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CN-122028939-A - Thyroid hormone delivery system comprising lipid or polymer nanoparticles

CN122028939ACN 122028939 ACN122028939 ACN 122028939ACN-122028939-A

Abstract

The present invention relates to a thyroid hormone delivery system comprising lipid or polymer nanoparticles, preferably comprising a targeting agent for the TRCP6 receptor. Such delivery systems may be used to treat diabetic cardiomyopathy or diabetic nephropathy.

Inventors

  • Christodoros Sinaris
  • Angelo Michele. Lavekia
  • Olivier Zerfati
  • Yordanis Muruzis
  • CONSTANTINOS PANTOS
  • Elmoraos Etruscan
  • Dimitrios Scottie's

Assignees

  • 里卡尔多·泰尔齐与西尔维奥·阿尔比尼基金会
  • 雅典大学
  • 奥兹生物科学简易股份公司

Dates

Publication Date
20260512
Application Date
20240718
Priority Date
20230720

Claims (16)

  1. 1. A thyroid hormone delivery system comprising polymeric nanoparticles comprising an amphiphilic block copolymer comprising a hydrophobic block of poly (gamma-benzyl-L-glutamic acid) and a hydrophilic block of amino-polyethylene glycol or amino-N 3 -polyethylene glycol, wherein the thyroid hormone is immobilized on the nanoparticle by covalently binding the hormone to the pH-sensitive bridge of the hydrophobic block.
  2. 2. The delivery system of claim 1, wherein the pH sensitive bridge is a bridge of formula (III) 。
  3. 3. The delivery system of claim 1, further comprising a targeting agent.
  4. 4. The delivery system of claim 3, wherein the targeting agent is selected from the group consisting of 4- [ [ (1R, 2R) -2- [ (3R) -3-amino-1-piperidinyl ] -2, 3-dihydro-1H-inden-1-yl ] oxy ] -3-chlorobenzonitrile dihydrochloride (SAR 7334), acetic acid, fall She Songzhi, 1, 3-dihydro-1- [1- [ (5, 6,7, 8-tetrahydro-4H-cyclohepta [ b ] thiophen-2-yl) carbonyl ] -4-piperidinyl ] -2H-benzimidazol-2-one (GSK-2934A), 1- (2- (3- (4-methoxyphenyl) propoxy) -4-methoxyphenylethyl) -1H-imidazole (SKF 96365), [4- (6-aminopyridin-3-yl) piperidin-1-yl ] - [4- [4- (trifluoromethyl) phenoxy ] phenyl ] methanone (BI 749327), 4- [ (1R, 3aR, 7S) -2H-benzimidazol-2-one (GSK-2934A), 1- (3- (4-methoxyphenyl) propoxy) -4-methoxyphenylethyl) -1H-imidazole (SKF 96365), [4- (6-aminopyridin-3-yl) piperidin-1-yl ] - [4- [4- (trifluoromethyl) phenoxy ] phenyl ] methanone (BI-749327) (1S, 4aR,8 aS) -4- [ (3S) -3-hydroxy-3-methylpent-4-en-1-yl ] -4a, 8-trimethyl-3-methylene-decahydronaphthalen-1-yl N-methylcarbamate (SH 045) [4- (6-aminopyridazin-3-yl) piperidin-1-yl ] - [4- [4- (trifluoromethyl) phenoxy ] phenyl ] methanone (BI 749327), 4- [ 7-hydroxy-2-methyl-3- [4- (trifluoromethyl) phenyl ] pyrazol [1,5-a ] pyrimidin-5-yl ] piperidine-1-carboxylic acid ethyl ester (HDM), 4- [ 7-hydroxy-2, 5-dimethyl-3- [4- (trifluoromethyl) phenyl ] pyrazol [1,5-a ] pyrimidin-5-yl ] piperidine-1-carboxylic acid ethyl ester (HQR).
  5. 5. Thyroid hormone delivery system comprising polymeric nanoparticles comprising amino-polyethylene glycol or amino-N 3 -polyethylene glycol residues and a thioketal bridge having the formula (II) , Wherein the thyroid hormone is immobilized on the nanoparticle.
  6. 6. The delivery system of claim 5, further comprising a targeting agent.
  7. 7. The delivery system of claim 6, wherein the targeting agent is selected from the group consisting of 4- [ [ (1R, 2R) -2- [ (3R) -3-amino-1-piperidinyl ] -2, 3-dihydro-1H-inden-1-yl ] oxy ] -3-chlorobenzonitrile dihydrochloride (SAR 7334), acetic acid drop She Songzhi, 1, 3-dihydro-1- [1- [ (5, 6,7, 8-tetrahydro-4H-cyclohepta [ b ] thiophen-2-yl) carbonyl ] -4-piperidinyl ] -2H-benzimidazol-2-one (GSK-2934A), 1- (2- (3- (4-methoxyphenyl) propoxy) -4-methoxyphenylethyl) -1H-imidazole (SKF 96365), [4- (6-aminopyridin-3-yl) piperidin-1-yl ] - [4- [4- (trifluoromethyl) phenoxy ] phenyl ] methanone (BI 749327), 4- [ (1R, 3aR, 7S) -2H-benzimidazol-2-one (GSK-2934A), 1- (3- (4-methoxyphenyl) propoxy) -4-methoxyphenylethyl) -1H-imidazole (SKF 96365), [4- (6-aminopyridin-3-yl) piperidin-1-yl ] - [4- [4- (trifluoromethyl) phenoxy ] phenyl ] methanone (BI-749327) (1S, 4aR,8 aS) -4- [ (3S) -3-hydroxy-3-methylpent-4-en-1-yl ] -4a, 8-trimethyl-3-methylene-decahydronaphthalen-1-yl N-methylcarbamate (SH 045) [4- (6-aminopyridazin-3-yl) piperidin-1-yl ] - [4- [4- (trifluoromethyl) phenoxy ] phenyl ] methanone (BI 749327), 4- [ 7-hydroxy-2-methyl-3- [4- (trifluoromethyl) phenyl ] pyrazol [1,5-a ] pyrimidin-5-yl ] piperidine-1-carboxylic acid ethyl ester (HDM), 4- [ 7-hydroxy-2, 5-dimethyl-3- [4- (trifluoromethyl) phenyl ] pyrazol [1,5-a ] pyrimidin-5-yl ] piperidine-1-carboxylic acid ethyl ester (HQR).
  8. 8. A thyroid hormone delivery system comprising lipid nanoparticles comprising: (1) At least one lipid; (2) At least one lipid having cryptic properties; (3) At least one functionalized lipid having structure (I); , wherein the targeting agent is a targeting agent for TRCP6 receptor, And wherein the thyroid hormone is encapsulated in or immobilized on the nanoparticle.
  9. 9. The delivery system according to claim 8, wherein the lipid (1) is a phospholipid.
  10. 10. The delivery system of claim 8, wherein the lipid (1) is selected from the group consisting of 1-palmitoyl-2-oleoyl-glycerol-3-phosphorylcholine (POPC), 1, 2-distearoyl-glycerol-3-phosphorylcholine (DSPC), 1, 2-dipalmitoyl-glycerol-3-phosphorylcholine (DPPC), dioleoyl-phosphatidylethanolamine (DOPE), distearoyl-phosphatidylethanolamine (DSPE), dipalmitoyl phosphatidylethanolamine (DPPE), dimyristoyl-phosphatidylethanolamine (DMPE), dilauroyl-phosphatidylethanolamine (DLPE), di-acyl-phosphatidylethanolamine, monomethyl phosphatidylethanolamine, dimethyl phosphatidylethanolamine, dilauroyl phosphatidylethanolamine (DEPE) and stearoyl-base oil phosphatidylethanolamine (SOPE), palmitoyl-oleoyl-phosphatidylethanolamine (POPE), 1, 2-dioleoyl-sn-glycero-3-phosphorylethanolamine (DOPC), distearoyl-phosphatidylethanolamine (DSPE), dipalmitoyl-phosphatidylethanolamine (DSPE), dilauroyl-phosphatidylethanolamine (DLPE), di-phosphatidylethanolamine (DPPC), dimyristoyl-phosphatidylethanolamine (DLPC), di-phosphatidylethanolamine (dipalmitoyl-phosphatidylethanolamine (DSPE), dilauroyl-phosphatidylethanolamine (nude), dilauroyl phosphatidylethanolamine (nude (nuceloyl) and stearoyl phosphatidylethanolamine (sapaloyl) Palmitoyl oleyl-phosphatidylglycerol (POPG), dioleoyl-phosphatidylglycerol (DOPG), distearoyl-phosphatidylglycerol (DSPG), dipalmitoyl-phosphatidylglycerol (DPPG), dimyristoyl-phosphatidylglycerol (DMPG), dilauroyl-phosphatidylglycerol (DLPG), glycosyl-diacylglycerols, phosphatidylinositol, phosphatidylserine, ceramides, cerebrosides, cephalins, sphingolipids, phosphatidic acids, lysophosphatidic acids, desialylated gangliosides, cardiolipins, bis (monoacylglycerophospholipids) phosphate esters, prostaglandins, eicosanoids, glycerides, etherlipids, oxidized lipids, sterol-modified phospholipids, lysophospholipids, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylinositol, lysophosphatidylserine, lysophosphatidylglycerol, lysophosphatidylserine, lysophosphatidic acids, and mixtures thereof.
  11. 11. The delivery system of claim 8, wherein the lipid with cryptic properties is selected from the group consisting of polyethylene glycol (PEG) modified lipids, monosialoganglioside (Gm 1), and polyamide oligomers.
  12. 12. The delivery system of claim 8, wherein the functionalized lipid having structure (I) comprises: a targeting agent selected from the group consisting of 4- [ [ (1R, 2R) -2- [ (3R) -3-amino-1-piperidinyl ] -2, 3-dihydro-1H-inden-1-yl ] oxy ] -3-chlorobenzonitrile dihydrochloride (SAR 7334), acetic acid, fall She Songzhi, 1, 3-dihydro-1- [1- [ (5, 6,7, 8-tetrahydro-4H-cyclohepta [ b ] ethylene-2-yl) carbonyl ] -4-piperidinyl ] -2H-benzimidazol-2-one (GSK-2934A), 1- (2- (4-methoxyphenyl) propoxy) -4-methoxyphenylethyl) -1H-imidazole (SKF 96365), [4- (6-aminopyridazin-3-yl) piperidin-1-yl ] [4- (4- (trifluoromethyl) phenoxy) phenyl) methanone (BI 749327), 4- [ (1R, 3aR,7 aS) -2- [ (3R) -3-aminopiperidin-1-yl ] -7-methyl-inden-1-yl ] oxy ] -4-piperidinyl-2H-benzimidazol-2-one (GSK-2934A), 1- (4- (6-aminopyridin-3-yl) piperidin-1-yl) piperidin-yl ] [4- (4- (6-aminopyridin-3-yl) phenyl) methanone (BI 749327) (1S, 4aR,8 aS) -4- [ (3S) -3-hydroxy-3-methylpent-4-en-1-yl ] -4a, 8-trimethyl-3-methylene-decahydronaphthalen-1-yl N-methylcarbamate (SH 045), [4- (6-aminopyridazin-3-yl) piperidin-1-yl ] - [4- [4- (trifluoromethyl) phenoxy ] phenyl ] methanone (BI 749327), 4- [ 7-hydroxy-2-methyl-3- [4- (trifluoromethyl) phenyl ] pyrazol [1,5-a ] pyrimidin-5-yl ] piperidine-1-carboxylic acid ethyl ester (HDM), 4- [ 7-hydroxy-2, 5-dimethyl-3- [4- (trifluoromethyl) phenyl ] pyrazol [1,5-a ] pyrimidin-5-yl ] piperidine-1-carboxylic acid ethyl ester (HQR); -a linker selected from the group consisting of azide, carboxy-N-hydroxysuccinimide, isothiocyanate, isocyanate, acyl azide, N-hydroxysuccinimide ester, sulfonyl chloride, aldehyde, glyoxal, epoxide, ethylene oxide, carbonate, arylating agent, imido ester, carbodiimide, anhydride, haloacetyl derivative, haloalkane derivative, maleimide, aziridine, acryloxy derivative, thiol disulfide, carbonyldiimidazole, diazo compound, diazoacetyl compound, N' -disuccinimidyl carbonate, hydrazine derivative, homofunctional linker, heterobifunctional linker, trifunctional crosslinker; -lipids selected from the group consisting of 1-palmitoyl-2-oleoyl-glycero-3-phosphorylcholine (POPC), 1, 2-distearoyl-glycero-3-phosphorylcholine (DPPC), 1, 2-dipalmitoyl-glycero-3-phosphorylcholine (DPPC), dioleoyl phosphatidylethanolamine (DOPE), distearoyl phosphatidylethanolamine (DSPE), dipalmitoyl phosphatidylethanolamine (DPPE), dimyristoyl-phosphatidylethanolamine (DMPE), dilauroyl phosphatidylethanolamine (DLPE), diacyl phosphatidylethanolamine, monomethyl phosphatidylethanolamine, Dimethyl phosphatidylethanolamine, dilauroyl phosphatidylethanolamine (DEPE), stearoyl-oleoyl phosphatidylethanolamine (SOPE), palmitoyl-phosphatidylethanolamine (POPE), dioleoyl-phosphatidylcholine (DOPC), distearoyl-phosphatidylcholine (DSPC), dipalmitoyl-phosphatidylcholine (DPPC), dimyristoyl-phosphatidylcholine (DMPC), dilauroyl-phosphatidylcholine (DLPC), diacyl-phosphatidylcholine, palmitoyl-phosphatidylcholine (POPC), palmitoyl-phosphatidylglycerol (POPG), palmitoyl-phosphatidylcholine (DPPC), di-oleoyl-phosphatidylglycerol (DOPG), distearoyl-phosphatidylglycerol (DSPG), dipalmitoyl-phosphatidylglycerol (DPPG), dimyristoyl-phosphatidylglycerol (DMPG), dilauroyl-phosphatidylglycerol (DLPG), glycosyl-diacylglycerols, phosphatidylinositol, phosphatidylserine, ceramides, cerebrosides, cephalins, sphingolipids, phosphatidic acids, lysophosphatidic acids, desialylated gangliosides, cardiolipins, bis (monoacylglycerols) phosphate esters, prostaglandins, eicosanoids, glycerides, ether lipids, oxidized lipids, sterol-modified phospholipids, lysophospholipids, lysophosphatidylcholines, Lysophosphatidylethanolamine, lysophosphatidylinositol, lysophosphatidylserine, lysophosphatidylglycerol, lysophosphatidylserine, lysophosphatidic acid, PEG-modified phosphatidylethanolamine and PEG-modified phosphatidic acid, PEG-ceramide conjugate PEG-modified dialkylamine, PEG-modified 1, 2-diacyloxypropan-3-amine, PEG-modified diacylglycerol and dialkylglycerol, mPEG (pm=2000) -distearylphospholipid ethanolamine (PEG-DSPE), 1, 2-distearyl glycerol-3-phosphoethanolamine-N- [ amino (polyethylene glycol) ] (DSPE-PEG), and, 1, 2-Dimyristoyl-glycerol-3-methoxy [ polyethylene glycol ] (DMG-PEG), 1, 2-dioleoyl-glycerol-3-phosphoethanolamine-N- [ amino (polyethylene glycol) ] ] (DOPE-PEG), 1- (monomethoxypolyethylene glycol) -2, 3-dimyristoyl glycerol (PEG-DMG), pegylated phosphatidylethanolamine (PEG-PE), dimyristoyl-rac-glycerol-3-methoxy-polyethylene glycol (PEG-S-DMG), pegylated ceramide (PEG-cer), pegylated dialkoxypropylcarbamate, PEG-modified phosphatidic acid, PEG-ceramide conjugates, PEG-modified dialkylamines, PEG-modified 1, 2-diacyloxypropan-3-amines, PEG-modified diacylglycerols and dialkylglycerols, and mixtures thereof.
  13. 13. The delivery system according to any one of claims 8 to 12, further comprising at least one of (4) at least one sterol, (5) at least one cationic lipid, and (6) at least one ionizable lipid.
  14. 14. The delivery system of any one of claims 1 to 13, wherein the thyroid hormone is selected from the group consisting of triiodothyronine and thyroxine.
  15. 15. The delivery system according to any one of claims 1 to 13 for use in the treatment of a disease selected from the group consisting of diabetic cardiomyopathy and diabetic nephropathy.
  16. 16. A pharmaceutical formulation comprising the delivery system according to any one of claims 1 to 13.

Description

Thyroid hormone delivery system comprising lipid or polymer nanoparticles Cross Reference to Related Applications The present application claims priority from italian application No. 102023000015291 filed 7/20 in 2023, the entire contents of which are incorporated herein by reference. Technical Field The present invention relates to a thyroid hormone-containing, in particular triiodothyroxine (T3) and/or thyroxine (T4), delivery system comprising lipid or polymer nanoparticles, intended to specifically target damaged tissues in diabetes and for the treatment of Diabetic Cardiomyopathy (DC) and Diabetic Nephropathy (DN). Background Diabetes is one of the most serious health crisis in the 21 st century, affecting hundreds of millions of people worldwide. In europe, tens of millions of people have diabetes mellitus, with men about 10.3% being 25 years old and older, and women about 9.6%. The incidence of diabetes is on the rise at all ages, mainly due to overweight and obesity, unhealthy diet, lack of exercise, etc., and it is expected that diabetic adults will continue to increase in the future. Diabetes can progressively damage the heart, blood vessels, kidneys, eyes and nerves. About 7 people die per minute from diabetic complications (WHO, diabetes, 2018). Diabetic Nephropathy (DN) and Diabetic Cardiomyopathy (DC) are major complications and causes of death. About 40% of diabetics will develop diabetic nephropathy, with 25% to 45% of patients progressing to End Stage Renal Disease (ESRD). Cardiovascular disease, on the other hand, is the most common cause of death and morbidity in the diabetic population (Matheus AS et al, 2013). Diabetes increases the risk of Heart Failure (HF), coronary artery disease, and Myocardial Infarction (MI). After myocardial infarction, the morbidity, mortality and re-infarction rate of diabetics are higher than those of non-diabetics, and the annual mortality rate is close to 50%. Standard treatment for diabetics includes controlling blood glucose and blood pressure, reducing blood lipid and blocking the renin-angiotensin system, however, there is still a lack of effective treatments for DN and DC in the medical community. Developing a therapy that can prevent or even reverse diabetic cardiac and renal complications would save millions of people's lives, significantly improve the quality of life for cardiac HF and ESRD patients, and save a great deal of public and private funds currently used to treat diabetic complications. Diabetes Mellitus (DM) causes chronic stress in cells due to hyperglycemia, oxygen radicals, hypoxia and glycation end products. Thus, diabetic organs undergo a range of structural, metabolic and functional changes, which often lead to diabetic cardiomyopathy and diabetic nephropathy. There is evidence that the phenotypic and morphological changes that occur after chronic injury in cardiomyocytes and podocytes are markers of incomplete/poorly adapted reproduction at the early developmental (i.e. embryonic) stage, and this process is regulated by the Thyroid Hormone (TH)/thyroid hormone receptor α1 (trα1) axis. In fetal phase, when L-triiodothyronine (T3) is low, highly expressed TR α1 acts as an aporeceptor (unbound state), inhibiting and activating expression of adult and fetal genes, respectively. After birth, T3 levels are significantly elevated, trα1 changes to a full receptor state (binding state), inducing and promoting expression of adult genes and structural and functional maturation of organs. Interestingly, fetal patterns of the T3-trα1 axis (low T3 and high trα1) reappear under various stress conditions and disease states, suggesting that trα1 plays a crucial role in reactivating fetal gene programs. In particular, stress stimulation (e.g., adrenergic stimulation) induces up-regulation of trα1 expression in cardiomyocytes. Furthermore, in the post-infarct viable/intact myocardium, TRα1 is expressed in vivo to increase, whereas TRα1 significantly inhibits post-ischemic cardiac function and further worsens calcium ion treatment. Similarly, diabetes results in reduced in vivo T3 levels, overexpression of TR. Alpha.1 in podocytes, and re-expression of fetal genes, whereas in vitro experiments indicate that high blood glucose levels result in overexpression of TR. Alpha.1 in human podocytes, down-regulation of adult markers, and up-regulation of embryo markers. Consistent with the foregoing, epidemiological studies have shown that reduced T3 levels due to stress are closely related to adverse clinical outcomes in heart and kidney disease patients. Thus, it is not surprising that exogenous administration of Thyroid Hormone (TH) under stress conditions shows great therapeutic potential. Administration of TH treatment after myocardial infarction increases the viable myocardial mass with a physiological adult phenotype and improves cardiac function in diabetic patients with concomitant MI. In addition, TH treatment can improve kidney function in chronic k