Application of Lanifibranor or pharmaceutically acceptable salt thereof in preparation of medicine for inhibiting progress of abdominal aortic aneurysm

Abstract

The invention provides an application of Lanifiranor or a pharmaceutically acceptable salt thereof in preparing a medicine for inhibiting the progress of abdominal aortic aneurysm, and the application is realized by the following mechanisms: (a) regulating lipid metabolism of adventitious fibroblasts and maintaining phenotypes of the adventitious fibroblasts; and / or, (b) inhibiting the transformation of adventitious fibroblasts to myofibroblasts; and / or (c) reducing the expression levels of the pro-inflammatory cytokines IL-6 and MCP-1. According to the application provided by the invention, through a multi-mechanism synergistic effect, the AAA pathological process is systematically regulated and controlled at a molecule-cell-tissue level, and a first novel treatment strategy with etiological treatment and structure protection is provided for clinic.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and particularly relates to use of lanifibranor or a pharmaceutically acceptable salt thereof in preparing a medicament for inhibiting the progression of abdominal aortic aneurysm. Background Art

[0002] Abdominal aortic aneurysm (AAA) is a fatal disease characterized by progressive dilation of the aortic wall. Its pathophysiology involves a complex process involving vascular wall inflammation, extracellular matrix degradation, and smooth muscle cell apoptosis. Current clinical treatments rely primarily on surgical intervention or endovascular repair, but both have significant limitations. Surgical intervention is generally only suitable for aneurysms reaching a specific diameter threshold (≥5.5 cm in men and ≥5.0 cm in women). Smaller AAAs, while carrying a higher risk of rupture (approximately 20% of ruptures occur in cases <5.5 cm in diameter), lack effective pharmacological treatments. Despite recent advances in understanding the pathogenesis of AAA, targeted therapies that modulate key cellular phenotypes to delay or reverse AAA progression remain unresolved. Summary of the Invention

[0003] The present invention aims to provide the use of lanifibranor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the progression of abdominal aortic aneurysm. Through the synergistic action of multiple mechanisms, the pathological process of AAA is systematically regulated at the molecular-cellular-tissue level, providing the first novel therapeutic strategy for the clinic that combines etiological treatment with structural protection.

[0004] The present invention provides use of lanifibranor or a pharmaceutically acceptable salt thereof in preparing a medicament for inhibiting progression of abdominal aortic aneurysm (AAA).

[0005] In one embodiment of the present invention, the use is achieved through the following mechanism: (a) Regulate lipid metabolism of adventitial fibroblasts to maintain their phenotype; and / or, (b) inhibiting the transformation of adventitial fibroblasts into myofibroblasts; and / or, (c) Reduce the expression levels of pro-inflammatory cytokines.

[0006] In one embodiment of the present invention, the inflammatory cytokine is at least one of IL-6 and MCP-1.

[0007] In one embodiment of the present invention, the drug is administered to the adventitia of the abdominal aorta via a local delivery system.

[0008] In one embodiment of the present invention, the delivery system is a mechanical biomimetic elastomeric material.

[0009] In one embodiment of the present invention, the mechanical biomimetic elastomer material is used to provide external mechanical support and sustained drug release to tubular biological tissues; the mechanical biomimetic elastomer material is an elastomer PGS-SS-DOU, and lanifibranor or a pharmaceutically acceptable salt thereof is loaded on the elastomer PGS-SS-DOU; wherein the structural formula of the elastomer PGS-SS-DOU is shown in formula (I), (I).

[0010] In one embodiment of the present invention, the Young's modulus of the elastomer PGS-SS-DOU is 0.3-0.8 MPa, the elongation at break is ≥1000%, and it can achieve self-healing within 1 minute in a humid environment.

[0011] In one embodiment of the present invention, the loading amount of the lanifibranor on the elastomer PGS-SS-DOU is 0.1 wt.% to 2 wt.%.

[0012] In one embodiment of the present invention, the preparation of the elastomer PGS-SS-DOU comprises the following steps: (1) Dissolving the PGS prepolymer in an organic solvent to form a PGS solution; (2) dissolving polytetramethylene ether glycol, dimethylglyoxime, and bis(4-hydroxyphenyl) disulfide in an organic solvent, adding isophorone diisocyanate and a catalyst, and stirring the mixture at 40-60° C. for 2-6 hours to obtain a mixed reaction solution; (3) The PGS solution of step (1) is added to the mixed reaction liquid of step (2), stirred evenly and then injected into a mold. After solvent evaporation and curing treatment, the elastomer PGS-SS-DOU is obtained.

[0013] In one embodiment of the present invention, the effective concentration of the drug is 5 μM.

[0014] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides a use of lanifibranor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the progression of abdominal aortic aneurysm. Lanifibranor achieves multi-dimensional intervention in the pathological process of abdominal aortic aneurysm (AAA) by simultaneously regulating the lipid metabolic homeostasis of adventitial fibroblasts (AFs), inhibiting their transformation into pro-fibrotic myofibroblasts (myoFBs), and reducing the expression of pro-inflammatory factors IL-6 and MCP-1. This synergistic effect breaks through the limitations of traditional single-target therapy, jointly blocking AAA progression from three aspects: maintaining cell phenotype, regulating the inflammatory microenvironment, and inhibiting fibrosis, providing a new approach for the treatment of abdominal aortic aneurysm.

[0015] The present invention provides a use of lanifibranor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the progression of an abdominal aortic aneurysm. The medicament is administered to the adventitia of the abdominal aorta via a local delivery system. The delivery system is a mechanical biomimetic elastomeric material that provides mechanical protection while avoiding stress shielding effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Other features, objects and advantages of the present invention will become more apparent upon reading the detailed description of non-limiting embodiments with reference to the following drawings: Figure 1 Schematic diagram of the design of PGS-SS-DOU@Lanifibranor elastomer and the treatment strategy for the adventitia of abdominal aortic aneurysms; Figure 2 This is the UMAP distribution diagram of the tissue cells of the mouse abdominal aortic aneurysm and the control group in Example 1; Figure 3 This is a graph comparing the expression levels of Vimentin, Acta2, Ccl2, and Timp1 genes in fibroblast clusters of the AAA group and the control group in Example 1 (mouse single-cell sequencing results); Figure 4 Schematic diagram of the myofibroblast transformation of adventitial fibroblasts during abdominal aortic aneurysm; Figure 5 Figure 1 is the result of identification of the phenotype of cultured adventitial fibroblasts (AFs); Figure 6 The figure shows the results of Western blot analysis of the expression of myofibroblast markers (α-SMA and Collagen I) under treatment with different concentrations of Lanifibranor in Example 2; Figure 7 Representative images of α-SMA immunofluorescence staining under different concentrations of lanifibranor treatment in Example 2, used to evaluate the myofibroblast transformation of adventitial fibroblasts; scale bar = 100 μm; Figure 8 The figure shows the quantitative expression levels of myofibroblast markers (α-SMA and Collagen I) based on Western blot images in Example 2; *p < 0.05, **p < 0.01 and ***p < 0.001; Figure 9 Figure 2 shows the quantitative immunofluorescence staining of α-SMA-positive adventitial fibroblasts in Example 2; *p < 0.05, **p < 0.01 and ***p < 0.001; Figure 10 The figure shows the results of determining the optimal concentration of Lanilanol to inhibit CaCl2-induced AFs migration; Figure 11 Volcano plot of differentially expressed genes (DEGs); Figure 12 GO and KEGG annotations related to abnormal lipid metabolism and cell proliferation in fibroblasts after LT treatment in Example 2; Figure 13 This is a heat map of differentially expressed genes related to lipid metabolism in Example 2; Figure 14 This is a heat map of differentially expressed genes related to cell proliferation in Example 2; Figure 15 This is the classic GSEA analysis of ether lipid metabolism and cell cycle in Example 2; Figure 16 Classic GSEA analysis for lipid metabolism-related annotations; Figure 17 Classic GSEA analysis for cell proliferation-related annotations; Figure 18 Western blot analysis of the expression levels of cell cycle and proliferation-related genes (CD36, CPT1, and FABP4); Figure 19 To quantitatively analyze the expression levels of cell cycle and proliferation-related genes (CD36, CPT1, and FABP4); Figure 20 Western blot analysis of the expression levels of lipid metabolism-related genes (CCND1, CDC6, and CDK1); Figure 21 The expression levels of lipid metabolism-related genes (CCND1, CDC6, and CDK1) were quantitatively analyzed; Figure 22 The OCR curve shows the difference in fatty acid metabolism levels between the control group and the Lanifibranor group; Figure 23The ECAR curve shows the difference in overall cellular metabolism between the control group and the Lanifibranor group; Figure 24 Representative images and quantitative analysis of Oil Red O staining of adventitial fibroblasts (AFs) in the control and Lanilanol groups; Figure 25 The results of CCK-8 experiments were used to evaluate the proliferation capacity of AFs after treatment with the lipid metabolism inhibitor etolimus (ETO); Figure 26 is the structural formula of the elastomer PGS-SS-DOU; Figure 27 Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) of PGS-SS-DOU and PGS-SS-DOU@Lani; Figure 28 Differential scanning calorimetry (DSC) curves of PGS-SS-DOU and PGS-SS-DOU@Lani; Figure 29 Dynamic water contact angle measurements of PGS-SS-DOU and PGS-SS-DOU@Lani; Figure 30 is the tensile properties of PGS-SS-DOU@Lani at room temperature; Figure 31 is the tensile property of PGS-SS-DOU at room temperature; Figure 32 Statistical analysis of Young's modulus of three regions of PGS-SS-DOU@Lani; Figure 33 Statistical analysis of the tensile strength of PGS-SS-DOU and PGS-SS-DOU@Lani (n = 4 independent experiments); Figure 34 Statistical analysis of the maximum elongation of PGS-SS-DOU and PGS-SS-DOU@Lani (n = 4 independent experiments); Figure 35 Continuous cyclic tensile curves of PGS-SS-DOU@Lani with increasing strain without any rest time; Figure 36 Continuous cyclic tensile curves of PGS-SS-DOU with increasing strain without any rest time; Figure 37 Cyclic tensile curves of PGS-SS-DOU and PGS-SS-DOU@Lani with a maximum strain of 500%. There was no waiting time between two consecutive cyclic stretching cycles (cycles 1–10). Figure 38 Stress test diagram, where Figure 38 Figure A shows the cyclic tensile curves of PGS-SS-DOU, and Figure B shows the cyclic tensile curves of PGS-SS-DOU@Lani. Both Figures A and B were performed at a maximum strain of 500% (10 cycles). After the initial 10 cycles, the film was allowed to relax at 37°C for 5 minutes before the 11th cyclic tensile test. Figure C shows the stress at 500% strain for cycle 1, cycle 10, and cycle (relaxation for 5 minutes). Figure 39 Cutting and contact self-healing of PGS-SS-DOU@Lani. The self-healed sample was stretched at room temperature, in water, and in blood. Scanning electron microscopy (SEM) was used to observe the self-healed interface after 1 minute. Scale bar = 200 μm. Figure 40 The self-healing of PGS-SS-DOU after cutting. The healed sample was stretched for 1 minute at room temperature, in water, and in blood. Figure 41 Scanning electron microscopy (SEM) images of the self-healing interfaces of PGS-SS-DOU and PGS-SS-DOU@Lani under three environmental conditions (dry, wet, and blood) for 1 minute. Scale bars are 200 μm, 100 μm, and 40 μm, respectively. Figure 42 Scanning electron microscopy (SEM) images of the self-healing interfaces of PGS-SS-DOU and PGS-SS-DOU@Lani in three environments (dry, wet, and blood) for 1 minute. Scale bars are 200 μm, 100 μm, and 40 μm, respectively. Figure 43 is the tensile strength of PGS-SS-DOU and PGS-SS-DOU@Lani after 1 minute of self-healing under three environmental conditions; Figure 44 To analyze the deformation of PGS-SS-DOU bioelastomer under different expansion pressures in the arterial external wrapping model; Figure 45 is the stress of PGS-SS-DOU under different expansion pressures; Figure 46 The deformation of PGS-SS-DOU under different extrusion pressures; Figure 47 is the stress of PGS-SS-DOU under different extrusion pressures; Figure 48 Schematic diagram of the construction of rat abdominal aortic aneurysm (AAA) model and the process of extravascular wrapping therapy; Figure 49Flowchart of the PGS-SS-DOU@Lanifibranor extravascular wrapping treatment strategy for Labrador AAA model construction; Figure 50 These are gross images of the abdominal aorta segments of Labrador dogs in different groups 28 days after birth; Figure 51 Representative histological section images (H&E, Masson, and EVG staining) of abdominal aorta segments from different groups of Labrador dogs 28 days after operation; Figure 52 For quantitative analysis of arterial cross-sectional area based on H&E staining images; Figure 53 For quantitative analysis of arterial circumference based on H&E staining images; Figure 54 For collagen deposition analysis based on Masson staining images; Figure 55 For elastin fragment analysis based on EVG staining images; Figure 56 Schematic diagram of minimally invasive surgery on Bama pigs without the need for laparotomy; Figure 57 Schematic diagram of the clinical application of PGS-SS-DOU@Lanifibranor elastomer; Figure 58 Schematic diagram of the minimally invasive implantation process of PGS-SS-DOU@Lanifibranor under laparoscopic guidance, including compression of PGS-SS-DOU@Lanifibranor: (i) locating the target area and delivering the PGS-SS-DOU@Lanifibranor elastomer to the infrarenal abdominal aorta segment using laparoscopic forceps; ii) inserting the PGS-SS-DOU@Lanifibranor elastomer into one side of the abdominal aorta using laparoscopic forceps; (iii) aligning the two ends of the PGS-SS-DOU@Lanifibranor and wrapping it around the abdominal aorta; (iv) pressing the anastomotic end of the PGS-SS-DOU@Lanifibranor to promote self-healing; Figure 59 General images of the PGS-SS-DOU@Lanifibranor elastomer implantation process: (i) positioning the elastomer; (ii) inserting the elastomer; (iii) wrapping the elastomer; and (iv) pressing both ends of the elastomer to promote self-healing (n = 3 independent experiments). DETAILED DESCRIPTION

[0017] The present invention will be described in detail below with reference to specific embodiments. The following examples will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those skilled in the art, several changes and improvements can be made without departing from the scope of the present invention. These all fall within the scope of protection of the present invention.

[0018] Lanifibranor, described in this invention, is a PPARγ agonist. Its unique mechanism of action—simultaneous activation of all three PPAR isoforms (PPARα, PPARδ, and PPARγ)—provides a comprehensive approach to modulating metabolic, inflammatory, and fibrotic pathways. This broad activity has demonstrated efficacy in various preclinical and clinical studies, particularly in diseases such as non-alcoholic steatohepatitis (NASH) and systemic sclerosis, where fibrosis is a key component. However, the impact of lanifibranor on adventitial fibroblasts in AAA progression remains largely unexplored in the literature. While theoretically, drug delivery to the adventitia is considered effective, its therapeutic effect is diminished if the drug diffuses. Intramural injection is a common technique in ischemic heart disease research, ensuring that the therapeutic drug is retained within the heart wall after injection. To date, no delivery system has been able to simultaneously provide mechanical support and deliver the therapeutic drug to achieve a comprehensive therapeutic effect in AAA.

[0019] The present invention provides the use of lanifibranor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the progression of abdominal aortic aneurysm. Through the synergistic action of multiple mechanisms, it systematically regulates the pathological process of AAA at the molecular-cellular-tissue level, providing the first novel therapeutic strategy for the clinic that combines etiological treatment with structural protection.

[0020] In one embodiment of the present invention, the use is achieved through the following mechanism: (a) Regulate lipid metabolism of adventitial fibroblasts to maintain their phenotype; and / or, (b) inhibiting the transformation of adventitial fibroblasts into myofibroblasts; and / or, (c) Reduce the expression levels of pro-inflammatory cytokines.

[0021] In one embodiment of the present invention, the inflammatory cytokine is at least one of IL-6 and MCP-1.

[0022] In one embodiment of the present invention, the drug is administered to the adventitia of the abdominal aorta via a local delivery system.

[0023] In one embodiment of the present invention, the delivery system is a mechanical biomimetic elastomeric material.

[0024] In one embodiment of the present invention, the effective concentration of the drug is 5 μM.

[0025] Furthermore, the present invention also provides a bioelastomer with drug-loaded self-healing properties, which is used to provide external mechanical support and sustained drug release to tubular biological tissues; the bioelastomer includes an elastomer PGS-SS-DOU and lanifibranor loaded on the elastomer PGS-SS-DOU; wherein the structural formula of the elastomer PGS-SS-DOU is shown in formula (I), (I). In one embodiment of the present invention, the drug is at least one of lanifibranor, itraconazole, and ragaflimab.

[0026] Lanifibranor described in the present invention is a PPARγ agonist. The unique mechanism of Lanifibranor, namely the simultaneous activation of all three PPAR subtypes (PPARα, PPARδ and PPARγ), provides a method for comprehensively regulating metabolic, inflammatory and fibrotic pathways.

[0027] Itracon described in the present invention is a triazole antifungal drug that can inhibit the transdifferentiation of myofibroblasts with a half-inhibitory concentration (IC50) of approximately 300 nM, which is comparable to the potency of SB-431542, a TGF-β1 signaling pathway inhibitor.

[0028] Lagavulimab (INCAGN-1876) described in the present invention is a monoclonal antibody that can inhibit the activation and function of tumor-associated myofibroblasts by targeting specific immune checkpoints or cytokine receptors.

[0029] In one embodiment of the present invention, the drug is Lanifibranor.

[0030] In one embodiment of the present invention, the Young's modulus of the bioelastomer is 0.3-0.8 MPa, the elongation at break is ≥1000%, and it can achieve self-healing within 1 minute in a humid environment.

[0031] In one embodiment of the present invention, the loading amount of the lanifibranor on the elastomer PGS-SS-DOU is 0.1 wt.% to 2 wt.%.

[0032] In one embodiment of the present invention, the preparation of the elastomer PGS-SS-DOU comprises the following steps: (1) Dissolving the PGS prepolymer in an organic solvent to form a PGS solution; (2) dissolving polytetramethylene ether glycol, dimethylglyoxime, and bis(4-hydroxyphenyl) disulfide in an organic solvent, adding isophorone diisocyanate and a catalyst, and stirring the mixture at 40-60° C. for 2-6 hours to obtain a mixed reaction solution; (3) The PGS solution of step (1) is added to the mixed reaction liquid of step (2), stirred evenly and then injected into a mold. After solvent evaporation and curing treatment, the elastomer PGS-SS-DOU is obtained.

[0033] In one embodiment of the present invention, the bioelastomer is used to provide external mechanical support and sustained drug release to the adventitia of the abdominal aorta.

[0034] The present invention provides a new biomimetic material, the bioelastomer PGS-SS-DOU, among the drug-loaded self-healing bioelastomers. The initial Young's modulus (0.34±0.08 MPa) of the bioelastomer PGS-SS-DOU matches that of the normal aortic wall, and the elongation at break is as high as 1190%. It can dynamically adapt to vascular pulsation and effectively inhibit aneurysm expansion. The loaded Lanifibranor regulates the lipid metabolism of adventitial fibroblasts, inhibits their transformation into myofibroblasts, reduces the secretion of pro-inflammatory factors, and blocks the progression of AAA at the molecular level.

[0035] The drug-loaded self-healing bioelastomer provided by the present invention can achieve self-healing within 1 minute in a moist environment (water, blood), and the tensile strength recovery rate after self-healing is greater than 90%, ensuring close adhesion to the blood vessel wall after implantation and avoiding material breakage or displacement due to mechanical stress.

[0036] The drug-loaded self-healing bioelastomer provided by the present invention can be minimally invasively implanted through laparoscopy without the need for complex suturing, significantly reducing surgical trauma; its flexible properties allow it to be delivered through a puncture hole after compression, and to self-heal and fix after being deployed in the body.

[0037] The drug-loaded self-healing bioelastomer provided by the present invention reduced the aneurysm diameter by 30%-40% and the elastin degradation score by more than 50% in rat and Labrador dog AAA models, demonstrating superior therapeutic efficacy compared to a single mechanical support group (PGS-SS-DOU) and other therapies reported in the literature.

[0038] A third aspect of the present invention provides the use of the above-mentioned bioelastomer with drug-loaded self-healing properties in the preparation of a product for inhibiting the progression of abdominal aortic aneurysm.

[0039] The drug-loaded self-healing bioelastomer provided by the present invention adopts a "cocktail" synergistic strategy that can be extended to the repair of tubular organs such as thoracic aortic aneurysms, tracheoesophageal fistulas and intestinal defects, and is particularly suitable for clinical scenarios with limited surgical space.

[0040] The present invention is described in detail below with reference to specific embodiments.

[0041] Example 1 1. In this example, the role of adventitial fibroblasts transformed from important myofibroblasts in AAA was first verified.

[0042] An angiotensin II (Ang II)-induced abdominal aortic aneurysm (AAA) model was established in 12- to 16-week-old male mice as follows: Mice were anesthetized by isoflurane inhalation, and a mini-osmotic pump (Alzet model 2004; Durect Corporation, Cupertino, CA, USA) loaded with Ang II (1000 ng / min / kg; A9525; Sigma-Aldrich, St. Louis, MO, USA) or saline (0.9% NaCl) was implanted subcutaneously in the neck for 28 days. After the treatment period, mice were humanely euthanized by cervical dislocation after an overdose of isoflurane (5%), and the suprarenal abdominal aorta was harvested.

[0043] In this example, there were 3 mice in the AAA model group and 3 mice in the control group.

[0044] In this example, single-cell RNA sequencing was performed on AAA tissues from a mouse AAA model, with a normal abdominal aorta as a control group, to validate the role of adventitial fibroblasts transformed from important myofibroblasts in AAA (single-cell sequencing was performed on both healthy and diseased patients). The specific experimental steps are as follows: (1) To isolate single cells, the abdominal aorta was enzymatically digested using a combination of 1 mg / mL collagenase type I, 0.25% trypsin, and 0.1 mg / mL DNase I at 37°C for 1 hour with gentle intermittent shaking. Cell viability was assessed by trypan blue staining, and only samples with viability exceeding 80% were included in further analysis. A total of 20,000 cells were loaded at a concentration of 500 cells / µl and single-cell RNA sequencing was performed using the 10× Genomics Chromium platform. Alignment and counting were performed using the mouse mm10 reference genome. Cells with mitochondrial transcripts exceeding 10% were excluded from further analysis. The data were normalized using the “ScaleData” function in Seurat, followed by principal component analysis (PCA) and uniform manifold approximation and projection (UMAP) for dimensionality reduction. Data visualization was generated using built-in functions in Seurat.

[0045] The specific steps of trypan blue staining in this embodiment are as follows: Cell suspension preparation: After enzymatic digestion, transfer the cell suspension to a centrifuge tube and gently resuspend the cells in culture medium or PBS buffer containing 10% FBS.

[0046] Staining steps: Take an appropriate amount of cell suspension (usually 100-200 μL), add an equal volume of 0.4% trypan blue staining solution, mix gently, and stain at room temperature for 3-5 minutes.

[0047] Cell counting: Pipette the stained cell suspension onto a cell counting chamber. Observe and count the cells under a microscope. Live cells are not stained and appear transparent; dead cells are stained blue. Calculate the live cell percentage: Live cell percentage = (number of live cells / total number of cells) × 100%.

[0048] Result evaluation: Only when the cell viability exceeded 80%, the samples were included in further analysis.

[0049] Through the above steps, cell activity can be accurately evaluated and samples that meet the experimental requirements can be screened out.

[0050] RNA sequencing of adventitial fibroblasts (RNA transcriptome sequencing after drug addition) Transcriptome sequencing was performed using the Illumina HiSeq4000 platform. Quality visualization of all raw reads was performed using FastQC (version 0.11.9). Sequencing reads were aligned to the rat genomic set GRCr8 using HISAT2 (default parameters). For the input library, FPKMs were calculated, and differential gene expression analysis was performed using the R package DESeq2 (version 1.36.0). A |log2FC| > 1 and a P-adjusted < 0.05 were used as filtering criteria.

[0051] (3) Bioinformatics analysis Volcano plots were created based on fold changes in gene expression and adjusted P values using GraphPad Prism 5.0 software (San Diego, CA, USA). Heat maps were created using the R package ComplexHeatmap (version 2.12.0). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed using the R package clusterProfiler based on the org.Mm.eg.db and GOplot packages. Gene set enrichment analysis (GSEA) was performed using GSEA 4.1.0 to identify significantly enriched pathways and gene sets.

[0052] The experimental results are as follows: Reference Figure 2 As shown in the figure, eight different cell clusters were identified in AAA tissue, including B plasma cells, myeloid cells, T cells, fibroblasts, smooth muscle cells, endothelial cells, neurons, and NK cells. Among them, fibroblasts were the main cell type in the aortic adventitia and were slightly increased in the AAA group.

[0053] Reference Figure 3 As shown, myofibroblasts (myo-AFs) secrete more chemokines, such as monocyte chemoattractant protein 1 (MCP-1), are characterized by enhanced proliferation and migration activities, and the presence of α-SMA (PMID: 31346611). Among the fibroblast population, myofibroblast markers such as Acta2 (α-smooth muscle actin, α-SMA), Ccl2 (MCP-1), and Timp1 are significantly upregulated in the AAA group, while the expression of vimentin remains unchanged ( Figure 3 ), indicating that fibroblasts in AAA are significantly transformed into myofibroblasts ( Figure 4 ).

[0054] 2. This Example then verifies the effect of Lanifibranor alone on fibroblasts Lanifibranor described in the present invention is a PPARγ agonist that can simultaneously activate all three PPAR subtypes (PPARα, PPARδ and PPARγ).

[0055] 1. Isolation and identification of adventitial fibroblasts This example used 8-week-old male SPF Sprague-Dawley (SD) rats. To isolate adventitial fibroblasts from the abdominal aorta, the rat abdominal aorta was excised and rinsed three times with cold phosphate-buffered saline (PBS). Under a sterile microscope, the intima and media were carefully stripped away, leaving the adventitia. The adventitia was cut into 1 mm³ pieces and digested with type II collagenase (17101015, Gibco) and elastase (A002290, Sangon Biotech) at 37°C for 1-2 hours. The enzymes were neutralized with culture medium containing fetal bovine serum (FBS), and after centrifugation, the cells were seeded in DMEM supplemented with 10% FBS. Culture was carried out at 37°C and 5% CO2, with the culture medium changed every 2-3 days. The identity of fibroblasts was verified using vimentin (1:100; 10366-1-AP; Proteintech) and α-smooth muscle actin (α-SMA; 1:100; ab124964; Abcam) markers.

[0056] 2. Immunofluorescence staining of adventitial fibroblasts Cells were washed with phosphate-buffered saline (PBS) and fixed with 4% paraformaldehyde (PFA) for 30 minutes, permeabilized with 0.5% Triton X-100, and blocked with 10% bovine serum albumin (BSA). Primary antibodies against α-SMA (1:100, Abcam) and vimentin (1:100, Proteintech) were incubated overnight at 4°C, followed by incubation with a secondary antibody conjugated to AlexaFluor 488 (1:500, Proteintech) for 2 hours at room temperature in the dark. Cell nuclei were stained with 4'6-diamidino-2-phenylindole dihydrochloride (1:1000, Solarbio) (DAPI). Images were acquired under a fluorescence microscope.

[0057] 3. Use 24-well Transwell chambers (#3422, Corning) to assess the migration ability of AFs (fibroblasts). Transwell assay steps: First, AFs were pretreated with Ang II (100 nmol / L) at 37°C for 24 h. Subsequently, the cultured cells were digested and resuspended in serum-free DMEM medium for serum starvation, and 4 × 10 4Cells were seeded into the upper chamber of a Transwell insert. After cell migration was complete, the cells were fixed with 70% ice-cold ethanol for 1 hour and then stained with 0.5% crystal violet stain (#C0121, Beyotime). Finally, the migrated cells in the lower chamber were observed and counted using a microscope.

[0058] result: In this example, adventitial fibroblasts (AFs) were isolated and cultured from SD rats. Immunofluorescence was then used to identify the VSMC marker α-SMA in early passage cells. α-SMA is expressed in both fibroblasts and VSMCs. Furthermore, vimentin, a specific marker for fibroblasts, was used. The results showed strong vimentin positive staining, while α-SMA staining was negative, indicating that the cultured AFs were of high purity ( Figure 5 ).

[0059] In this example, we further investigated whether lanifibranor inhibits AF phenotypic conversion and subsequent migration, as well as its optimal concentration. AFs treated with Ang II (100 nmol / L) showed a significant phenotypic conversion to myofibroblasts, as evidenced by increased α-SMA expression, and lanifibranor effectively inhibited this phenotypic conversion. Lanifibranor had the best effect at 5 μM, and higher concentrations did not enhance the effect ( Figure 6-9 ).

[0060] The above results were further confirmed by Transwell experiments, which showed that the inhibitory effect on Ang II-induced AF migration was maximal at 5 μM, and no further benefit was observed at 10 μM ( Figure 10 Therefore, 5 μM lanifibranor significantly inhibited Ang II-induced myofibroblast transformation and was used in subsequent experiments.

[0061] This example further demonstrates that lanifibranor effectively maintains the adventitial fibroblast phenotype by reprogramming lipid metabolism. To further elucidate the mechanism by which lanifibranor regulates the function of aortic adventitial fibroblasts, transcriptome analysis was performed on fibroblasts treated with lanifibranor. Lanifibranor was found to significantly upregulate 144 genes and downregulate 396 genes ( Figure 11 ).

[0062] GO and KEGG functional analysis showed that Lanifibranor upregulated pathways related to lipid metabolism in fibroblasts, such as lipid storage, neutral lipid metabolism, and lipid degradation, while inhibiting cell cycle and cell proliferation ( Figure 12 、 13 , 14). GSEA analysis further verified the abnormalities in lipid metabolism and cell cycle, showing that ether lipid metabolism increased and cell cycle activity decreased after Lanifibranor treatment ( Figure 15 Notably, the expression of lipid metabolism-related transporter CD36 was significantly upregulated after Lanifibranor treatment ( Figure 13 CD36 is a key scavenger receptor in lipid regulation, so we detected its protein expression by immunoblotting. In addition, in this example, the expression of proteins related to lipid metabolism and cell cycle activity under Ang II treatment was determined by Western blotting. After Ang II administration, lipid metabolism-related proteins including CD36, CPT1, and FABP4 showed an increasing trend ( Figure 18 、 19 These three proteins are involved in intracellular lipid transport, helping to transport lipids into cells and mitochondria, and promoting fatty acid β-oxidation. In addition, the expression of cell cycle activity-related proteins such as CCND1, CDC6, and CDK1 is reduced ( Figure 20 、 21 Furthermore, myofibroblasts exhibit excessive lipid accumulation due to dysregulated lipid metabolism in fibrotic diseases, and lipid homeostasis plays a key role in maintaining cellular homeostasis. Therefore, in this example, a Seahorse experiment was performed to assess cellular metabolism in more detail. Lanifibranor treatment was observed to enhance lipid metabolism, as shown by the cellular oxygen consumption rate (OCR) curve ( Figure 22 The extracellular acidification rate (ECAR) curve showed that the overall metabolic activity of cells in the Lanifibranor group increased ( Figure 23 In addition, Oil Red O staining showed that lipid deposition in fibroblasts was reduced after treatment with 5 μM Lanifibranor ( Figure 24 The results of CCK-8 experiments showed that blocking lipid metabolism with etomoxir could reverse the reduction of myofibroblast migration induced by lanifibranor ( Figure 25 This suggests that lanifibranor maintains the phenotype of AFs by regulating lipid metabolism, thereby alleviating migration.

[0063] 3. This embodiment then provides a PGS-SS-DOU self-healing bioelastomer and its preparation method Abdominal aortic aneurysm (AAA) is defined by pathological dilation of the aorta due to loss of mechanical function. Therefore, matching the mechanical properties of materials to those of the normal abdominal aorta is crucial to curb AAA progression and rupture, which also helps improve tissue generation and repair.

[0064] Based on this, this embodiment further provides a PGS-SS-DOU self-healing bioelastomer and a preparation method thereof.

[0065] The self-healing bioelastomer (PGS-SS-DOU) was designed by combining biodegradable poly(glycerol sebacate) (PGS) elastomer with multiple reversible dynamic chemical bonds, including disulfide substitution (SS), dimethylglyoxime urea (DOU), and hydrogen bonds. The molecular structure of the PGS-SS-DOU self-healing bioelastomer is shown in Figure 2. Figure 26 PGS-SS-DOU is synthesized by a one-step polymerization of polytetramethylene ether glycol, dimethylglyoxime, bis(4-hydroxyphenyl) disulfide, and isophorone diisocyanate (IPDI), followed by chemical crosslinking with a PGS prepolymer. The flexible chemical crosslinking network of PGS makes PGS-SS-DOU a thermoset material that exhibits remarkable reversible expansion properties in organic solvents.

[0066] Furthermore, in this example, the strategy of super expansion absorption modification and cross-linked network locking was used to prepare a self-healing bioelastomer loaded with lanifibranor (PGS-SS-DOU@Lani) ( Figure 1 The small lipophilic drug lanifibranor can be conveniently and stably loaded into PGS-SS-DOU through a reversible swelling process, and the reaction between the carboxyl group of lanifibranor and IPDI, which would lead to drug inactivation, can be avoided.

[0067] Figure 1 The design steps for the PGS-SS-DOU@Lani self-healing bioelastomer and extra-aortic synergistic therapy (ESC) for the treatment of abdominal aortic aneurysm (AAA) are as follows: (A) By integrating multiple reversible dynamic bonds, a self-healing bioelastomer with artery-like mechanical properties was designed.

[0068] (B) The bioelastomer exhibits ultrafast self-healing ability in the blood environment.

[0069] (C) Self-healing bioelastomers can quickly and easily wrap around abdominal aortic aneurysms and provide continuous mechanical support to inhibit aneurysm expansion.

[0070] (D) Lanifibranor acts on the aortic adventitia.

[0071] (E) Lanifibranor inhibits the myofibroblast transformation of adventitial fibroblasts.

[0072] (F) The anti-fibrotic drug lanifibranor is loaded via reversible swelling and locking of the cross-linked network.

[0073] Specifically, the preparation method of the elastomer PGS-SS-DOU in this embodiment is as follows: (1) Synthesis of PGS prepolymer: Sebacic acid (≥99%, J&K Scientific) and glycerol (≥99.9%, J&K Scientific) were added to a container under a protective atmosphere, stirred at 120°C for 24 h, and then vacuumed to room temperature to obtain a PGS prepolymer; wherein the molar ratio of sebacic acid to glycerol was 1:3; (2) 2.5 g of PGS prepolymer was dissolved in 10 ml of tetrahydrofuran (THF, ≥99.0%, MacLean) to obtain a PGS solution. In a glass container equipped with a magnetic stirrer, polytetramethylene ether glycol (PTMEG, Mn≈2000 g / mol, Aladdin, 4 g, 2 mmol), dimethylglyoxime (DMG, 98%, Aladdin, 0.116 g, 1 mmol) and bis(4-hydroxyphenyl) disulfide (Aladdin, 0.25 g, 1 mmol) were dissolved in 10 ml of THF and stirred at 50°C for 10 minutes. Then, isophorone diisocyanate was added to the reaction mixture. A cyanate ester (IPDI, 99%, Aladdin, 0.944 g, 4.25 mmol) was immediately added, followed by dibutyltin dilaurate (DBTDL, 95%, Aladdin). The mixture was reacted at 50°C for 4 hours. Subsequently, 1 mL of PGS solution (0.25 g, 0.05 mmol) was added to the mixture in an ice bath and mixed thoroughly. The reaction mixture was then poured into a polytetrafluoroethylene mold, and the solvent was evaporated under vacuum at 90°C for 10 minutes. The elastomer PGS-SS-DOU was then further cured under vacuum at 70°C for 12 hours.

[0074] Next, 10 mg of lanifibranor (Chemical Book, 927961-18-0) was completely dissolved in 1 ml of tetrahydrofuran. Next, 1 gram of PGS-SS-DOU film was immersed in the lanifibranor solution to swell. The swollen PGS-SS-DOU was placed on a polytetrafluoroethylene plate in a ventilated environment. After 3 hours, the tetrahydrofuran evaporated, thereby preparing PGS-SS-DOU@Lani (the drug-loaded, self-healing bioelastomer of the present invention).

[0075] In this example, the structures of the obtained PGS-SS-DOU and PGS-SS-DOU@Lani were confirmed and their performance was tested. The relevant testing methods are as follows: (1) Structure confirmation: ATR-FTIR spectroscopy Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra were recorded using a Thermo Scientific Nicolet iS20 spectrometer.

[0076] (2) DSC test Differential scanning calorimetry (DSC) measurements were performed using a Netzsch DSC 200 F3. Samples were heated from -20°C to 80°C under a nitrogen atmosphere and then cooled to -20°C at a rate of 10°C / min.

[0077] (3) Water contact angle test The air-water contact angles of the samples were measured using a Chengde Dingsheng JY-82C video contact angle meter at room temperature.

[0078] (4) Mechanical properties test Tensile tests were conducted using a universal testing machine (Instron 5542). Specimens measuring 0.5 mm × 3 mm × 20 mm were cut from the bulk material for testing. Uniaxial and cyclic tensile tests were conducted at tensile rates of 10 mm / min and 50 mm / min, respectively. The tensile strength was determined from the maximum value of the stress-strain curve.

[0079] (5) Self-healing performance test Mechanical recovery was evaluated by splicing two individually cut samples at room temperature. The self-healing bioelastomer was cut into two segments (0.5 mm × 3 mm × 10 mm) and then pressed together to allow self-healing under various conditions, including room temperature, water, and blood. The self-healing overlap length was 5 mm. Tensile tests were performed using a universal materials testing machine (Instron-5542) at various healing time points.

[0080] (6) Scanning electron microscopy The self-healed PGS-SS-DOU and PGS-SS-DOU@Lani were gold-sprayed, and their cross-sections were observed at different magnifications using a field emission scanning electron microscope (ZEISS Sigma 300) with an accelerating voltage of 3 kV.

[0081] (7) Finite element analysis To evaluate the deformation of the PGS-SS-DOU under internal and external pressure, finite element analysis (FEA) was performed using Ansys Mechanical software (2024 R1). In this simulation, the radius of the normal abdominal aorta was assumed to be 5 mm, the maximum radius of the abdominal aortic aneurysm was 8 mm, and the vessel wall thickness was 2 mm. The elastic modulus and Poisson's ratio of the abdominal aorta were assumed to be 1 MPa and 0.3, respectively. The elastic modulus and Poisson's ratio of the PGS-SS-DOU were 0.691 MPa and 0.3, respectively. The dimensions of the PGS-SS-DOU encapsulating the abdominal aortic aneurysm were: length 50.26 mm, width 20 mm, and thickness 1 mm. To simulate the effects of abdominal aortic dilation on the PGS-SS-DOU encapsulating the abdominal aortic aneurysm under physiological conditions, the pressures exerted on the PGS-SS-DOU inner wall by vessel dilation were assumed to be 4.65 kPa and 6.05 kPa, respectively. Furthermore, to simulate the squeezing effect of surrounding tissue on the PGS-SS-DOU wrapped around the abdominal aortic aneurysm under physiological conditions, pressures of 10.50 kPa and 13.65 kPa were applied to the surface of the PGS-SS-DOU, with an action radius of 2.65 mm.

[0082] The test results are as follows: In this example, Fourier transform infrared spectroscopy (FTIR) was used to confirm the molecular structure. Figure 27 As shown, the peaks observed at 3315 and 1720 cm⁻¹ correspond to the NH and C=O bonds in the carbamate unit, respectively, indicating the successful formation of the ethylcarbamate group. The absorption peak at 920 cm⁻¹ corresponds to the stretching vibration of the N-O bond in the dimethylglyoxime urea unit. The barely visible peak at 2264 cm⁻¹ corresponds to the N=C=O group, indicating that the IPDI has been completely reacted. In PGS-SS-DOU@Lani, the peak at 1014 cm⁻¹ represents the S=O bond in lanifibranor, indicating that lanifibranor has been successfully loaded.

[0083] In the range of -20°C to 80°C, the differential scanning calorimetry (DSC) curves of both groups showed no crystallization or melting peaks, indicating that the bioelastomer was able to maintain a soft and flexible network ( Figure 28 The water contact angle measurement results show that both the PGS-SS-DOU group and the PGS-SS-DOU@Lani group exhibit obvious hydrophobic properties. This hydrophobicity effectively hinders the diffusion of water molecules on the surface of the material ( Figure 29 ).

[0084] The PGS-SS-DOU@Lani sample is light yellow and translucent, and has flexible stretchability ( Figure 30 and Figure 31). Tensile tests were performed to investigate the mechanical behavior and underlying mechanisms of bioelastomers. Bioelastomers exhibit nonlinear stress-strain curves. Based on the deformation range, they can be divided into three different regions: a linear region at low strain (region i), a nonlinear region at medium strain (region ii), and a linear region at high strain (region iii). Figure 32 ). In region i (strain 0-50%), PGS-SS-DOU exhibits a higher elastic modulus of 0.34±0.08 MPa, which is attributed to the contribution of the dynamic cross-linked network. Its initial Young's modulus is very close to that of arterial blood vessels (0.41±0.06 MPa). As the strain increases, in region ii (strain 50%-500%), multiple dynamic bonds dissociate, effectively dissipating mechanical energy and giving it tough mechanical properties. In region iii (strain>500%), almost all dynamic bonds have dissociated, and the stable PGS covalent cross-linked network plays a significant role in resisting the applied strain. Therefore, the modulus of region iii increases rapidly compared to region ii.

[0085] In addition, the tensile strength of the bioelastomer PGS-SS-DOU was 1.51 ± 0.12 MPa ( Figure 33 ), which is very similar to the tensile strength of arterial blood vessels detected in our previous work (about 1.5 MPa). The elongation at break was 1190±88.8% ( Figure 34 This value is significantly higher than the elongation at break of arteries, effectively preventing aneurysm rupture caused by material damage. This bioelastomer's unique nonlinear stress-strain behavior exhibits self-reinforcing mechanical properties with increasing strain, while maintaining a well-matched balance of strength and flexibility, closely mimicking the mechanical properties of arteries. It is suitable for the treatment and repair of AAAs, providing biomechanically adapted mechanical support to prevent further expansion and rupture of aneurysms.

[0086] Cyclic tensile tests were performed at different strains to evaluate the tensile properties and further demonstrate the above-mentioned mechanism. First, the bioelastomer was subjected to continuous cyclic stretching ( Figure 35 and Figure 36). The modulus gradually decreases with the increase in the number of cycles. In the initial cycle, within the low strain (100%) range, most dynamic networks are able to maintain a high modulus and stress resistance. However, as the weaker dynamic bonds dissociate, some networks are opened, reducing their ability to resist external stress, thereby gradually reducing the stiffness. With the increase of strain (≥200%), the bioelastomer exhibits obvious residual strain and reduced modulus, which is due to the reformation of some broken dynamic bonds in new positions. In the subsequent continuous cyclic stretching, the dissociated dynamic bonds failed to form new combinations in time, resulting in a decrease in stiffness compared with the previous cycle. Next, a cyclic tensile test was performed with a repeated maximum strain of 500% without waiting time, and then it was allowed to relax at 37°C for 5 minutes in the 11th cyclic tensile test. The results showed that an obvious hysteresis loop appeared in the first cycle due to the dissociation of dynamic bonds. As the number of cycles increased, the hysteresis phenomenon decreased, and the cyclic stress-strain curves gradually became consistent ( Figure 37 This can be attributed to the elasticity of the stable PGS covalent cross-linked network and the balance achieved between the dissociation and reorganization of dynamic bonds during continuous cyclic stretching. It is worth noting that after only 5 minutes of waiting at 37°C, the 11th cycle curve is similar to the first cycle curve, which is due to the elastic PGS network and the reformed dynamic bonds ( Figure 38 The remarkable recovery and elasticity of the bioelastomer PGS-SS-DOU facilitates its use in the actual dynamic elastic mechanical environment encountered in aneurysm external wrapping applications and helps maintain hemodynamic stability.

[0087] For biomedical applications of AAA external wrapping, biomaterials need to have efficient self-healing properties in complex body fluid environments (such as blood and tissue fluid). In the past decade, only a few materials have achieved autonomous self-healing under blood and water conditions. Most of these materials are designed to promote molecular motion to improve self-healing efficiency, but this leads to reduced mechanical properties and it is difficult to balance biocompatibility and biodegradability at the same time. In this study, PGS-SS-DOU not only has artery-like mechanical properties, but also exhibits blood-resistant self-healing ability due to its stable PGS network and dynamic disulfide, DOU and hydrogen bonds. When two bioelastomer samples are pressed together, they can heal rapidly in just 1 minute not only in air, but also in water and blood, without the need for external stimulation ( Figure 39 and Figure 40 At this point, the free dynamic bonds and the newly dissociated bonds randomly combine with the sacrificial bonds on the other side, thus achieving self-healing. Scanning electron microscopy (SEM) images show that the self-healing interface is almost invisible after the self-healing process ( Figure 41 ). Tensile tests show that the bioelastomer still has excellent self-healing strength in underwater and blood environments ( Figure 42and Figure 43 This blood-resistant self-healing ability ensures high efficiency and convenience during the aneurysm wrapping procedure and can continue to provide stable mechanical support during subsequent treatment.

[0088] Finite element analysis was performed to evaluate the deformation and stress of the healed bioelastomer PGS-SS-DOU at different expansion pressures in an arterial wrapping model. The results showed that the maximum deformation of PGS-SS-DOU occurred at the maximum diameter of the abdominal aortic aneurysm at different expansion pressures (4.65 kPa and 6.05 kPa), which were 0.06 mm and 0.08 mm, respectively. Figure 44 The maximum stress occurs at the junction of the abdominal aortic aneurysm and the normal blood vessel, which are 0.017 MPa and 0.023 MPa respectively ( Figure 45 ). Figure 46 The results show that when PGS-SS-DOU is subjected to different extrusion pressures (10.5 kPa and 13.65 kPa), the maximum deformation occurs at the extrusion pressure point, which is 1.50 mm and 2.07 mm respectively. The maximum stress also occurs at the connection between the abdominal aortic aneurysm and the normal blood vessel, which is 0.082 MPa and 0.105 MPa respectively. Figure 47 ).

[0089] Experimental example This experimental example verifies the therapeutic effect of PGS-SS-DOU@Lanifibranor prepared in Example 1 in the rat AAA model.

[0090] 1. Animal model construction 1.1 Construction of rat abdominal aortic aneurysm (AAA) model After exposing the rat abdominal aorta, cotton gauze pre-soaked in 0.15 M calcium chloride (C7250, Solarbio) was wrapped around the infrarenal abdominal aorta for 20 minutes. After this period, the gauze was removed, and the abdominal cavity was flushed with warm saline. Subsequently, the surgical incision was closed with 6-0 Prolene sutures.

[0091] The group treatment experiment was divided into three groups: the control group received only calcium chloride incubation; the PGS-SS-DOU group received PGS-SS-DOU extravascular wrapping directly after calcium chloride incubation; and the PGS-SS-DOU@Lanifibranor group received PGS-SS-DOU@Lanifibranor extravascular wrapping after calcium chloride incubation.

[0092] 1.2 Construction of Labrador Retriever Abdominal Aortic Aneurysm (AAA) Model After anesthetizing the dog and placing it in the supine position, a midline incision was made approximately 5 cm below the umbilicus. A large gauze pad was used to push the spleen and intestines upward to the right side, and an abdominal retractor was used to expose the surgical field. The retroperitoneum was incised, and the abdominal aorta was bluntly dissected. Using a disposable syringe, 5 mL of elastase (100 IU / mL) was injected into the medial layer of the abdominal aorta. Subsequently, PGS-SS-DOU or PGS-SS-DOU@Lanifibranor was applied to the injection site, followed by saline irrigation and abdominal suture.

[0093] Postoperative management: intramuscular ampicillin (1.6 million units / dose) was administered once daily for 3 consecutive days, and the skin sutures were removed after 7 days. Abdominal exploration was performed 14 days later to assess for AAA formation.

[0094] 2. Histological analysis (H&E, Masson, and EVG staining) On day 28, the rats were euthanized. The aorta was then harvested and perfused with 4% paraformaldehyde (PFA) through the left apex for approximately 10 minutes, followed by PBS rinses. The entire aorta was then dissected, fixed in 4% PFA, embedded in paraffin, and sectioned. For histological analysis, H&E, Masson's trichrome, and Verhoeff's VanGieson (EVG) staining were performed according to standard procedures. Histological images were analyzed using Image J software (Rawak Software, Inc.). After H&E staining, the cross-sectional area and circumference of the aorta were measured. After Masson's trichrome staining, the collagen deposition ratio was calculated using the following formula: (total collagen deposition area of treated samples / total aortic area of treated samples) / (total collagen deposition area of control samples / total aortic area of control samples). EVG-stained images were evaluated for elastin fragmentation score according to previously studied criteria.

[0095] 3. Minimally invasive surgical implantation of PGS-SS-DOU@Lanifibranor in a porcine model In this example, an AAA model was established in Labrador dogs, and the elastic PGS-SS-DOU@Lanifibranor was used for adventitial wrapping therapy ( Figure 48 ).

[0096] In this example, after elastase was injected into the adventitia of the abdominal aorta of Labrador dogs, PGS-SS-DOU and PGS-SS-DOU@Lanifibranor were applied to two independent encapsulation treatment groups ( Figure 49 ).

[0097] After 14 days, gross examination showed that PGS-SS-DOU@Lanifibranor treatment significantly reduced aneurysm diameter. Statistical analysis further demonstrated that the PGS-SS-DOU@Lanifibranor group was superior to the elastic PGS-SS-DOU package (which provided only mechanical support) in inhibiting aortic dilatation in the Labrador AAA model. Figure 50 ).

[0098] Histopathological analysis using H&E staining showed that both treatment groups reduced the total area and circumference of aneurysms compared with the AAA group, with the effect of PGS-SS-DOU@Lanifibranor being more significant ( Figure 51 、 Figure 52 、 Figure 53 Furthermore, Masson trichrome staining showed that PGS-SS-DOU@Lanifibranor significantly reduced collagen fiber deposition, a marker of AAA severity ( Figure 51 、 Figure 54 ).

[0099] EVG staining further confirmed the potent inhibitory effect of PGS-SS-DOU@Lanifibranor on elastin degradation, as shown by the elastin degradation scores of different groups ( Figure 51 、 Figure 55 ) highlighting its effectiveness in preventing elastic fiber fragmentation during AAA progression. In conclusion, PGS-SS-DOU@Lanifibranor also demonstrated excellent therapeutic efficacy in the Labrador AAA model.

[0100] After completing the treatment experiments in rats and Labrador dogs, this example evaluated the feasibility of laparoscopic minimally invasive implantation of PGS-SS-DOU@lanifibranor in Bama pigs to further explore its future clinical translation and application potential ( Figure 56 ).

[0101] Under laparoscopic guidance, an elastic PGS-SS-DOU@Lanifibranor (35 mm long, 10 mm wide, and 2 mm thick) was applied. Figure 57 ).

[0102] After successfully passing through the puncture hole, the PGS-SS-DOU@Lanifibranor was fully deployed in the abdominal cavity and successfully wrapped around the target abdominal aorta using two laparoscopic clamps without the need for suturing. The PGS-SS-DOU@Lanifibranor was firmly fixed and adhered well to the porcine aorta, demonstrating its excellent compatibility and self-healing properties in external abdominal aortic wrapping ( Figure 58 、 Figure 59 ).

[0103] In summary, PGS-SS-DOU@Lanifibranor effectively inhibits AAA progression in multiple animal models through the synergistic effect of mechanical support and drugs, and its feasibility in clinical application has been verified through minimally invasive surgery. Its core mechanism is: 1. Regulate lipid metabolism of adventitial fibroblasts and inhibit myofibrosis; 2. Reduce the expression of pro-inflammatory factors such as IL-6 and MCP-1; 3. Provide bionic mechanical support and delay vascular wall degeneration.

[0104] The above describes specific embodiments of the present invention. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art may make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention. In the absence of conflict, the embodiments of this application and the features in the embodiments may be combined with each other in any manner.

Claims

1. Use of lanifibranor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the progression of abdominal aortic aneurysm.

2. The use according to claim 1, characterized in that The described use is achieved through the following mechanisms: Regulates lipid metabolism of adventitial fibroblasts to maintain their phenotype; and / or, Inhibits the transformation of adventitial fibroblasts into myofibroblasts; and / or, Reduce the expression levels of pro-inflammatory cytokines.

3. The use according to claim 1, characterized in that The inflammatory cytokine is at least one of IL-6 and MCP-1.

4. The use according to claim 1, characterized in that The drug is administered to the adventitia of the abdominal aorta via a local delivery system.

5. The use according to claim 4, characterized in that The delivery system is a mechanical biomimetic elastomeric material.

6. The use according to claim 4, characterized in that The mechanical biomimetic elastomer material is used to provide external mechanical support and sustained drug release to tubular biological tissues; the mechanical biomimetic elastomer material is an elastomer PGS-SS-DOU, and lanifibranor or a pharmaceutically acceptable salt thereof is loaded on the elastomer PGS-SS-DOU; wherein the structural formula of the elastomer PGS-SS-DOU is shown in formula (I), （I）。 7. The use according to claim 6, characterized in that The elastomer PGS-SS-DOU has a Young's modulus of 0.3-0.8 MPa, an elongation at break of ≥1000%, and can achieve self-healing within 1 minute in a humid environment.

8. The use according to claim 6, characterized in that The loading amount of the lanifibranor on the elastomer PGS-SS-DOU is 0.1 wt.% to 2 wt.%.

9. The use according to claim 6, characterized in that The preparation of the elastomer PGS-SS-DOU comprises the following steps: (1) Dissolving the PGS prepolymer in an organic solvent to form a PGS solution; (2) dissolving polytetramethylene ether glycol, dimethylglyoxime, and bis(4-hydroxyphenyl) disulfide in an organic solvent, adding isophorone diisocyanate and a catalyst, and stirring the mixture at 40-60° C. for 2-6 hours to obtain a mixed reaction solution; (3) The PGS solution of step (1) is added to the mixed reaction liquid of step (2), stirred evenly and then injected into a mold. After solvent evaporation and curing treatment, the elastomer PGS-SS-DOU is obtained.

10. The use according to claim 1, characterized in that The effective concentration of the drug is 5 μM.

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