WO2023125404A1 - Médicament ciblé contre une lésion de la moelle épinière, micelle de composé hydrophobe polymère et procédé de préparation d'un médicament ciblé contre une lésion de la moelle épinière - Google Patents

Médicament ciblé contre une lésion de la moelle épinière, micelle de composé hydrophobe polymère et procédé de préparation d'un médicament ciblé contre une lésion de la moelle épinière Download PDF

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WO2023125404A1
WO2023125404A1 PCT/CN2022/141903 CN2022141903W WO2023125404A1 WO 2023125404 A1 WO2023125404 A1 WO 2023125404A1 CN 2022141903 W CN2022141903 W CN 2022141903W WO 2023125404 A1 WO2023125404 A1 WO 2023125404A1
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alkyl
group
formula
spinal cord
hydrophobic
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PCT/CN2022/141903
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Chinese (zh)
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王绪化
左彦明
叶婧佳
蔡万雄
陈向峰
林灵敏
郭滨杰
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浙江大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2/00—Processes of polymerisation
    • C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
    • C08F293/005—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2438/00—Living radical polymerisation
    • C08F2438/03—Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]

Definitions

  • the invention relates to a polymer-hydrophobic compound micelle, in particular to a targeted drug for spinal cord injury, and also to a preparation method for a polymer-hydrophobic compound micelle and a targeted drug for spinal cord injury.
  • Non-Patent Document 1 Korean Chemical Company LLC Xiaosong of Nantong University suggested a therapy (see Non-Patent Document 1), mentioning KCC2 agonists as a promising treatment to promote functional recovery after spinal cord injury, which used (neuron Agonists of specific K+-Cl cotransporters (KCC2 agonists, eg CLP290, CLP257).
  • KCC2 agonists eg CLP290, CLP257
  • Non-Patent Document 1 Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations Cell[J].Volume 174,ISSUE 3,P521-535.e13,July 26,2018
  • KCC2 agonists such as CLP290 and CLP257 have poor water solubility, which limits their application.
  • These potential drugs are mainly neuronal ion channel protein regulators, and the actual animal experiments are also very small.
  • they are ubiquitous, have poor selectivity, and cannot be targeted to the affected area (damaged spinal cord tissue) of patients with spinal cord injury. It is inevitable that the large amount of medication and low delivery efficiency will cause poor functional recovery and large side effects. safety and other shortcomings.
  • the existing literature reports such as the above-mentioned non-patent literature 1
  • the inventors first used the small molecular neurokines secreted by nerve cells to modify the structure of existing nerve drugs (such as CLP) for spinal cord injury to increase the selectivity of drugs for specific nerve cells.
  • existing nerve drugs such as CLP
  • CLP existing nerve drugs
  • Nanomedicines are known to improve drug availability and drug delivery efficiency. Passive targeted delivery and active targeting of specific neurons for spinal cord injury can greatly improve drug efficacy and reduce possible side effects. Therefore, the synthesis of targeted nanomedicine for spinal cord injury needs to be developed urgently
  • the inventors of the present invention have successfully developed a polymer-hydrophobic compound water-soluble micelle, which can assist the dissolution of insoluble compounds, and the micelle When the bundle itself is made into an aqueous solution, it has a targeted enrichment effect on the spinal cord injury site, and can assist insoluble nerve repair drugs to be enriched in the spinal cord injury tissue, and can be used to prepare targeted drugs for spinal cord injury.
  • the present invention provides a targeted drug for spinal cord injury, which includes amphoteric polymer micelles and hydrophobic nerve repair drugs, and the hydrophobic nerve repair drugs are encapsulated by amphoteric polymer micelles to form water-soluble particles.
  • Micelles are formed by the association of amphiphilic polymers containing hydrophilic segments and hydrophobic segments.
  • the chemical structure of the hydrophobic neurorestoration drug contains a fragment of small molecule neurokines secreted by neurons. These fragments form chemical bonds through chemical reactions and connect to hydrophobic nerve repair drugs.
  • the small molecule nerve factor fragments secreted by nerve cells have their own transport mechanism in nerve cells. Using these molecular guidance, the effect of hydrophobic nerve repair drugs on nerves can be realized.
  • the active selectivity of cells the so-called active selectivity, means that the drug itself improves the transport and entry ability in nerve cells through structural modification. After the factor fragment is connected to the hydrophobic nerve repair drug, it can still be removed through cell metabolism after entering the cell, so that the hydrophobic nerve repair drug can play a role in the cell.
  • the hydrophobic nerve repairing drug is not particularly limited, as long as it is used for nerve repairing and neurotrophic drugs, and it is a drug that is poorly soluble in water, it can be used in the present invention, and can be selected as Any drug from CLP257, CLP290, baclofen, bumetanide, NMDA receptor antagonist CP101606, 8-OHDPAT, quinazine, 4-AP, coupled with the small molecular nerve factors secreted by nerve cells through chemical bonds The resulting hydrophobic nerve repair drug.
  • the nerve Small-molecule neurokines secreted by cells include, but are not limited to, the following small-molecule neurokines secreted by nerve cells.
  • modification by these compounds refers to the formation of chemical bonds between the hydrophobic drug molecules and the above-mentioned molecules, and the above-mentioned molecules are connected to the hydrophobic molecules, so that the nerve cells can improve the hydrophobicity through the recognition and transport of the above-mentioned molecules. Transport efficiency of drug molecules into nerve cells.
  • the hydrophobic nerve repair drug can be selected from CLP257, CLP290, baclofen, bumetanide, NMDA receptor antagonist CP101606, 8-OHDPAT, Any one of quinozine and 4-AP, but not limited to these.
  • the method is to link the ROS sacrificial agent on the amphoteric polymer micelle of the targeting drug for spinal cord injury, that is, in the preferred embodiment of the present invention, the Active oxygen sacrificial groups capable of reacting with active oxygen to consume active oxygen are attached to the amphoteric polymer micelle chain.
  • the active oxygen sacrificial group is preferably a group selected from the following groups,
  • R 8 and R 9 are each independently hydrogen, C1-C5 alkyl, C6-C10 aryl, C1-C5 alkyl sulfide group;
  • R 10 are each independently hydrogen, C1-C5 alkane; group, hydroxyl group, C1-C5 alkyl ether group, C1-C5 alkyl sulfide group.
  • the amphoteric polymer micelles in the targeted drug for spinal cord injury are micelles formed by the association of amphoteric polymer compounds represented by formula (1),
  • Z represents C1 ⁇ C15 alkyl group, C1 ⁇ C15 alkylthio group, C6 ⁇ C10 aryl group
  • R1 and R2 are each independently selected from hydrogen, C1 ⁇ C5 alkyl group, cyano group, and R 1 and R 2 are not cyano at the same time
  • E represents C1 ⁇ C5 alkylene, C6 ⁇ C10 arylene, C1 ⁇ C5 alkylene-C6 ⁇ C10 arylene, C6 ⁇ C10 arylene Aryl-C1 ⁇ C5 alkylene, or E may not exist
  • R 3 represents C1 ⁇ C5 alkyl, hydroxyl, COOR 5
  • R 5 represents hydrogen, C1 ⁇ C5 alkyl, N-succinyl imines, PEG residues
  • R 4 and R 7 are each independently hydrogen or methyl
  • R x represents a divalent group selected from phenylene substituted by phenyl, -ph-COO-, ph-CONH-, -COO-, -CONH-;
  • R y represents absence, or a divalent group selected from C1-C5 alkyl, N-succinimide, and PEG residues;
  • R 6 represents hydrogen, amino, carboxyl, hydroxyl, C1-C5 alkyl, N-succinimide, PEG residue;
  • X is one of the groups of the following formulas (2) to (5):
  • R 8 and R 9 are each independently hydrogen, C1-C5 alkyl, C6-C10 aryl, C1-C5 alkyl sulfide group;
  • R 10 are each independently hydrogen, C1-C5 alkyl, Hydroxyl, C1 ⁇ C5 alkyl ether group, C1 ⁇ C5 alkyl sulfide group,
  • the hydrophilic residues in ( ) p in the compound represented by formula (1) form the outer hydrophilic layer, providing the water solubility of the micelles, and the remaining parts form the inner hydrophobic inner core, and the hydrophobic inner core Hydrophobic nerve restoration drugs are encapsulated, and the diameter of the micelles is 10nm-300nm.
  • amphoteric polymer compound shown in formula (1) is the amphoteric polymer compound shown in formula (1-1),
  • Z, R 1 , E, R 3 , R 5 , R 4 and R 7 , R 6 , o, p, X, R 8 , R 9 , and R 10 have the same meanings as in formula (1), q is an integer of 6-20, Preferably it is an integer of 7-12.
  • the expression of Ca ⁇ Cb means that the number of carbon atoms of the group is a ⁇ b, and unless otherwise specified, generally speaking, the number of carbon atoms does not include the number of carbon atoms of the substituent.
  • the expressions of chemical elements generally include the concept of isotopes with the same chemical properties, such as the expression "hydrogen”, and also include the concepts of "deuterium” and “tritium” with the same chemical properties, unless otherwise specified.
  • the so-called C1-C15 alkyl group includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 2-methylbutyl base, n-pentyl, sec-pentyl, neopentyl, n-hexyl, neohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, etc., but not Among these, C1-C5 alkyl groups are preferred, and preferred groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl , 2-methylbutyl, n-pentyl, sec-pentyl,
  • the C1-C15 alkylthio group refers to the above-mentioned C1-C15 alkyl-S group, and among them, dodecylthio group and the like are preferable.
  • alkylene group refers to a divalent group obtained by removing one hydrogen atom from the above-mentioned alkyl group, for example, methylene group, ethylene group and the like.
  • C6-C10 aryl group includes phenyl, naphthyl, anthracenyl, phenanthrenyl and the like, among which phenyl is preferred.
  • the C6-C10 arylene group includes divalent groups obtained by removing one hydrogen atom from the above-mentioned C6-C10 aryl group, among which phenylene and naphthylene are preferable.
  • Z is preferably methyl, phenyl or dodecylthio; R and R are preferably hydrogen, methyl, cyano; E is preferably methylene, ethylene, methylene Phenyl, methylene-phenylene, phenylene-methylene,; R3 is preferably methyl, ethyl, hydroxyl, COOR5 , R5 is preferably hydrogen, methyl, ethyl, N-succinate imide, PEG residues;
  • R 4 and R 7 are each independently preferably hydrogen or methyl;
  • R 6 represents hydrogen or methyl;
  • o is an integer of 2 to 4;
  • p is an integer of 20 to 40, preferably an integer of 25 to 35;
  • q is 6 An integer of -20, preferably 8-12.
  • C1 ⁇ C5 alkylene group-C6 ⁇ C10 arylene group refers to C1 ⁇ C5 alkylene group and C6 ⁇ C10 arylene group
  • divalent groups formed by linking groups can refer to the above-mentioned specific examples of C1-C5 alkylene groups and specific examples of C6-C10 arylene groups.
  • PEG residues refer to The group is a residue that is capped with a polyethylene glycol-like structure.
  • the present invention can provide a targeted drug for spinal cord injury with excellent performance.
  • the present invention also provides an injection for spinal cord injury, which contains the above-mentioned targeted drug for spinal cord injury of the present invention and pharmaceutically acceptable auxiliary materials.
  • the invention provides a new drug synthesis method, which has high water solubility, can passively target the spinal cord injury area and can actively target specific neurons, and can promote the recovery of motor function when applied to rehabilitation after spinal cord injury.
  • the amphiphilic polymer compound and the hydrophobic nerve repair drug to be encapsulated are dissolved in an organic solvent, and then water is slowly injected into it, stirred slowly, and passed through the Self-assembled to form micelles, then the micelles solution was transferred to a dialysis bag, and deionized water was used for dialysis for 12-72 hours, and the nano micelles solution was freeze-dried,
  • the organic solvent is selected from DMSO, DMF, tetrahydrofuran, halogenated hydrocarbon solvents, C1-C6 alkanol solvents, ester solvents, benzene, toluene, pyridine and the like.
  • halogenated hydrocarbon solvent refers to a saturated or unsaturated chlorinated hydrocarbon with 1 or 2 carbon atoms, usually selected from dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane alkane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,1,2-tetrachloroethane, 1,1, 2,2-tetrachloroethane, pentachloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, trichloroethylene and tetrachloroethylene.
  • dichloromethane More preferred are dichloromethane, chloroform, 1,1,1-trichloroethane, trichloroethylene, and tetrachloroethylene, and further preferred are dichloromethane and chloroform.
  • C1-C6 alkanol solvents commonly used methanol, ethanol, isopropanol, n-butanol, cyclohexanol, etc. can be used, but not limited to these solvents.
  • ester solvents include solvents such as ethyl acetate, methyl acetate, and ethyl formate, but are not limited to these solvents.
  • the organic solvent is selected from DMSO, DMF, THF, halogenated hydrocarbons, C1-C6 alkanol solvents, ester solvents, benzene, toluene, and pyridine.
  • the targeted drug for spinal cord injury of the present invention is a polymer-hydrophobic compound micelle (hereinafter also referred to as the micelle of the present invention) is a class of nanomicelle, composed of a hydrophilic layer and a hydrophobic inner core, and the hydrophilic layer is composed of block
  • the brush-like PEG segment of the polymer provides the water solubility of the nanoparticles
  • the hydrophobic core is composed of a hydrophobic layer and a hydrophobic drug
  • the hydrophobic layer is composed of phenylboronic acid groups of block polymers and other similar segments.
  • the hydrophobic compound can pass through The self-assembly process is loaded within the hydrophobic layer.
  • the overall size is uniform in appearance, spherical in shape, and has good monodispersity.
  • the micelles of the present invention are particularly suitable for encapsulating hydrophobic drugs.
  • the above micelles of the present invention have good water solubility and can be made into injections. Therefore, the micelles of the present invention can be used for injection administration of poorly soluble drugs.
  • the amphoteric polymer compound used for self-assembly is preferably a compound represented by the above formula (1), more preferably the above formula (1- 1) Compounds shown.
  • the micelles of the present invention have a very obvious enrichment effect in the damaged spinal cord tissue after being administered by injection. Since the micelle of the present invention not only solves the water-solubility problem of poorly soluble drugs, but also has an enrichment effect in damaged spinal cord tissue, it greatly improves the delivery efficiency of therapeutic drugs after spinal cord injury.
  • a targeted drug for spinal cord injury which comprises the polymer-hydrophobic compound water-soluble micelle according to claim 1, and the hydrophobic compound is a hydrophobic drug.
  • X is preferably a group represented by formula (2), which has excellent encapsulation efficiency, is easier to prepare, and has less toxicity.
  • the principle of the present invention is shown in Figure 1.
  • the targeted nanomedicine is mainly composed of two parts, one of which is a block amphiphilic polymer, in which the hydrophobic part of the chain segment has the ability to react with active oxygen to provide ROS sacrificial agents and response functions.
  • the water chain segment provides nanometer water solubility; the second is targeting small molecule drugs, the main drug components of which are known neuron-related ionic protein agonists/inhibitors, and the targeting end is composed of neurotransmitters and their derivatives.
  • the hydrophobic drug is preferably GABA-modified CLP257, which has higher binding efficiency and delivery efficiency in the micelle delivery system of the present invention, and has significantly improved water solubility.
  • the present invention also provides a method for constructing active targeting drugs for neurons.
  • active targeting refers to increasing the uptake rate of drugs by neuron cells through structural modification.
  • the aggregation effect of the micelles of the present invention in the spinal cord injury tissue can be understood as a passive targeting effect. If the passive targeting effect of the micelles of the present invention is combined with the neuron active targeting drug, the most ideal technical effect of the present invention can be realized.
  • the invention realizes the construction of the neuron-targeted drug by linking the specific neurotransmitter with the drug precursor.
  • GABAergic neurons as the target and neuronal excitability regulator CLP-257 as the prodrug as an example
  • a brief introduction to its construction method is as follows (it should be noted that the following example is only for a clearer explanation , the synthesis method of the present invention is not limited thereto): dissolving CLP-257 in dimethyl sulfoxide (DMSO); then adding N, N'-carbonyldiimidazole, stirring slowly for 30 minutes; then adding ⁇ -aminobutyric acid (GABA), reacted overnight. The mixture was precipitated in deionized water and filtered to obtain a pale yellow solid. The resulting solid was then repeatedly washed with a large amount of methanol, and vacuum-dried to obtain the drug GABA-CLP that finally actively targets GABAergic neurons.
  • DMSO dimethyl sulfoxide
  • GABA ⁇ -a
  • the present invention provides a polymer-hydrophobic compound water-soluble micelle, which is formed by encapsulating the hydrophobic compound in the micelle formed by the association of amphoteric polymer compounds represented by the above formula (1).
  • the amphoteric polymer compound represented by the formula (1) of the present invention can not only be used in the present invention, but also can be used for the coating of other hydrophobic compounds to form water-soluble micelles, thereby improving the clinical use efficiency of poorly soluble drugs.
  • the present invention also provides a method for solubilizing insoluble drugs or insoluble compounds.
  • the so-called solubilization refers to increasing water solubility. Poorly soluble drugs or poorly soluble compounds.
  • an amphoteric polymer compound represented by the above formula (1) which can be used to form water-soluble micelles and can be used to solubilize poorly soluble substances.
  • active oxygen sacrificial groups on its surface, which is especially suitable for spinal cord injury drug delivery system, used for solubilization and drug delivery of poorly soluble drugs, not only increasing solubility, but also increasing tissue selectivity for spinal cord injury, It can also improve the therapeutic effect through active oxygen sacrificial groups, and has various excellent technical effects.
  • Hydrophilic segment construction step S1 using the chain transfer catalyst shown in formula (6), in the presence of a free radical initiator, the compound shown in formula (7) undergoes a free radical polymerization reaction, by controlling the formula (6)
  • the equivalent ratio of the shown chain transfer catalyst and the compound shown in formula (7) controls the degree of polymerization to be 20 ⁇ 40 to obtain the compound shown in formula (8),
  • the hydrophobic segment is combined with step S2 to make the compound represented by the formula (8) react with the compound of the formula (9) by free radical polymerization, and control the degree of polymerization to be 2 to 4 by controlling the equivalent ratio and reaction time to obtain the compound represented by the formula (1).
  • Z represents C1 ⁇ C15 alkyl group, C1 ⁇ C15 alkylthio group, C6 ⁇ C10 aryl group, preferably methyl, phenyl, dodecylthio group;
  • R1 and R2 are each independently Selected from hydrogen, C1-C5 alkyl, cyano, and R 1 and R 2 are not cyano at the same time;
  • E represents C1-C5 alkylene, C6-C10 arylene, C1-C5 alkylene Group-C6 ⁇ C10 arylene group, C6 ⁇ C10 arylene group-C1 ⁇ C5 alkylene group, or E may not exist;
  • R 3 represents C1 ⁇ C5 alkyl group, hydroxyl group, COOR 5 , R 5 represents hydrogen, C1-C5 alkyl, N-succinimide, PEG residue;
  • R 4 and R 7 are each independently hydrogen or methyl;
  • R 6 represents hydrogen, C1-C5 alkyl, hydroxyl;
  • R x represents a divalent group selected from phenylene substituted by phenyl, -ph-COO-, ph-CONH-, -COO-, -CONH-;
  • R y represents absence, or a divalent group selected from C1-C5 alkyl, N-succinimide, and PEG residues;
  • X is one of the groups of the following formulas (2) to (5):
  • R 8 and R 9 are each independently hydrogen, C1-C5 alkyl, C6-C10 aryl, C1-C5 alkyl sulfide group;
  • R 10 are each independently hydrogen, C1-C5 alkyl, Hydroxyl group, C1-C5 alkyl ether group, C1-C5 alkyl sulfide group.
  • the compound of formula (7) is the compound of following formula (7-1)
  • the compound of formula (9) is the compound of following formula (9-1)
  • the synthesis method of the amphoteric polymer compound represented by the above formula (1) of the present invention is essentially to self-assemble the hydrophilic-lipophilic block polymer prepared by controllable polymerization in aqueous solution to form nanocarriers.
  • preferred polymer can be POEGMA (methacrylic acid polyethylene glycol monomethyl ether, namely in above-mentioned formula (7), R Be hydrogen , R 4 is methyl).
  • the chain transfer catalyst shown in formula (6) can be synthesized by oneself, also can obtain commercially available product, for example can obtain following available chain transfer catalyst from Merck reagent company: 4-cyano group-4-(phenyl thioformyl Thio)valeric acid, 4-cyano-4-[(phenylthiomethyl)thio]-2,5-dioxo-1-pyrrolidinylvaleric acid (Cas No.864066-74- 0), 2-[dodecylthio(thiocarbonyl)thio]-2-methylpropionic acid (Cas No.461642-78-4), 2-cyano-2-propyldodecyl Trithiocarbonate (Cas No.870196-83-1), 2-cyano-2-propyl-4-cyanobenzenedithiocarbonate (Cas No.851729-48-1), polyethylene glycol Alcohol-4-cyano-4-(phenylcarbonylthio)pentanoate PEG CTA,
  • the radical polymerization initiator used in the above method of the present invention is not particularly limited, and azo compounds and peroxides can be used.
  • Azo compounds with hydrophilic groups such as carboxyl and sulfonic acid groups are suitable for aqueous solution polymerization, and the water-soluble ones include azodiisobutylamidine hydrochloride (V-50 initiated agent), suitable for initiating decomposition reactions at moderate temperatures.
  • V-50 initiated agent azodiisobutylamidine hydrochloride
  • peroxygen compound As a peroxygen compound, it is a kind of compound containing peroxy group (—O—O—). After being heated, the—O—O—bond is broken and split into two corresponding free radicals, thereby initiating the polymerization of monomers, which is called peroxide. oxide initiator. There are two types of inorganic peroxides and organic peroxides.
  • Inorganic peroxide initiators include hydrogen peroxide, ammonium persulfate or potassium persulfate, etc., which are soluble in water and used as initiators for aqueous solution polymerization and emulsion polymerization; organic peroxide initiators include benzoyl peroxide , benzoyl tert-butyl peroxide, methyl ethyl ketone peroxide, etc.
  • Preferably used in the present invention are azos, particularly preferably AIBN.
  • the first step is to dissolve polyethylene glycol monomethyl ether methacrylate, controllable chain transfer agent (chain transfer catalyst shown in formula (6), 2,2-azobisisobutyronitrile (AIBN) in 1, 4 dioxane; after it is fully dissolved, add the mixed solution to the Schlenk tube, connect it with nitrogen, and fill it with nitrogen; then the mixed solution is frozen by liquid nitrogen and vacuum pumped for 5-10 minutes, and the After thawing with nitrogen filling, repeat freezing and pumping three times; then transfer the thawed mixed solution to a 70°C oil bath, continue filling nitrogen, and stir slowly for 12-24 hours; then remove the solvent in the mixed solution by rotary evaporation, and dry it in anhydrous Settled three times in ether; finally obtained a red oily polymer POEGMA.
  • chain transfer catalyst shown in formula (6) 2,2-azobisisobutyronitrile (AIBN) in 1, 4 dioxane
  • the second step is also to synthesize a hydrophobic ROS-responsive segment after the obtained water-soluble polymer through a controlled polymerization method
  • the so-called ROS-responsive segment refers to that the phenylboronic acid in the phenylboronic acid segment can react with active oxygen and consume Active oxygen generates phenolic groups and produces phenylboronic acid which is removed from the polymer main chain, which affects the stability of micelles
  • BAA 3-acrylamidophenylboronic acid
  • the present invention cleverly designs the amphoteric polymer compound shown in formula (1), so that hydrophobic molecules, especially hydrophobic drugs, can be conveniently self-assembled with it into nano-micelle particles.
  • hydrophobic molecules especially hydrophobic drugs
  • the operation method of self-assembly will be introduced in detail.
  • POEGMA-BAA and GABA-CLP were dissolved in DMSO, then slowly injected into ionized water and stirred slowly to form nanoparticles by self-assembly. Then the nanoparticle solution was transferred to a dialysis bag and dialyzed in deionized water for 24-72 hours; finally, the solution was lyophilized to obtain the nanomedicine GABA-Nano and stored in a refrigerator at 4°C.
  • the invention utilizes controllable polymerization to synthesize ROS-responsive polymers, utilizes the neurotransmitter modification of drug prodrugs, and loads drugs through self-assembly to prepare targeted nano-medicines for spinal cord injuries.
  • the present invention provides targeted nano-medicine for spinal cord injury and its synthesis method. Compared with the prior art, it has the following significant advantages:
  • nano-drugs are far superior to ordinary small-molecule drugs in water solubility, and have no obvious cytotoxicity and in vivo side effects;
  • the obtained nanomedicine can be efficiently enriched to the injured spinal cord, and can effectively target specific neurons to improve the efficacy of the drug;
  • the obtained drug can be easily injected into the tail vein, which is different from the more dangerous drug methods such as intrathecal injection of the spinal cord and secondary surgery, and the safety and possible clinical risks are greatly reduced;
  • the obtained drug has a long metabolism time in the body, and due to the targeting effect, etc., its dosage can be greatly reduced to reduce the side effects of the drug.
  • Figure 1 is a schematic diagram of the synthesis method of targeted nano-medicine for spinal cord injury
  • Figure 2 is a diagram representing the synthesis and characterization of nanomedicines
  • Figure 3 is a diagram of the characterization of targeted drugs
  • Fig. 4 is the figure of the cell safety and antioxidant characterization of nanomedicine
  • Figure 5 is a diagram of the spinal cord enrichment and targeting capabilities of nanomedicines
  • Fig. 6 is the graph of the breakthrough spinal cord-vascular barrier ability of nanomedicine
  • Figure 7 is a graph of the in vivo safety of nanomedicines
  • Fig. 8 is the figure that nano-medicine is to the evaluation of spinal cord tissue protection ability
  • Fig. 9 is a figure of functional recovery evaluation under ROS NANO and PBS treatment after spinal cord injury;
  • Figure 10 is a graph showing the functional recovery evaluation of nano-medicines GABA Nano and DOPA Nano after spinal cord injury.
  • BAA 3-acrylamidophenylboronic acid
  • GABA gamma-aminobutyric acid
  • ROS reactive oxygen species
  • ROS NANO active oxygen sacrificial agent nanoparticles
  • PBS Phosphate Buffered Saline
  • CCK-8 Cell Viability Detection Kit
  • LPS lipopolysaccharide
  • DOPA dopamine
  • PBST phosphate buffered saline containing Tween-20
  • iNOS/IBA1 Activated immune cell specific antibody/microglial cell specific antibody
  • GFAP/NeuN Astrocyte-specific antibody/Neuron cell-specific antibody.
  • the process of synthesizing POEGMA 30 is as follows:
  • Polymer POEGMA 30 (1.41g, ⁇ 0.1mmol, 1equ.), AIBN (1.6mg, 0.01mmol, 0.1equ.), BAA (12mg, 0.062mmol) were dissolved in N,N-dimethylformamide (1.5 mL); after it is fully dissolved, add the mixed solution to the Schlenk tube, connect it with nitrogen, and fill it with nitrogen for 2 minutes; then the mixed solution is frozen in liquid nitrogen, vacuum pumped for 5-10 minutes, and then thawed with nitrogen at normal pressure Then, repeat the operation three times; then, transfer the thawed mixed solution to an oil bath at 70°C, continuously fill with nitrogen, and stir slowly for 12 hours; then remove the solvent in the mixed solution by rotary evaporation, and settle twice in anhydrous ether, and then Dissolved in water and dialyzed for 24 hours to obtain an aqueous solution which is the nanocarrier.
  • the yellow oil obtained by freeze-drying is the polymer POEGMA 30 -BAA 2
  • the third step is the targeted modification of the drug, which is the synthesis of GABA-CLP.
  • the synthesis process is as follows:
  • the fourth step is the loading of targeted nano-drugs, the process is as follows:
  • Figure 7 shows the in vivo safety of nano-drugs; the specific meanings of each part are: (a, b) the metabolic distribution of main organs in the nano-drug; (c) H&E tissue sections of main organs and normal organs in the body after administration Compare;
  • GABA Nano@cy5.5 and DOPA Nano@cy5.5 were injected through the tail vein 3 hours after injury.
  • rats were deeply anesthetized with sodium pentobarbital (0.5 ml/100 g) and intracardiacly perfused with 4% paraformaldehyde.
  • the heart, liver, spleen, lung, kidney, brain and spinal cord were collected and observed with an in vivo fluorescence imaging system (CRi Company, MK50101-EX, USA).
  • intact animals and SCI animals were injected with GABA Nano@cy5.5 at 4, 7, and 14 days after injury. Spinal cords were dissected 6 hours after injection and tested with an in vivo fluorescence imaging system and immunofluorescent histology.
  • GABA-Nano (Cy5.5) is obtained through the above synthesis process by using the fluorescent agent Cy5.5 as a fluorescent label instead of the drug CLP257; in the second step, GABA-Nano (Cy5.5) is injected through the tail vein The method is to enter the spinal cord injury model rats; the third step is to take rats at different time periods (3h, 6h, 24h) to observe the spinal cord enrichment and GABAergic neuron targeting effect of GABA-Nano (Cy5.5).
  • the characterization results are shown in Figure 4.
  • GABA-Nano (Cy5.5) exhibits high enrichment of the spinal cord injury area and good targeting effect.
  • each part in Figure 5 are: (a, b) Nanomedicine Schematic diagram of the experimental process of timely delivery and fluorescent labeling after spinal cord injury; (c, d, e) fluorescent photos of the spinal cord in vivo and related statistics of nanomedicines; (f, g, h.i) photos of cell targeting of nanomedicines in the spinal cord and related statistics; (j) Targeting efficiency of nanomedicines GABA Nano and DOPA Nano.
  • water-soluble micelles (sometimes simply referred to as micelles in the present invention) can protect cells from ROS-induced apoptosis.
  • Medium containing H 2 O 2 (100 ⁇ M) was used in cell culture.
  • ROS Nano, GABA Nano, and DOPA Nano were also added to the medium at concentrations ranging from 0 to 1 mg/ml, respectively. After 24 hours, cells were washed twice with PBS and detected with CCK-8.
  • LPS-containing medium to mimic the ROS microenvironment after tissue injury.
  • Cells were cultured with medium containing LPS (100ng/mL), and treated with ROS Nano, GABA Nano and DOPA Nano (250 ⁇ g/ml) for 6 hours. Then, 10 ⁇ M of DCFH-DA was added, and DCFH-DA detection was performed at 37°C for 20 min, followed by observation with an inverted fluorescence microscope.
  • Figure 4(c) Quantitative statistics of dead and alive CCK8 after three drug nanomicelles ROS Nano, GABA Nano and DOPA Nano were co-cultured with PC12 cells treated with H 2 O 2 (100 ⁇ M) for 24 hours at different concentrations;
  • nanoparticles at a concentration of only 0.25 mg/mL can also significantly increase the survival rate of cells in the presence of hydrogen peroxide at a concentration of 100 ⁇ M.
  • the weekly intravenous injection of GABA Nano was used to observe the functional recovery within 9 weeks on the rat spinal cord injury model.
  • the specific operation method is as follows:
  • the spinal cord contusion model was established by an infinite vertical impactor (68099, China RWD Life Science Company). To expose the dorsal side of the spinal cord, a laminectomy was performed at the level of the 10th thoracic vertebra (T10-11), while the rat was anesthetized with sodium pentobarbital (0.5 ml/100 g). Then, the tip of the 68099 impactor was lowered until it just touched the exposed spinal cord. Spinal cord contusion was performed by hitting the spinal cord with a 3 mm diameter cylinder at a speed of 2.5 m/s. After the operation, the muscles and skin were sutured, and the rats were placed on an electric heating pad to maintain body temperature at 32°C until they woke up.
  • each section are: (a) Schematic diagram of the experimental process and design; (b, c) WB characterization and statistics of inflammatory and apoptotic factors in the spinal cord treated with ROS NANO and PBS after spinal cord injury; (d) After spinal cord injury Cross-sectional iNOS/IBA1 and GFAP/NeuN immunofluorescence photos of the injury center treated with ROS NANO and PBS to observe the inflammation and cell survival; (e, f, g) Optical photos, H&E staining and 3D reconstruction photos between the two groups; (h) Statistics of cavities and residual tissues after injury; (i-n) Histomorphological photographs and quantitative differences between the two groups.
  • Example protein 40 ⁇ g/sample protein was loaded onto a 10% polyacrylamide gel, separated by SDS PAGE, and transferred to a polyvinylidene fluoride membrane. After blocking with 5% skim milk in PBST for 1 hour at room temperature, the membrane was moved to primary antibodies (rabbit anti-TGF- ⁇ , rabbit anti-Bcl-2, rabbit anti-Bax, diluted 1:1000 in 5% BSA) and incubated in overnight at 4°C. After washing 3 times with PBST, the membrane was incubated in secondary antibody (goat anti-rabbit HRP) for 1 hour at room temperature. The protein signal was then visualized with an ECL kit and measured with Image Lab software provided by Bio-Rad. The results show that as shown in Figure 8(b,c), the nanomedicine has good anti-apoptosis and anti-inflammation effects. 2.3.5 Behavioral assessment and electromyography (EMG) recording
  • Rats were behaviorally assessed weekly in the open environment according to the original report from the BBB. For detailed hindlimb kinematic analysis, follow the reported procedure. The hindlimb movements of different groups of rats were recorded using MotoRater (Vicon Motion Systems, UK). Movements of stick views and rotational angles of the hindlimbs were performed by MATLAB in a blinded manner.
  • bipolar electrodes Eight weeks after contusion, implantation of bipolar electrodes was performed as reported. Briefly, the electrode (AS632, Connor wire) was drawn out from a 5-gauge needle and inserted into the mid-abdomen of the medial gastrocnemius (GS) and tibialis anterior (TA) muscles of the hindlimb of the rats, while the rats were deeply anesthetized. Insert a common ground wire subcutaneously in the Achilles tendon region of the hindlimb. The wires run subcutaneously through the back to a small percutaneous connector firmly secured to the rat's skull.
  • AS632 medial gastrocnemius
  • TA tibialis anterior
  • EMG signals were acquired using a differential neuronal signal amplifier (BTAM01L, Braintech, China), filtered at 30–2000 Hz, sampled at 30 kHz using a Neurostudio system (Braintech, China), and analyzed by a custom MATLAB code.
  • BTAM01L differential neuronal signal amplifier
  • Neurostudio system Braintech, China
  • Figure 9 shows the evaluation of functional recovery under the treatment of ROS NANO and PBS after spinal cord injury; the specific meanings of each part are: (a) BBB score statistics between the two groups; (b) schematic diagram of the rat hindlimb movement process; (c, d , e) Comparison of hindlimb gait, movement angle, muscle signal of normal group, ROS NANO and PBS group.
  • Figure 10 shows the evaluation of the functional recovery of the nano-medicines GABA Nano and DOPA Nano after spinal cord injury; the specific meanings of each part are: (a) BBB score statistics among the four groups; (b) the specific recovery degree distribution within the four groups; (c) , d, e) Comparison of hindlimb gait, movement angle, and muscle signals of normal group, GABA Nano and DOPA Nano groups; (f, g) Statistics of hindlimb muscle signals of GABA Nano and DOPA Nano groups; (h) four groups Statistical arrangement of differences in motor function between
  • GABA Nano can effectively improve the functional recovery effect of rats.
  • the behavioral BBB score of the rats has increased by nearly 4 points.
  • it can effectively improve the movement state of the rat's hind limbs, increase the amplitude of the joint activity of the rat's hind limbs, improve the control of the muscles by the spinal cord, and significantly enhance the muscle signals during the movement of the hind limbs.

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Abstract

Micelle hydrosoluble de composé hydrophobe polymère, qui peut aider à la dissolution de composés faiblement solubles. Lorsque la micelle est transformée en une solution aqueuse, la micelle présente un effet d'enrichissement ciblé et l'effet de promotion de la pénétration d'une barrière hémato-médullaire au niveau d'un site de lésion de la moelle épinière, peut aider à enrichir des médicaments neuromodulateurs faiblement solubles dans des tissus lésés de la moelle épinière, et peut être utilisée pour préparer des médicaments ciblés destinés à des lésions de la moelle épinière. L'invention concerne également un procédé de modification permettant d'améliorer le ciblage de médicaments neuromodulateurs faiblement solubles. Un polymère sensible aux ROS est synthétisé à l'aide d'une polymérisation contrôlée, des modifications de neurotransmetteur d'un promédicament sont utilisées, et un médicament est chargé au moyen d'un auto-assemblage pour préparer un nano-médicament ciblé destiné à une lésion de la moelle épinière.
PCT/CN2022/141903 2021-12-31 2022-12-26 Médicament ciblé contre une lésion de la moelle épinière, micelle de composé hydrophobe polymère et procédé de préparation d'un médicament ciblé contre une lésion de la moelle épinière WO2023125404A1 (fr)

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