CN-122005860-A - Synergistic therapeutic pharmaceutical composition for preventing and treating recurrence of hepatocellular carcinoma after thermal ablation and application thereof

Abstract

The invention provides a synergistic therapeutic pharmaceutical composition for preventing and treating recurrence of hepatocellular carcinoma after thermal ablation and application thereof. Aiming at the malignant tumor progress driven by ACSS3 gene silencing after thermal ablation, the invention creatively combines an epigenetic editing technology with metabolite supplementation, and uses a preparation for specifically activating or promoting ACSS3 gene expression and sodium propionate cooperatively, so that ACSS3 can be remarkably reactivated or expression can be promoted in a cell line and a patient-derived xenograft model, propionyl coenzyme A synthesis and normal propionic acid metabolism can be restored, and fatty acid beta-oxidation can be inhibited, thereby effectively blocking growth and metastasis of hepatocellular carcinoma (HCC) after ablation, and overcoming the limitation of monotherapy. The invention provides a more definite mechanism target for preventing recurrence after HCC thermal ablation operation, and the prepared targeting nanoliposome preparation has a synergistic effect and is used as a brand new treatment strategy to overcome the defect of insufficient intervention of recurrence sources in the prior art.

Inventors

• CHEN YE
• Zhu Kangshun
• CAI YUJUN
• ZHANG YIN
• JIA CHENGYU
• XU HAN

Assignees

• 广州医科大学附属第二医院

Dates

Publication Date

20260512

Application Date

20260122

Claims (10)

1. 1. A pharmaceutical composition is characterized by comprising a preparation for specifically activating or promoting ACSS3 Gene expression and sodium propionate, wherein the mass ratio of nucleic acid to sodium propionate in the preparation is (0.1-1) (10-120), and the ACSS3 Gene ID in NCBI is 79611.
2. 2. The pharmaceutical composition of claim 1, wherein the agent that specifically activates or promotes expression of the ACSS3 gene is a recombinant vector, recombinant bacterium, or recombinant virus that specifically activates or promotes expression of a fragment of the ACSS3 gene.
3. 3. The pharmaceutical composition according to claim 2, wherein the preparation for specifically activating or promoting the expression of the ACSS3 gene is prepared by connecting a DNA sequence of a specific sgRNA targeting a CG island of a promoter region of the ACSS3 gene to a vector by a gene editing technology, wherein the DNA sequence of the sgRNA is shown as SEQ ID NO 3-5.
4. 4. The pharmaceutical composition of claim 3, wherein a CRISPR-dCas9 editing system is used to prepare a vector comprising a dCas9-TET1CD fusion protein coding sequence and a DNA sequence of sgRNA, wherein the dCas9-TET1CD fusion protein coding sequence is shown in SEQ ID No. 1.
5. 5. Use of a composition according to any one of claims 1 to 4 for the preparation of a product for the prevention and treatment of recurrence after thermal ablation of hepatocellular carcinoma.
6. 6. A product comprising a composition according to any one of claims 1 to 4.
7. 7. The product of claim 6, wherein the product is a targeted nanoliposome preparation, and wherein the surface of the targeted nanoliposome preparation is modified with a ligand that targets HCC.
8. 8. The method for preparing the product according to claim 7, wherein the carrier comprising the dCAS9-TET1CD fusion protein coding sequence and the sgRNA DNA sequence in claim 4 and sodium propionate are encapsulated in lipid nanoparticles together, and the surface of the particles is subjected to targeted ligand modification to prepare the targeted preparation, wherein the mass ratio of the lipid to the carrier is 10-50:1.
9. 9. Use of the product according to claim 6 or 7 for the preparation of a medicament for the prevention and treatment of recurrence after thermal ablation of hepatocellular carcinoma.
10. 10. The application of an agent for activating or promoting ACSS3 Gene expression in preparing a product for blocking liver cancer tumor growth and metastasis enhancement induced by heat stress is characterized in that the agent for activating or promoting ACSS3 Gene expression is a recombinant vector, recombinant bacteria or recombinant virus for specifically activating or promoting ACSS3 Gene expression fragments, and the ACSS3 Gene in NCBI has Gene ID of 79611.

Description

Synergistic therapeutic pharmaceutical composition for preventing and treating recurrence of hepatocellular carcinoma after thermal ablation and application thereof Technical Field The invention relates to the technical field of biological medicines, in particular to a synergistic therapeutic pharmaceutical composition for preventing recurrence after thermal ablation of hepatocellular carcinoma and application thereof. Background Thermal ablation is a first-line radical therapy for early unresectable hepatocellular carcinoma (HCC), but clinically faces the serious challenge of high postoperative recurrence rate. The existing research shows that sublethal heat stress caused by incomplete ablation is an important root of recurrence, and can promote survival and invasion of residual tumor cells through various ways of inducing expression of heat shock proteins (such as HSP 90) and triggering DNA damage reaction. In recent years, the role of epigenetic changes in tumor stress adaptation has been gradually recognized, and studies have also pointed out that heat stress may affect DNA methylation patterns (references 1, 2). Prior art interventions for post-ablative recurrence have typically focused on non-specific adjuvant chemotherapy, targeted therapies (such as sorafenib) or secondary ablations, which either lack specificity for the specific biological process of "post-ablative recurrence" or are limited by lack of toxicity or efficacy. Even if research focuses on the association of heat stress with epigenetic properties, it rarely goes back to specific functional metabolic targets downstream and provides an accurate means of reversal. Current studies have a significant drawback and disadvantage in understanding the mechanism of recurrence after ablation-first, cognition presents fragmentation. The current research focused on single pathways triggered by heat stress (e.g., HSP, apoptosis) failed to integrate these cues into a complete, ordered cascade of molecules from stress perception to epigenetic remodeling to downstream functional metabolic reprogramming. Second, key effector targets and intervention approaches are absent. Wherein the critical downstream effector genes and their specific role in metabolic remodeling have not been elucidated, resulting in the lack of specific therapeutic targets capable of precisely reversing this malignancy. The existing means for preventing recurrence is not designed for the specific biological process of recurrence after ablation, so the curative effect is limited and the side effect is large. Therefore, the state of the art stays in observation of phenomena and part of intermediate links, and the fundamental defect is that the core axis mechanism driving the continuous progress of HCC after ablation cannot be resolved, so that accurate therapies and medicines thereof for intervention from the root cannot be developed. The present application is thus presented. Reference is made to: 1.Zhu, S. et al. Targeting N(7)-methylguanosine tRNA modification blocks hepatocellular carcinoma metastasis after insufficient radiofrequency ablation. Mol. Ther. 31, 1596-1614 (2023). 2.Su, T. et al. Insufficient radiofrequency ablation promotes hepatocellular carcinoma metastasis through N6-methyladenosine mRNA methylation-dependent mechanism. Hepatology. 74, 1339-1356 (2021). Disclosure of Invention The invention aims to solve the technical problems that the existing research causes unclear intervention targets, lack of treatment means, difficulty in specifically and radically blocking malignant progress of HCC after ablation and the like due to unclear cognition of a recurrence driving mechanism of thermal ablation, and the defect of treatment drugs for preventing recurrence after the thermal ablation of hepatocellular carcinoma. The invention provides a synergistic therapeutic pharmaceutical composition for preventing recurrence after thermal ablation of hepatocellular carcinoma and application thereof. It is a first object of the present invention to provide a pharmaceutical composition. A second object of the present invention is to provide the use of a pharmaceutical composition. A third object of the invention is to provide a product. A fourth object of the present invention is to provide a process for the preparation of the above-mentioned product. It is a fifth object of the present invention to provide the use of the above product. A sixth object of the present invention is to provide the use of a preparation for activating or promoting ACSS3 gene expression in the preparation of a product for blocking the growth and metastasis enhancement of liver cancer tumors induced by heat stress. The above object of the present invention is achieved by the following technical scheme: The invention discloses that silencing of acyl-CoA synthetase short chain family member 3 (ACSS 3) directly leads to propionic acid metabolic disorder for the first time, thereby driving fatty acid oxidation an