CN-119875122-B - Hyperbranched polymer, nano preparation, and preparation methods and applications thereof

Abstract

The invention relates to a hyperbranched polymer, a nano preparation, a preparation method and application thereof, belonging to the technical field of functional medical materials and nano. The hyperbranched polymer provided by the invention can be used for releasing dihydrolipoic acid in a breaking way in an ROS environment, playing an antioxidant role, reducing the dihydrolipoic acid into lipoic acid in vivo, playing a role of the lipoic acid serving as a coenzyme, participating in mitochondrial tricarboxylic acid circulation and recovering mitochondrial functions, thereby playing an antioxidant role and a role in treating ischemic cerebral apoplexy. The nano preparation provided by the invention can be rapidly distributed to the brain in a short time, the paracellular permeability of the BBB is temporarily increased by inhibiting the expression of multi-drug resistant protein P-gp and ATP-dependent drug efflux protein on the BBB, and the process of opening the BBB by borneol is physiological and reversible and does not damage the structural integrity of blood brain barrier.

Inventors

• HE ZHIYU
• MA XUTAO
• WANG YANAN
• LIU LIRU
• CUI PENGFEI
• QIU CHENHU

Assignees

• 中国海洋大学

Dates

Publication Date

20260512

Application Date

20250109

Claims (9)

1. 1. A nano-formulation, characterized in that the nano-formulation comprises a hyperbranched polymer and borneol; the nano preparation is prepared by performing polycondensation on hyperbranched polymer and borneol under the action of condensing agent, and then performing self-assembly; the molar ratio of the hyperbranched polymer to the borneol is (1.00-5.00): 0.20-1.00; The hyperbranched polymer is prepared from a compound A and a compound B through mercapto-alkynyl click chemical photoinitiated free radical polymerization, wherein the structure of the compound A is shown in a formula I, and the structure of the compound B is shown in a formula II: wherein R 1 and R 2 are each independently-OH.
2. 2. The preparation method of the hyperbranched polymer according to claim 1 comprises the steps of mixing a compound A, a compound B and a photoinitiator, and irradiating the mixture by an ultraviolet lamp to obtain the hyperbranched polymer.
3. 3. The nanoformulation of claim 2, wherein the photoinitiator comprises at least one of benzoin monomethyl ether, benzophenone, phenothiazine, vinyl styrene, and cyclohexylamino benzophenone.
4. 4. The nano-preparation according to claim 2, wherein the molar ratio of the compound A to the compound B to the photoinitiator is (4.00-20.00): 1.00-5.00): 0.50-2.50.
5. 5. The nano preparation according to claim 2, wherein the preparation method of the compound A comprises the following steps of carrying out reduction reaction on a raw material A under the action of a reducing agent to obtain the compound A, wherein the structure of the raw material A is shown as a formula A: In formula A, R 1 is-OH.
6. 6. The nano-formulation according to claim 2, wherein the preparation method of the compound B comprises the steps of: (1) Esterifying lipoic acid to obtain lipoic acid ester; (2) Carrying out reduction reaction on the lipoic acid ester obtained in the step (1) under the action of a reducing agent to obtain dihydro lipoic acid ester; (3) And (3) carrying out an alkynylation reaction of sulfhydryl groups on the dihydrolipoic acid ester obtained in the step (2) and an alkynyl-containing compound, and then carrying out hydrolysis to obtain the compound B.
7. 7. A method for preparing the nano-preparation according to claim 1, which is characterized by comprising the steps of polycondensing hyperbranched polymer and borneol under the action of condensing agent, and then self-assembling to obtain the nano-preparation.
8. 8. The method of claim 7, wherein the molar ratio of hyperbranched polymer to borneol is (1.00-5.00): 0.20-1.00.
9. 9. The use of the nano-preparation of claim 1 in the preparation of a medicament for treating ischemic stroke.

Description

Hyperbranched polymer, nano preparation, and preparation methods and applications thereof Technical Field The invention belongs to the technical field of functional medical materials and nano, and particularly relates to a hyperbranched polymer, a nano preparation, a preparation method and application thereof. Background Ischemic stroke (Ischemic Stroke, IS) IS mainly caused by cerebral vessel occlusion, resulting in a decrease or interruption of blood supply to brain tissue, and thus in a decrease in the delivery of essential nutrients and oxygen, thereby inducing an anoxic state in brain tissue, and the anoxic condition promotes the recruitment of leukocytes to the focus, exacerbating oxidative stress and inflammatory injury, and further exacerbating brain tissue injury. In addition, recanalization of occluded blood vessels may lead to secondary cerebral ischemia/reperfusion (I/R) injury, thereby expanding infarct size, exacerbating neuronal damage and dysfunction. And damaged neurons and astrocytes produce Reactive Oxygen Species (ROS), which in turn exacerbate neuronal and vascular damage. Thus, prolonged oxidative stress and inflammatory reactions may ultimately lead to disruption of the blood brain barrier (Blood brain barrier, BBB), further exacerbation of brain tissue, and may ultimately lead to brain parenchymal necrosis. The blood brain barrier is a physiological barrier between blood and brain tissue formed by brain capillary endothelial cells and glial cells, and can effectively prevent toxins and other exogenous harmful substances from entering the brain to damage the nerve cells. It has been reported that only small molecules with lipid solubility and molecular weight <400Da can cross the BBB, and that about 98% of small molecule drugs and almost 100% of large molecule drugs cannot enter the brain through peripheral administration, so the presence of the BBB greatly hinders the development of drugs for central nervous system diseases. At present, no good medicine capable of being widely used for treating cerebral apoplexy exists. The appearance of thrombolytic agents has epoch-making significance for the study and treatment of cerebral apoplexy. A clinically common drug for treating stroke is tissue plasminogen activator (Tissue plasminogen activator, tPA), which can be used for intravenous thrombolysis, but only a few patients can be effectively treated at present, and most stroke patients are not effectively treated due to the limitation of treatment conditions and side effects of the drug (increasing the risk of cerebral hemorrhage). In addition, neuroprotective agents such as glutamate receptor antagonists, antioxidants, apoptosis inhibitors, cell membrane stabilizers, etc. have been found in preclinical trials to be the most potential therapeutic agents for stroke in current neuroprotection protocols by antagonizing, interfering with or slowing down the main pathophysiological processes of nerve damage. Unfortunately, most neuroprotective drugs have proven ineffective in clinical phase II/III trials. There are two structures of lipoic acid in organism, one is oxidation type alpha-lipoic acid (alpha-Lipoic Acid, ALA) and one is reduction type dihydro lipoic acid (Dihydrolipoic Acid, DHLA), both of which have antioxidant capacity in vivo, and both of which can mutually transform to cooperatively play the role of antioxidant. Lipoic acid is an effective mitochondrial antioxidant and plays a central role in the establishment and maintenance and enhancement of the antioxidant defense network in vivo by effectively scavenging ROS and regenerating key antioxidants (e.g., glutathione, GSH). In addition, lipoic acid is an essential coenzyme for mitochondrial metabolism, and is a coenzyme involved in the reaction necessary for the catalysis of mitochondrial 2-ketoacid dehydrogenase complex, and it acts on important enzyme systems such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and branched-chain ketoacid dehydrogenase. The absence of lipoic acid blocks the tricarboxylic acid cycle (the alpha-ketoglutarate cycle to succinyl-CoA). When inflammation occurs, down-regulated expression of Lipoic Acid Synthase (LASY) decreases, and down-regulation of LASY results in a decrease in endogenous lipoic acid that results in redox imbalance, leading to inflammation and mitochondrial dysfunction. Compared with the traditional nanometer preparation, the lipoic acid is easy to be rapidly metabolized in the first pass metabolism process of liver after being orally taken, the elimination half-life is within 30min, the effective concentration of the lipoic acid in the body is insufficient, and the bioavailability is low. Therefore, development of prodrug nano-formulations based on which lipoic acid is constructed is particularly urgent to improve the bioavailability and enhance the therapeutic effect. Disclosure of Invention The invention aims to overcome the problems in the prior art and provide a h