CN-121987784-A - Photothermal-enzymatic nanoparticle as well as preparation method and application thereof

Abstract

The invention relates to the technical field of nano biological medicines, and discloses a photo-thermal-enzymatic nanoparticle, a preparation method and application thereof. The photo-thermal-enzyme catalytic nanoparticle comprises a water-soluble self-doped polyaniline nanoparticle, human serum albumin, lactic acid oxidase and collagenase which are crosslinked and constructed through an active oxygen cleavable thioacetal linker. According to the invention, collagenase and lactate oxidase (LOx) are integrated into the same nanoparticle system through Thioacetal (TK) linker, under the action of active oxygen (ROS) in tumor microenvironment and H 2 O 2 generated by LOx catalysis, the TK linker is cracked, the activities of the two enzymes are synchronously activated, collagen matrix (physical barrier) is respectively degraded, lactic acid (chemical barrier) is removed, the tumor microenvironment is efficiently remodeled, and the problems that the regulation effect of a single barrier is limited and the tumor microenvironment is difficult to improve are solved.

Inventors

• Wu Jiayingzi
• Ma Peijia
• Mu ankang
• WANG HANQING

Assignees

• 深圳大学

Dates

Publication Date

20260508

Application Date

20260409

Claims (10)

1. 1. The photo-thermal-enzymatic nanoparticle is characterized by comprising water-soluble self-doped polyaniline nanoparticle, human serum albumin, lactic oxidase and collagenase which are crosslinked and constructed through active oxygen cleavable thioacetal linker.
2. 2. The photo-thermo-enzyme catalytic nanoparticle according to claim 1, wherein the hydrodynamic diameter of the photo-thermo-enzyme catalytic nanoparticle is 197.6nm and the surface potential is-3.5 mV.
3. 3. The photo-thermo-enzyme catalyzed nanoparticle according to claim 1 wherein the mass ratio of water soluble self-doped polyaniline nanoparticle, human serum albumin, lactate oxidase, collagenase and reactive oxygen cleavable thioacetal linker in the photo-thermo-enzyme catalyzed nanoparticle is 20:5:1:5:10.
4. 4. The photo-thermo-enzyme catalytic nanoparticle according to claim 1, wherein the water-soluble self-doped polyaniline nanoparticle has a hydrodynamic diameter of 3.9nm and a surface potential of-24.1 mV.
5. 5. A method of preparing a photo-thermo-enzymatic nanoparticle according to any one of claims 1-4, comprising the steps of: Mixing water-soluble self-doped polyaniline nano-particles, human serum albumin, lactic acid oxidase and collagenase, and adding an active oxygen cleavable thioacetal linker to obtain a mixture; and (3) carrying out a crosslinking reaction on the mixture to obtain the photo-thermal-enzyme catalytic nano-particles.
6. 6. The method for preparing photo-thermal-enzymatic nanoparticle according to claim 5, wherein the crosslinking reaction is performed under the condition that the mixture is stirred at room temperature at 450rpm for 15min.
7. 7. The method for preparing the photo-thermal-enzymatic nanoparticle according to claim 5, wherein the preparation of the water-soluble self-doping polyaniline nanoparticle comprises the steps of mixing aniline-N-propane sulfonic acid with aniline, and carrying out copolymerization reaction to obtain the water-soluble self-doping polyaniline nanoparticle.
8. 8. Use of the photo-thermo-enzymatic nanoparticle of any one of claims 1-4 in the preparation of a tumor diagnosis and treatment formulation.
9. 9. The use of claim 8, wherein the tumor diagnosis and treatment preparation realizes accurate tumor treatment by synergistic remodeling of tumor microenvironment through photothermal treatment and enzyme catalysis.
10. 10. The use of claim 8, wherein the tumor is a solid tumor.

Description

Photothermal-enzymatic nanoparticle as well as preparation method and application thereof Technical Field The invention relates to the technical field of nano biological medicine, in particular to a photo-thermal-enzymatic nanoparticle, a preparation method and application thereof. Background The rise of nano medicine provides a new strategy for accurate tumor treatment. Compared with the traditional small molecule drugs, the nano-drugs have obvious advantages in improving pharmacokinetics, improving bioavailability, realizing passive targeting enrichment of tumors and reducing systemic toxicity by virtue of the unique physical and chemical properties. In addition, the multifunctional performance of the nano platform enables the nano platform to integrate various functions such as imaging, treatment and monitoring, and lays a foundation for constructing a diagnosis and treatment integrated system. However, despite the broad prospect, the clinical transformation process of nano-drugs is very slow, and nano-preparations for solid tumor treatment are available in batches on a global scale. The design of nanomedicines in the treatment of solid tumors has long been based primarily on enhancing the osmotic retention effect. The theory holds that the vascular structure of tumor tissue has poor integrity, increased permeability and lack of lymphatic return function, so that nanoparticles with specific size can be selectively accumulated at tumor sites. However, with the intensive research, enhancing the clinical effectiveness of the osmotic retention effect (EPR effect) is being severely challenged. Quantitative analysis results showed that on average, only less than 1% (about 0.7%) of the injected nanoparticles could be successfully delivered to the tumor lesions by this effect. This extremely low delivery efficiency has become a fundamental bottleneck limiting the efficacy of nanomedicines and impeding their clinical transformation. One of the core reasons for the inefficiency of nano-drug delivery is the multiple physiological barriers present in the tumor microenvironment (Tumor Microenvironment, TME). Among them, dense extracellular matrix (Extracellular Matrix, ECM) composed of crosslinked collagen fibers and hyaluronic acid, etc. constitutes a major physical barrier. The abnormal matrix structure not only remarkably increases tissue interstitial pressure and seriously hinders the penetration and uniform distribution of large-size nano particles to the deep part of the tumor, but also can repel the infiltration of immune effector cells such as cytotoxic T lymphocytes and the like through physical shielding effect, thereby leading to the formation of an immunosuppressive microenvironment. For this physical barrier, researchers have attempted to integrate matrix degrading enzymes such as collagenase into nano-delivery systems in an effort to achieve remodeling of tumor vasculature and interstitial pressure by in situ enzymolysis of ECM, thereby improving the perfusion of nanomedicines and immune effector cells. In addition to the physical barrier, the unique metabolic characteristics of tumors create another serious chemical barrier. Driven by the warburg effect, tumor cells tend to undergo efficient glycolysis even under aerobic conditions, resulting in a large accumulation of lactic acid in the tumor microenvironment. The excessive accumulation of lactic acid is not only a product of tumor metabolism reprogramming, but also a powerful immunosuppressive signal. Studies have shown that high concentrations of lactic acid microenvironment can induce Tumor-associated macrophages (Tumor-Associated Macrophages, TAMs) to polarization of the Tumor-promoting M2 type while directly inhibiting proliferation and cytotoxic activity of effector T cells, resulting in functional depletion. In addition, lactic acid can also be used as a signal molecule to activate Cancer-related fibroblasts (Cancer-Associated Fibroblasts, CAFs) so as to enhance the synthesis and secretion of collagen, further exacerbate the deposition of ECM and form a vicious circle of mutual reinforcement of physical barriers and chemical barriers. To scavenge lactate, researchers have introduced lactate oxidase (Lactate Oxidase, LOx) which specifically catalyzes the conversion of lactate to pyruvate and hydrogen peroxide (H 2O2), and remodelling of the immunosuppressive microenvironment by consumption of lactate. However, the direct use of exogenous enzymes for in vivo circulation suffers from the problems of uncontrollable activity, easy inactivation, potential immunogenicity, systemic side effects caused by nonspecific catalysis, and the like, severely limiting the therapeutic efficacy thereof. Therefore, how to realize the cooperative regulation and control of physical and chemical barriers in the tumor microenvironment and ensure the accurate and controllable release of the therapeutic factors at the same time has become a key technical problem to be so