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CN-122005836-A - Targeted mitochondrial lactate nano-drug compound, preparation method and application thereof

CN122005836ACN 122005836 ACN122005836 ACN 122005836ACN-122005836-A

Abstract

The invention discloses a targeted mitochondrial lactate nano-drug compound, a preparation method and application thereof, and belongs to the technical field of biological medicines. The nano-drug complex comprises a liposome delivery carrier, a lactic acid transporter MCT1 inhibitor AZD3965 loaded in the liposome, and a mitochondria targeting cationic group triphenyl phosphate TPP and a heart targeting peptide CTP coupled on the surface of the liposome. The nano-drug provided by the invention can effectively and rapidly deliver the effective drug lactic acid transport protein MCT1 inhibitor AZD3965 to mitochondria in the heart, effectively reduce lactic acid from entering the mitochondria, reduce the richness of the lactic acid modification of cardiac mitochondrial proteins, improve the cardiac function index of myocarditis groups, reduce the degree of cardiac fibrosis, improve myocardial mitochondrial injury, reduce the level of inflammatory factors and further play a role in improving myocarditis. And the nano-drug shows good in vivo safety and biocompatibility in vivo. The invention provides a new scheme for myocarditis treatment.

Inventors

  • SUN XUAN
  • XU BIAO
  • ZHAO YAWEI
  • CAI YUE

Assignees

  • 南京鼓楼医院

Dates

Publication Date
20260512
Application Date
20260226

Claims (10)

  1. 1. The targeted mitochondrial lactate nano-drug complex is characterized by comprising a liposome delivery carrier, a lactic acid transporter MCT1 inhibitor AZD3965 loaded in the liposome, and a mitochondrial targeted cationic group triphenyl phosphate TPP and a cardiac targeted peptide CTP coupled on the surface of the liposome.
  2. 2. A method of preparing a nano-drug complex according to claim 1, comprising the steps of: (1) Dissolving AZD3965 and lipid components in chloroform, rotary evaporating, vacuum drying, removing residual solvent, adding deionized water, oscillating in water bath to dissolve to form multi-layer liposome, sequentially passing through polycarbonate membranes of 400nm and 200nm by adopting a liposome extruder, extruding to obtain drug-loaded small single-chamber liposome with uniform particle size, centrifuging, washing to remove free liposome, and obtaining AZD3965@LNP; (2) Dissolving the prepared AZD3965@LNP in a 2-morpholinoethanesulfonic acid buffer solution, dropwise adding 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide, performing a shaking table reaction at room temperature, adding a heart targeting peptide CTP, stirring overnight to obtain the AZD3965@LNP@CTP, dropwise adding a mitochondrial targeting peptide TPP into the AZD3965@LNP@CTP, performing a shaking table reaction at room temperature, dialyzing the solution by a dialysis bag, and freeze-drying to obtain the AZD3965@LNP@CTP@TPP, namely the targeted mitochondrial lactonization nano-drug compound.
  3. 3. The method of claim 2, wherein the lipid component in step (1) comprises lecithin, cholesterol, and DSPE-PEG-COOH.
  4. 4. The method according to claim 2, wherein the temperature of the rotary evaporation in step (1) is 60 ℃, and the time of the vacuum drying is 4 hours.
  5. 5. The method according to claim 2, wherein the 2-morpholinoethanesulfonic acid buffer solution in step (2) has a pH of 5.5.
  6. 6. The method according to claim 2, wherein the temperature of the shaking table in the step (2) is 37 ℃.
  7. 7. The method of claim 2, wherein the pH is slowly adjusted to 7.2-7.6 with NaOH after adding the cardiac targeting peptide CTP in step (2).
  8. 8. The use of the targeted mitochondrial lactate nano-drug complex according to claim 1 in the preparation of a medicament for treating myocarditis.
  9. 9. The use according to claim 8, wherein the nano-drug complex is used for inhibiting the level of myocardial tissue protein lactogenesis, improving cardiac function index, improving myocardial sarcomere rupture, interstitial fibrosis and mitochondrial damage caused by myocarditis, and reducing myocardial inflammatory factor level.
  10. 10. The use of claim 8, wherein the myocardial inflammatory factors include IL-1 β, IL-6 and TNF- α.

Description

Targeted mitochondrial lactate nano-drug compound, preparation method and application thereof Technical Field The invention relates to a targeted mitochondrial lactate nano-drug compound, a preparation method and application thereof, and belongs to the technical field of biological medicines. Background Myocarditis is a non-ischemic heart disease characterized by immune inflammatory infiltration, usually caused by acute inflammation, and a part of patients can progress to continuous cardiac insufficiency, causing dilated cardiomyopathy, heart failure, sudden cardiac death, etc. In view of acute onset and poor prognosis of myocarditis, immunosuppressants (such as corticosteroids) are mainly used for first-line treatment clinically, and only mechanical circulatory assistance or heart transplantation can be used for patients with end-stage myocarditis. Current treatment regimens only alleviate the symptoms of the patient, and do not reverse the intrinsic damage of the cardiomyocytes, and there is no radical treatment to ameliorate myocarditis damage. The functioning of cardiac function is highly dependent on adequate energy supply, and cardiac dysfunction is often closely related to metabolic changes. The glycolysis level in the body of the myocarditis patient is obviously increased, a large amount of lactic acid is accumulated, and enters mitochondria to carry out lactate modification on key mitochondrial enzymes, so that mitochondrial dysfunction is caused, ATP energy is insufficient, and the myocarditis is promoted to progress. There is currently no research or clinical application of related types of drugs. Disclosure of Invention The invention aims to provide a nano-drug compound capable of precisely targeting heart mitochondria and reducing the modified abundance of protein lactonization, a preparation method thereof and application thereof in preparing medicaments for treating myocarditis. The targeted mitochondrial lactate nano-drug complex comprises a liposome delivery carrier, a lactic acid transporter MCT1 inhibitor AZD3965 loaded in the liposome, and a mitochondrial targeted cationic group triphenyl phosphate TPP and a cardiac targeting peptide CTP coupled on the surface of the liposome. The preparation method of the nano-drug compound comprises the following steps: (1) Dissolving AZD3965 and lipid components in chloroform, rotary evaporating, vacuum drying, removing residual solvent, adding deionized water, oscillating in water bath to dissolve to form multi-layer liposome, sequentially passing through polycarbonate membranes of 400nm and 200nm by adopting a liposome extruder, extruding to obtain drug-loaded small single-chamber liposome with uniform particle size, centrifuging, washing to remove free liposome, and obtaining AZD3965@LNP; (2) Dissolving the prepared AZD3965@LNP in a 2-morpholinoethanesulfonic acid buffer solution, dropwise adding 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide, performing a shaking table reaction at room temperature, adding a heart targeting peptide CTP, stirring overnight to obtain the AZD3965@LNP@CTP, dropwise adding a mitochondrial targeting peptide TPP into the AZD3965@LNP@CTP, performing a shaking table reaction at room temperature, dialyzing the solution by a dialysis bag, and freeze-drying to obtain the AZD3965@LNP@CTP@TPP, namely the targeted mitochondrial lactonization nano-drug compound. Further, the lipid component in step (1) comprises lecithin, cholesterol and DSPE-PEG-COOH. Further, the temperature of the rotary evaporation in the step (1) is 60 ℃, and the time of the vacuum drying is 4 hours. Further, the pH of the 2-morpholinoethanesulfonic acid buffer solution in the step (2) is 5.5. Further, the temperature of the shaking table in the step (2) is 37 ℃. Further, after the cardiac targeting peptide CTP is added in the step (2), the pH is slowly adjusted to 7.2-7.6 by NaOH. The invention relates to application of a targeted mitochondrial lactate nano-drug compound in preparation of a drug for treating myocarditis. Furthermore, the nano-drug compound is used for inhibiting the lactogenesis level of myocardial tissue protein, improving cardiac function index, improving myocardial sarcomere fracture, interstitial fibrosis and mitochondrial injury caused by myocarditis, and reducing the level of myocardial inflammatory factors. Further, the myocardial inflammatory factors include IL-1 beta, IL-6 and TNF-alpha Compared with the prior art, the nano-drug provided by the invention has the advantages that the nano-drug can effectively and rapidly deliver an effective drug lactic acid inhibitor AZD3965 to mitochondria in the heart, reduce the accumulation of lactic acid in the mitochondria, effectively reduce the lactic acid modification abundance of mitochondrial proteins of the heart, improve the cardiac function index of myocarditis groups, reduce the degree of cardiac fibrosis, improve myocardial mitochondrial injury, reduce the le