slowly added in portions at 0°C.
  • the solution is additionally stirred for 15 minutes at 0°C. This is followed by the addition of propargyl bromide (18.0 pL. 80% w/w solution in toluene) at 0°C and the stirring is continued at room temperature for another 6h.
  • the solvent is evaporated using V 10 evaporator system and the crude product is purified by passing through PD10 SEPHADEX® G25 M column. The aqueous solution is lyophilized to afford the product as off-white solid.
  • one or more fluorescent dyes such as infrared fluorescent Cy5 dyes are conjugated to generation two dendrimer D2-Glu24- OH96.
  • Cy5-D2-Glu24-OH96 (compound 7 of FIG. IB) is prepared according to the following: 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 25mL round bottom flask equipped with a magnetic stir bar. To this, CUSO4-5H2O (5mol%/acetylene, 0.3 mg) and sodium ascorbate (10 mol%/acetylene, 0.5 mg) dissolved in the minimum amount of water are added. The reaction is stirred at room temperature for 24 h. Upon completion, the DMF is evaporated using V10 and the purification is performed using PD10 Sephadex G25 M column. The aqueous solution is lyophilized to afford the product as blue solid.
  • the total hydroxyl groups for further conjugation to active agents including therapeutic and/or diagnostic agents are about 1-30, 2-20, or 5-10 out of total 96 available hydroxyl groups of the exemplary generation 2 dendrimer with 24 glucose molecules containing 96 surface hydroxyl groups.
  • one or more agents are covalently attached to the dendrimers.
  • the agents are attached to the dendrimer via a spacer that is designed to be non-cleavable in vivo.
  • the agents are attached to the dendrimer via a spacer that is designed to be cleaved in vivo.
  • the spacer can be designed to be cleaved hydrolytically, enzy matically, or combinations thereof, so as to provide for the sustained release of the agents in vivo.
  • both the chemical structure of the spacer and its point of attachment to the agent can be selected so that cleavage of the spacer releases either an agent, or a suitable prodrug thereof.
  • the chemical structure of the spacer can also be selected in view of the desired release rate of the agents.
  • the conjugation between the agent and dendrimer is via one or more of disulfide, ester, ether, phosphodiester, triglycyl peptide, hydrazine, amide, or amino alkyl linkages.
  • the conjugation between the agent and dendrimer is via an appropriate spacer that provides an ester bond or an amide bond between the agent and the dendrimer depending on the desired release kinetics of the agent.
  • an ester or disulfide bond is introduced for releasable form of agents.
  • an amide or amino alkyl bond is introduced for non-releasable form of agents.
  • Spacers generally contain one or more organic functional groups.
  • suitable organic functional groups contained in the spacers include secondary amides (-CONH-), tertiary amides (-CONR-), sulfonamide (-S(O)2-NR-), secondary carbamates (-OCONH-; -NHCOO-), tertiary carbamates (-OCONR-; -NRCOO-), carbonate (-O-C(O)-O-), ureas (- NHCONH-; -NRCONH-; -NHCONR-, -NRCONR-), carbinols (-CHOH-, - CROH-), disulfide groups, hydrazones, hydrazides, ethers (-O-), and esters (- COO-, -CH2O2C-, CHRO2C-), wherein R is an alkyl group, an aryl group, or a heterocyclic group.
  • the identity of the one or more organic functional groups within the spacer is chosen in view of the desired release rate of the agents.
  • the one or more organic functional groups can be selected to facilitate the covalent conjugation of the agents to the dendrimers.
  • the conjugation between the agent and dendrimer is via an appropriate spacer that provides a disulfide bridge between the agent and the dendrimer.
  • the dendrimeractive agent conjugates are capable of rapid release of the agent in vivo by thiol exchange reactions, under the reduced conditions found in body.
  • the spacer contains one or more of the organic functional groups described above in combination with a linking group.
  • the linking group can be composed of any assembly of atoms, including oligomeric and polymeric chains; for example, 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.
  • suitable linking groups include alkyl groups, heteroalkyl groups, alkylaryl groups, oligo- and polyethylene glycol chains, and oligo- and poly(amino acid) chains. Variation of the linking group provides additional control over the release of the agents in vivo.
  • one or more organic functional groups will generally be used to connect the linking group to both the anti-inflammatory agent and the dendrimers.
  • the amount of active agent in the dendrimer-active agent conjugates depends on many factors, including the choice of active agent, dendrimer structure and size, and tissues to be treated.
  • the one or more antidepressant and/or antipsychotic agents are conjugated to the dendrimer at a concentration between about 0.01% and about 45%, inclusive; between about 0.1% and about 30%, inclusive; between about 0. 1 % and about 20%, inclusive; between about 0.1% and about 10%, inclusive; between about 1% and about 10%, inclusive; between about 1% and about 5%, inclusive; between about 3% and about 20% by weight, inclusive; or between about 3% and about 10% by weight, inclusive.
  • specific drug loading for any given active agent, dendrimer, and site of target can be identified by routine methods, such as those described.
  • the conjugation of agents/spacers occurs via about 1%, 2%, 3%, 4%, or 5% of the total available surface functional groups, such as hydroxyl groups, of the dendrimers prior to the conjugation. In other embodiments, the conjugation of agents/spacers occurs on less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75% total available surface functional groups of the dendrimers prior to the conjugation with active agents.
  • compositions including dendrimer-active agent conjugates may be formulated in a conventional manner using one or more physiologically acceptable carriers, optionally including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically, for oral, mucosal (intranasal, buccal, sublingual, vaginal, rectal or pulmonary), transdermal, or injection (intravenous, subcutaneous, intraperitoneal, intramuscular, or intrathecal administration).
  • excipients include aqueous buffers, wetting agents, viscosity modifiers, tonicity agents, stabilizing agents, and combinations thereof.
  • Suitable pharmaceutically acceptable excipients are preferably selected from materials which are generally recognized as safe (GRAS) and may be administered to an individual without causing undesirable biological side effects or unwanted interactions.
  • GRAS generally recognized as safe
  • pharmaceutically acceptable salts of the actives can be prepared by reaction of the free acid or base forms of an agent with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Pharmaceutically acceptable salts include salts of an agent derived from inorganic acids, organic acids, alkali metal salts, and alkaline earth metal salts as well as salts formed by reaction of the drug with a suitable organic ligand (e.g., quaternary ammonium salts). Lists of suitable salts are found, for example, in Remington’s Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704. Examples of ophthalmic drugs sometimes administered in the form of a pharmaceutically acceptable salt include timolol maleate, brimonidine tartrate, and sodium diclofenac.
  • Therapeutic efficacy and toxicity of conjugates can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e g., ED50 (the dose is therapeutically effective in 50% of the population) and LD50 (the dose is lethal to 50% of the population).
  • the dose ratio of toxic to therapeutic effects is the therapeutic index, and is expressed as the ratio, LD50/ED50.
  • Pharmaceutical compositions which exhibit large therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for human use.
  • the compositions are administered locally, for example, by injection directly into a site to be treated or by an implant.
  • the compositions are injected, topically applied, or otherwise administered directly into the vasculature onto vascular tissue at or adjacent to a site of injury, surgery, or implantation.
  • the compositions are topically applied to vascular tissue that is exposed, during a surgical procedure, or as a cream, gel or lotion.
  • local administration causes an increased localized concentration of the compositions, which is greater than that which can be achieved by systemic administration.
  • oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, fish-liver oil, sesame oil, cottonseed oil, com oil, olive, petrolatum, and mineral.
  • Suitable fatty acids 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.
  • injectable pharmaceutical carriers for injectable compositions are well-known to those of ordinary skill in the art (see, e.g.. Pharmaceutics and Pharmacy Practice, IB. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Trissei, 15th ed., pages 622-630 (2009)).
  • 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 can 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 that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Vehicles can include, for example, fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer’s dextrose.
  • water, saline, aqueous dextrose and related sugar solutions are preferred liquid carriers. These can also be formulated with proteins, fats, saccharides, and other components of infant formulas.
  • cleavable linkages examples include, esterase sensitive ester bond, glutathione sensitive disulfide bond, phosphatase-sensitive phosphodiester bond, triglycyl peptide linker (CX) capable of lysosomal release, and acid cleavable hydrazine linkage.
  • non-cleavable linkages include ether, amino alkyl, or amide bonds.
  • cleavable linkages include esterase sensitive ester bond, glutathione sensitive disulfide bond, phosphatase-sensitive phosphodiester bond, triglycyl peptide linker (CX) capable of lysosomal release, and acid cleavable hydrazine linkage.
  • non- cleavable linkages include ether or amide bonds.
  • the glucose dendrimer-psilocin conjugate was prepared with a cleavable ester linkage according to the reactions illustrated in FIG. 7.
  • the procedure for the synthesis of psilocin-azide compound is shown in FIG. 1A.
  • the synthesis of glucose dendrimer and psilocin conjugate is achieved by the partial modification of OH groups of glucose dendrimers with a complimentary group on the surface of the glucose dendrimer which is reacted with a complimentary linker containing azide connected to the psilocin to generate the glucose dendrimer-psilocin conjugate (FIG. 7).
  • the glucose dendrimer-DMT conjugate was prepared with a non- cleavable amino-alkyl linkage according to the reactions illustrated in FIG. 11.
  • N,N dimethyl tryptamine analog (DMT analog) is first modified with an alkyne group as shown in FIG. 5A.
  • the exemplary synthesis route of glucose dendrimer and DMT conjugate is shown in FIG. 11.
  • the glucose dendrimer- Lysergic acid diethylamide (LSD) conjugate was prepared with a non-cleavable amino-alkyl linkage according to the reactions illustrated in FIG. 12.
  • LSD was first modified with an alkyne group as shown in FIG. 6A.
  • the exemplary synthesis route of glucose dendrimer and LSD conjugate is shown in FIG. 12.
  • the dendrimer conjugation provides site specific targeting by directing the drugs to the target site, decreasing the dose, enhancing efficacy, and reducing side-effects related to free drugs.
  • the glucose dendrimer platform has a very high water solubility (>500mg/mL). Most of the psychedelics have poor aqueous solubility in the ug/mL range.
  • the dendrimer conjugation will improve the water solubility 10-100 fold compared to an unconjugated free drug
  • the sustained intracellular release at the target will avoid the systemic and dose-related side-effects of free psychedelic drugs.
  • Dendrimer conjugation can significantly reduce the time required for onset of drug activity.
  • compositions can deliver drugs to receptors on specific cells (neuronal cells, glial cells, macrophages), including targets on their surface and inside them. These formulations can enhance the effectiveness of these drugs enabling lower doses, lead to new mechanistic insights, reduce side effects, improve solubility, formulation, pharmacokinetics.
  • dendrimer-based psychedelic agents will significantly improve the safety, efficacy, reproducibility, and ease of implementation of these molecules.
  • New chemical entities of psychedelic drugs and norketamine with hydroxyl -terminated PAMAM, and glucose dendrimers have been synthesized, and studies conducted to determine in vivo efficacy and targeting data with norketamme/ketamine, and binding affinity data for D- tryptamine.
  • FIG. 14A is a schematic of the synthesis of a PAMAM dendrimer- norketamine conjugate.
  • FIG. 14B is a schematic of the synthesis of a Glucose dendrimer-norketamine conjugate.
  • NHS ester was purchased from Amersham Bioscience-GE Healthcare.
  • Deuterated solvents dimethylsulfoxide (DMSO- 6), water (D2O), and Chloroform (CDCh) 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, l-(2-amino-l-(4- methoxyphenyl)ethyl)cyclohexanol, Nor-ketamine, 5-hydroxy tryptamine, psilocybin analog, psilocyn analog and cannabidiol drugs were purchased from Cayman Chemicals.
  • the PAMAM-G4-OH (D4-OH) dendrimer composed of about 64 terminal hydroxyl groups was used for the synthesis. After each synthetic step, the product was purified via dialysis in DMF for 24 h to eliminate small molecule impurities followed by water dialysis to remove DMF. NMR (in DMSO-t/6 and D2O) and analytical HPLC were used to confirm the intermediates and final product formation and purity.
  • the mono-functional D4-OH was functionalized with alkyne group by treatment of 5-hexynoic acid under standard esterification conditions using EDC.HC1 and 4-DMAP in DMF for 36 h at room temperature to yield the D-hexyne bifunctional dendrimer.
  • the number of alkyne groups on dendrimer surface was chosen to be kept at -10-15 to maintain the overall water solubility of the conjugate.
  • the crude product was dialyzed by IkDa membrane against ultrapure water for 24 h to remove low molecular weight impurities via selective diffusion across the semi-permeable dialysis membrane.
  • the NMR and analytical HPLC were used to confirm the product formation and purity of the intermediates and final products. These are shown in FIG. 12A-12C.
  • glucose dendrimer (GD2) consists of 24 glucose molecules (96 surface hydroxyl groups) used for conjugation. Glucose dendrimers primarily are made of glucose moieties comprised of the central core of Di-pentaer thritol and one or more branching units of monosaccharide glucose molecules. Unlike hydroxyl-terminated PAMAM dendrimer, glucose dendrimers primarily are taken up by injured neurons and found to specifically target hyperexcitable neurons in both culture and in vivo mouse model.
  • the GD synthesis was begun by reacting hexapropargylated core with AB4,
  • the OH groups on GDI were propargyl ated to obtain GDI- Acetyl ene24, which was reacted with 0-D- glucose-PEG4-azide to obtain generation 2 (GD2) with 24 glucose moieties, providing 96 surface hydroxyl groups.
  • the Cy5 fluorescent tag was attached on GD2 by propargylation of ⁇ 2-3 hydroxyl groups to bring alkyne containing GD2 dendrimer.
  • the GD intermediates and final products were purified using dialysis and characterized using J H NMR.
  • the physicochemical properties of GD2 dendrimer were also evaluated (Table 2). Table 2: Physiochemical Properties of GD2
  • GD2-Drug conjugates were conjugated to the GD2-Hexynoic acid dendrimer using click chemistry strategy.
  • the linker attached drug moieties were conjugated to glucose dendrimer using Cu(I) catalyzed click (CuAAC) reaction in the presence of catalytic amount of CuSOiAHiO and sodium ascorbate to obtain GD2-drug conjugate.
  • the traces of copper were removed by dialyzing with ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • the results are expressed as a percent inhibition of the control radioligand specific binding.
  • the standard reference compound is DOI, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 is calculated.
  • Assay buffer Prior to testing cell plating media was exchanged with 15 pL of Assay buffer (HBSS + 10 mM HEPES). Briefly, intermediate dilution of sample stocks was performed to generate 4X sample in assay buffer. 5 pL of 4X was added to cells and incubated at 37°C for 30 minutes. Final assay vehicle concentration was 1 %.
  • results are expressed as a percent efficacy relative to the maximum response of the control ligand.
  • FIG. 16A and 16B are graphs of wild type, knock out saline (controls) versus knockout mice treated with dendrimer-ketamine conjuate composite neurobehavior score of (FIG. 16A) and probability of survival over post natal day (FIG. 16B).
  • FIG. 16C is a graph of the distance traveled (m);
  • FIG. 16D is a graph of the speed at which the mice traveled;
  • FIG. 16E is a graph of the time spent in comers.
  • Dendrimer conj ugated with ketamine leads to increased efficacy with increased binding to NMD AR without the associated side effects.
  • the dose used is significantly lower than free ketamine, which will reduce the side effects. This is tested in a mouse model of Rett syndrome as a proof of concept since Rett Syndrome is a disease that has increased glutamate production and increased NMD AR expression/activation.

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Abstract

L'invention concerne des formulations de dendrimères comprenant un ou plusieurs agents psychédéliques ou hallucinogènes, et leurs procédés d'utilisation. De préférence, les agents conjugués à un dendrimère se lient sélectivement à un ou plusieurs récepteurs sur la surface ou à l'intérieur des cellules cibles. Les formulations sont appropriées pour une administration entérale et/ou parentérale pour traiter des troubles médiés par un ou plusieurs récepteurs, y compris des troubles psychologiques, cognitifs, comportementaux et/ou de l'humeur.
EP23772729.2A 2022-08-26 2023-08-25 Compositions de dendrimères pour l'administration ciblée d'agents thérapeutiques psychédéliques Pending EP4577245A1 (fr)

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