DENDRIMER COMPOSITIONS AND METHODS FOR DRUG DELIVERY TO INJURED KIDNEY
In some aspects, the disclosure provides methods of treating or preventing one or more symptoms of a kidney injury, disease or disorder in a subject in need thereof. In some embodiments, the method comprises administering to the subject a dendrimer complexed, covalently conjugated, or intra-molecularly dispersed or encapsulated with one or more therapeutic or prophylactic agents, in an amount effective to treat, alleviate or prevent one or more symptoms of a kidney injury, disease or disorder. In some embodiments, the dendrimer is a. generation 4, 5, 6, 7, or 8 poly(amidoamine)(PAMAM) dendrimers, and the therapeutic agents are one or more anti-inflammatory agents and/or PPAR-δ agonists.
1 . A method for treating or preventing one or more symptoms of a kidney injury, disease, and/or disorder in a subject in need thereof, the method comprising:
administering to the subject a formulation comprising dendrimers complexed to, covalently conjugated to, or having intra-molecularly dispersed or encapsulated therein, one or more therapeutic or prophylactic agents,
wherein the dendrimer-agent formulation is administered in an amount effective to treat, alleviate or prevent one or more symptoms of the kidney injury, disease, and/or disorder.
2 . The method of claim 1 , wherein the kidney injury, disease and/or disorder is an acute or chronic kidney disease.
3 . The method of claim 1 or 2 , wherein the kidney injury, disease and/or disorder is caused by ischemia/reperfusion injury.
4 . The method of claim 3 , wherein the kidney injury, disease and/or disorder is caused by a condition selected from the group consisting of infection, sepsis, ischemia-reperfusion injury, diabetic complications, hypertension, obesity, autoimmunity diabetes, high blood pressure, heart failure, kidney disease, liver disease, and cancer.
5 . The method of any one of claims 1 - 4 , wherein the dendrimers are hydroxyl-terminated dendrimers.
6 . The method of any one of claims 1 - 5 , wherein the dendrimers are generation 4, generation 5, or generation 6 poly(amidoamine) dendrimers.
7 . The method of any one of claims 1 - 6 , wherein the therapeutic agent is an anti-inflammatory agent.
8 . The method of any one of claims 1 - 6 , wherein the therapeutic agent is a PPAR-δ agonist.
9 . The method of claim 8 , wherein the PPAR-δ agonist is GW0742, GW0742-amide derivative and GW0742-ester derivative, GW0742-amide derivative, or GW0742-ester derivative.
10 . The method of claim 7 where the anti-inflammatory agent is selected from the group consisting of N-acetylcysteine, steroidal anti-inflammatory drugs, non-steroidal drugs, cyclosporine, tacrolimus, rapamycin, SGLT2 inhibitors, LPA1 receptor antagonists, vasopression V2-receptor antagonists, endothelian receptor antagonists, and uric acid transporter inhibitors.
11 . The method of any one of claims 1 - 10 , wherein the formulation is administered in an amount effective to reduce inflammation in the kidney.
12 . The method of any one of claims 1 - 10 , wherein the formulation is administered in an amount effective to reduce tubular damage, tubular epithelial flattening, tubular dilatation, and tubular epithelial cell necrosis, and/or apoptosis in the kidneys.
13 . The method of any one of claims 1 - 10 , wherein the formulation is administered in an amount effective to reduce serum levels of creatinine and/or blood urea nitrogen (BUN); to reduce urine NGAL and/or KIM-1 content; and/or to improve glomerular filtration rate (GFR).
14 . The method of any one of claims 1 - 10 , wherein the formulation is administered in an amount effective to reduce the amount or presence of one or more pro-inflammatory cells, chemokines, and/or cytokines in the kidney.
15 . The method of claim 14 , wherein the formulation is administered in an amount effective to reduce one or more pro-inflammatory cytokines selected from the group consisting of TNF-α, TFN-γ, IL-6, IL-1β, IL-23, and IL-17.
16 . The method of any one of claims 1 - 15 , wherein the formulation comprises a therapeutic, prophylactic or diagnostic agent selected from the group consisting of chemotherapeutic agents, anti-angiogenic agents, anti-excitotoxic agents, inhibitors of glutamate formation/release, anti-VEGF agents including aflibercept, immunomodulators such as rapamycin, uric acid transporter (URAT1) inhibitors, vasopression V2-receptor antagonists, endothelin receptor antagonists, subtype 2 sodium-glucose transport protein (SGLT2) inhibitor, and LPA1 receptor antagonists.
17 . The method of any one of claims 1 - 16 , wherein the formulation is formulated for intravenous, subcutaneous, or intramuscular administration.
18 . The method of any one of claims 1 - 16 wherein the formulation is formulated for enteral administration.
19 . The method of any one of claims 1 - 16 , wherein the formulation is administered via the intravenous, subcutaneous, or intramuscular route.
20 . The method of any one of claims 1 - 19 , wherein the formulation is administered prior to, in conjunction, subsequent to, or in alternation with treatment with one or more additional therapies or procedures.
21 . The method of claim 20 , wherein the one or more additional procedures include administering intravenous fluids and/or hemodialysis.
22 . A pharmaceutical formulation for use in the method of any one of claims 1 - 21 .
23 . A kit comprising
(1) one or more single unit dose of a composition comprising dendrimers covalently conjugated with one or more PPAR-δ agonists, and
(2) instructions on how the dose is to be administered for treatment of one or more kidney injuries, diseases, and/or conditions.
24 . A composition comprising a compound that comprises a dendrimer conjugated to a PPAR-δ agonist through an ester, ether, or amide linkage, wherein the dendrimer comprises a high density of surface hydroxyl groups.
25 . The composition of claim 24 , wherein the PPAR-δ agonist is conjugated to the ester, ether, or amide linkage through a spacer.
26 . The composition of claim 25 , wherein the spacer comprises alkyl groups, heteroalkyl groups, or alkylaryl groups.
27 . The composition of claim 25 or 26 , wherein the spacer comprises a peptide.
28 . The composition of any one of claims 25 - 27 , wherein the spacer comprises polyethylene glycol.
29 . The composition of any one of claims 24 - 28 , wherein conjugation of the PPAR-δ agonist occurs on less than 50% of total available surface functional groups of the dendrimer prior to the conjugation.
30 . The composition of any one of claims 24 - 29 , wherein conjugation of the PPAR-δ agonist occurs on less than occurs on less than 5%, less than 10%, less than 20%, less than 30%, or less than 40% of total available surface functional groups of the dendrimer prior to the conjugation.
31 . The composition of any one of claims 24 - 30 , wherein the PPAR-δ agonist is an indanylacetic acid derivative.
32 . The composition of any one of claims 24 - 31 , wherein the PPAR-δ agonist is GW0742.
33 . The composition of any one of claims 24 - 32 , wherein the PPAR-δ agonist is a GW0742-amide derivative or a GW0742-ester derivative.
34 . The composition of any one of claims 24 - 33 , wherein the dendrimer comprises poly(amidoamine), polypropylamine (POPAM), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), and/or aromatic polyether.
35 . The composition of any one of claims 24 - 34 , wherein the dendrimer is a poly(amidoamine) dendrimer.
36 . The composition of any one of claims 24 - 35 , wherein the dendrimer is a generation 4, generation 5, or generation 6 poly(amidoamine) dendrimer.
37 . The composition of any one of claims 24 - 36 , wherein the zeta potential of the compound is between −25 mV and 25 mV.
38 . The composition of any one of claims 24 - 37 , wherein the zeta potential of the compound is between −20 mV and 20 mV, between −10 mV and 10 mV, between −10 mV and 5 mV, between −5 mV and 5 mV, or between −2 mV and 2 mV.
39 . The composition of any one of claims 24 - 38 , wherein the surface charge of the compound is neutral or near-neutral.
40 . The composition of any one of claims 24 - 39 , wherein the dendrimer conjugated to the PPAR-δ agonist through an ether or amide linkage.
41 . The composition of any one of claims 24 - 40 , wherein the dendrimer conjugated to the PPAR-δ agonist through an ether linkage.