CN-121987819-A - Co-assembled nanoparticle for controlling tumor cell apoptosis and matrix rigidity, method and application

CN121987819ACN 121987819 ACN121987819 ACN 121987819ACN-121987819-A

Abstract

The invention discloses a co-assembled nanoparticle for controlling tumor cell apoptosis and matrix rigidity, a method and application thereof, and belongs to the technical field of pharmaceutical preparations. The co-assembled nanoparticle disclosed by the invention is formed by co-assembling a cell apoptosis agonist and a FAK inhibitor through intermolecular forces, so as to form a co-assembled body, wherein the surface of the co-assembled body is modified with a PEG modifier. The invention uses two drug molecules as materials for co-assembly, and does not need or only needs a small amount of extra pharmaceutical auxiliary materials, thereby realizing carrier-free self-delivery, simplifying preparation components, reducing unknown toxicity risks and solving the technical problems of low solubility of hydrophobic micromolecular drugs in water and possible inherent toxicity of the traditional nano carrier in the prior art.

Inventors

RAO ZHIPING
WANG ZHONGLIANG
HAN ZIQI
YANG PENG
XIA YUQIONG
ZHANG XIANGHAN
NING PENGBO
CHEN ZHUANG
HU XIAO

Assignees

西安电子科技大学

Dates

Publication Date: 20260508
Application Date: 20260130

Claims (10)

1. The co-assembly nanoparticle for controlling tumor cell apoptosis and matrix rigidity is characterized by being formed by co-assembling a cell apoptosis agonist and a FAK inhibitor through intermolecular forces, and the surface of the co-assembly body is modified with a PEG modifier.
2. The co-assembled nanoparticle for controlling tumor cell apoptosis and matrix rigidity according to claim 1, wherein the molar ratio of the cell apoptosis agonist to the FAK inhibitor is 1:1-5:1; the PEG modifier accounts for 0.5% -3% of the total molar amount of the cell apoptosis agonist and the FAK inhibitor.
3. A co-assembled nanoparticle for use in tumor cell apoptosis and matrix stiffness modulation according to claim 1, wherein said Jiao Wang agonist is 6, 7-dichloro-2-methanesulfonyl-3-N-t-butylaminoquinoxaline; The FAK inhibitor is (R) -1- (3-fluoro-4-methoxyphenyl) -N- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -2-oxo-1, 2-dihydropyrido [3,4-d ] pyrimidine-4-carboxamide, (S) -1- (4- ((4- ((4-fluoro-2-methoxyphenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) -3- (3-fluorophenyl) urea, N- [4- [ (3-fluoro-4- [ (6-methoxy-7-quinolinyl) oxy ] phenyl ] amino ] carbonyl ] phenyl ] -2-pyridinecarboxamide, 8- (1-aminocyclobutyl) -N- (2-methyl-5- ((R) -2- (methylamino) -2-phenylethyl) pyridin-3-yl) -2- (3- (trifluoromethyl) phenyl) imidazo [1,2-a ] pyrazine-6-carboxamide and any one of (S) -N- (5- (2- (1- (3-fluoro-4- (6-methoxy-7-quinolinyloxy) phenyl) -2-methylpropan-2-ylamino) ethyl) -2-methylphenyl) -2-fluoronicotinamide.
4. The co-assembled nanoparticle for controlling tumor cell apoptosis and matrix stiffness according to claim 1, wherein the intermolecular forces are one or two of pi-pi stacking, hydrophobic interactions and intermolecular hydrogen bonds.
5. The co-assembled nanoparticle for controlling tumor cell apoptosis and matrix rigidity according to claim 1, wherein the PEG modifier is one or more of PCL-PEG, DMG-PEG, DSPE-PEG, PLGA-PEG and PE-PEG; The molecular weight of the PEG modifier is 200-20000.
6. The method for preparing the co-assembled nanoparticle for controlling the scorch and the matrix rigidity of a tumor cell according to any one of claims 1 to 5, which is characterized by comprising the following steps: respectively dissolving a cell apoptosis agonist, a FAK inhibitor and a PEG modifier in an organic solvent, then treating to obtain uniform co-assembled nanoparticles, and removing redundant organic solvents to obtain the co-assembled nanoparticles for controlling tumor cell apoptosis and matrix rigidity.
7. The method for preparing the co-assembled nanoparticle for controlling the scorch and the matrix rigidity of tumor cells according to claim 6, wherein the process for obtaining the uniform co-assembled nanoparticle comprises the following steps: Respectively dissolving a cell apoptosis agonist, a FAK inhibitor and a PEG modifier in an organic solvent, and then adding water to extrude the mixture in microfluidic equipment to obtain uniform co-assembled nanoparticles.
8. The method for preparing the co-assembled nanoparticle for controlling the scorch and the matrix rigidity of tumor cells according to claim 7, wherein the process for obtaining the uniform co-assembled nanoparticle further comprises the following steps: Respectively dissolving a cell apoptosis agonist, a FAK inhibitor and a PEG modifier in an organic solvent, uniformly mixing under vortex, dripping the uniformly mixed solution into water, and spontaneously forming uniform co-assembled nanoparticles under stirring; When the uniform co-assembled nano particles are prepared, the ratio of the organic phase to the water phase is 1:3-1:5; The mode of removing the redundant organic solvent is a solvent evaporation method, an ultrafiltration method or a dialysis method; The organic solvent is one or the combination of two of ethanol and dimethyl sulfoxide.
9. Use of co-assembled nanoparticles according to any one of claims 1 to 5 for the preparation of a drug delivery system, a systemic administration or a topical administration system.
10. Use of the co-assembled nanoparticle according to any one of claims 1 to 5 for the preparation of an antitumor drug.

Description

Co-assembled nanoparticle for controlling tumor cell apoptosis and matrix rigidity, method and application Technical Field The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a co-assembled nanoparticle for controlling tumor cell apoptosis and matrix rigidity, a method and application thereof. Background Currently, some combination therapeutic strategies and immunotherapy bring new dawn for tumor treatment. However, it is still difficult to obtain satisfactory clinical effects due to the restriction of apoptosis resistance of tumor cells and the complex immunosuppressive microenvironment. With the continued depth of research, cell apoptosis has attracted considerable attention from researchers as a novel highly immunogenic means of cell death. In recent years, various strategies for inducing apoptosis have been explored and developed, and most of the induction modes require cleavage of the apoptosis-carrying protein GASDERMIN by activating related enzymes to induce apoptosis, rely on upstream active enzymes and apoptosis proteins, and cause strong inflammatory reactions and toxicity. Notably, small molecule agonists, which are a newly discovered inducer of cell apoptosis, can activate low levels of cell apoptosis independent of cleavage by direct targeting of key sites of modification GASDERMIN, with low direct killing, which act primarily by activating body autoimmunity without causing unnecessary inflammation or other toxicity. In particular, when a cell-scorching agonist induces the death of tumor cells, a large amount of inflammatory factors (e.g., IL-1. Beta., IL-18) and the cell contents are released. The high inflammatory death mode can improve immunosuppression, improve immunogenicity, attract and activate immune cells (such as T cells and NK cells) in the body, and trigger anti-tumor immune response of the body. However, the dense matrix components of most solid tumors form a strong physical barrier, which severely impedes drug penetration and infiltration and function of immune cells, creating a new bottleneck. Therefore, to achieve deep delivery of the drug itself and effective positive feedback immune activation, the dense physical barrier of the tumor must be broken, reducing the rigidity of the tumor tissue. Traditional strategies directly use various enzymes to degrade extracellular matrix components, which may in turn increase the risk of tumor metastasis. It has been found that inhibition of Focal Adhesion Kinase (FAK) as a mechanical signal transduction pathway not only reduces collagen deposition and fibrosis, but also breaks through the matrix barrier, thereby promoting drug penetration and immune cell infiltration, and reducing the risk of metastasis. Therefore, by combining the cell apoptosis small molecule agonist and the FAK small molecule inhibitor, the solid tumor can be directly killed by the apoptosis, the extracellular compact matrix barrier can be broken through, the tumor immune microenvironment is regulated and controlled to activate the anti-tumor immune response, and multiple gains are realized, so that the method is a novel way which is fully expected on a tumor treatment road. However, most of the two types of small molecules have the problem of poor water solubility, and the traditional nano-carrier has the limitations of larger toxicity, low drug loading, complex preparation process and the like, so that the clinical transformation of the nano-carrier is severely restricted. With the continuous progress of biotechnology, a small molecule co-assembly system is based on an emerging carrier-free nano-drug strategy, and has great potential in anti-tumor drug delivery. The nano-structure is formed by self-assembly of drug molecules, and the use of traditional carrier materials is avoided, so that the toxic and side effects and drug-forming bottlenecks related to carriers are eliminated, and the preparation is simple and the core advantages of extremely high drug loading rate are achieved. More importantly, the co-assembly strategy has excellent universality and flexibility, not only can realize the high-efficiency delivery of single drugs, but also can co-load multiple hydrophobic drugs with complementary functions according to preset and strict stoichiometric ratios. This precise co-delivery capability lays a solid foundation for the implementation of multi-mode synergistic therapy. Disclosure of Invention The invention aims to provide a co-assembled nanoparticle for controlling tumor cell apoptosis and matrix rigidity, a method and application thereof, which are used for solving the technical problems of low solubility of hydrophobic micromolecular medicaments (such as a cell apoptosis agonist) in water and possible inherent toxicity of the traditional nano-carrier in the prior art, further solving the problem of poor cell apoptosis and immune activation effects caused by a tumor matrix rigidity barrier, and finally rea