Amphiphilic block polymer and application thereof

Abstract

The invention discloses an amphiphilic block polymer and application thereof, and relates to the technical field of polymer synthesis, and the technical key points are as follows: the amphiphilic block polymer formed by polypropylene sulfide (PPS) and polyethyleneimine (PEI) co-delivers a hydrophobic small molecule drug (such as curcumin) and a gene drug (such as anti-miR-33ASO or miR-126), the outer surface of the amphiphilic block polymer is easy to modify, and the amphiphilic block polymer has good biocompatibility, and can be used for preparing a drug carrier. The drug can be delivered to foam cells in atherosclerotic plaques through macrophage membrane coating, and responds to reactive oxygen species (ROS) to generate conversion from hydrophobic to hydrophilic to release the drug, so that foam cell formation and inflammatory response are inhibited; polysialic acid (PSA) can also be modified to overcome the blood-brain barrier, the polysialic acid is delivered to the focus position of sepsis-related encephalopathy (SAE) and responds to ROS to release drugs, and a new treatment choice is provided for diseases such as atherosclerosis, sepsis-related encephalopathy and blood-brain barrier injury and related cardiovascular diseases.

Description

Technical Field

[0001] The present invention relates to the technical field of polymer synthesis, and particularly relates to an amphiphilic block polymer and its applications. Background Art

[0002] PPS-b-PEI is a block copolymer composed of polypropylene sulfide (PPS) and polyethyleneimine (PEI), combining the excellent ROS responsiveness of PPS with the water solubility and positive charge properties of PEI. PPS-b-PEI is widely used in the biomedical field, especially in targeted drug delivery, gene delivery, and biosensors. First, in targeted drug delivery, the PEI part of PPS-b-PEI has cationic properties and can form complexes with negatively charged drug molecules, helping the drug cross the cell membrane through electrostatic interactions. The hydrophobicity of the PPS part helps increase the stability of the carrier and reduce the premature release of the drug, thus improving the targeting effect and reducing side effects. By adjusting the properties of the PPS chain, the release rate and targeting characteristics of the drug can be optimized, making it an effective drug delivery carrier. In the field of gene delivery, PPS-b-PEI forms a gene carrier using the electrostatic attraction between its PEI segment and gene drugs, effectively delivering foreign genes to target cells. The cationic properties of PEI ensure the binding of gene drugs to the carrier, while the PPS part provides additional stability to prevent the genetic material from being degraded by enzymes in the body. Such carriers have important applications in gene therapy and vaccine development, etc., and can improve the delivery efficiency of gene drugs. In addition, PPS-b-PEI can also be used as a component of biosensors. Since the PEI segment can specifically bind to target biomolecules (such as DNA, RNA, proteins, etc.), and the PPS part provides stability and improves the sensitivity of detection signals, the application of PPS-b-PEI in biosensors, especially in medical diagnosis and disease monitoring, has broad prospects. In summary, as a multifunctional material, PPS-b-PEI has broad application potential in the fields of targeted drug delivery, gene delivery, and biosensors.

[0003] However, at the current stage, when treating diseases such as atherosclerosis (AS), sepsis associated encephalopathy (SAE), and inhibiting blood brain barrier (BBB) injury, some challenges still remain. Traditional drug delivery systems are difficult to precisely target foam cells and inflammatory regions in atherosclerotic plaques, resulting in the accumulation of drugs in non-target tissues and side effects. Secondly, single-drug therapy often cannot comprehensively address the multi-faceted pathological processes of atherosclerosis, so combination drug therapy has become a trend, but the synergistic effects between drugs still need to be optimized.

[0004] To this end, the present invention aims to provide an amphiphilic block polymer and its application to solve the above problems. Summary of the Invention

[0005] The object of the present invention is to solve the above problems and provide an amphiphilic block polymer and its application. The present invention combines curcumin and anti-miR-33 ASO and delivers them to foam cells in atherosclerotic plaques through an amphiphilic block polymer formed by polypropylene sulfide (PPS) and polyethyleneimine (PEI), inhibiting the formation of foam cells and inflammatory responses, and providing a new treatment option for atherosclerosis and related cardiovascular diseases.

[0006] To achieve the above object, the technical solution of the present invention is as follows:

[0007] The present invention provides an amphiphilic block polymer and its application. The amphiphilic block polymer is polypropylene sulfide-polyethyleneimine (PPS-b-PEI). The preparation method of the amphiphilic block polymer is: using a fragment of ROS-sensitive polypropylene sulfide (PPS) to covalently connect polyethyleneimine (PEI) to form an amphiphilic block polymer: polypropylene sulfide-polyethyleneimine (PPS-b-PEI).

[0008] The polypropylene sulfide-polyethyleneimine (PPS-b-PEI) can be used to treat diseases such as atherosclerosis, sepsis-related encephalopathy, and inhibit blood-brain barrier damage. The polypropylene sulfide-polyethyleneimine (PPS-b-PEI) can co-load small molecule hydrophobic drugs and gene drugs. That is, the polypropylene sulfide-polyethyleneimine (PPS-b-PEI) can self-assemble into nanoparticles. The PPS part forms a hydrophobic core to load curcumin, and the PEI forms a hydrophilic layer in the aqueous phase and loads anti-miR-33 antisense oligonucleotide (anti-miR-33 ASO) by means of electrostatic interaction; the nanoparticles enhance the targeting ability by coating macrophage cell membranes, enabling the nanoparticles to specifically recognize and target atherosclerotic plaques and foam cells within the plaques.

[0009] Compared with the prior art, the beneficial effects of this solution are:

[0010] 1. PPS is responsive to reactive oxygen species (ROS) and can be converted into hydrophilic molecules in the redox environment of atherosclerotic plaques, promoting the release of drugs, thereby improving the targeting and effect of drug treatment;

[0011] 2. PPS-b-PEI can self-assemble into core-shell structured nanoparticles, where PPS serves as the hydrophobic core for loading drugs (such as curcumin), and PEI serves as the hydrophilic outer layer for loading gene drugs (such as anti-miR-33 ASO or miR-126). This structural design not only simplifies the preparation of drug carriers but also provides an intelligent platform for the combined delivery of small molecule drugs and gene drugs;

[0012] 3. PPS-b-PEI can simultaneously load drugs with different properties, exerting a synergistic therapeutic effect and further enhancing the curative effect. Through macrophage cell membrane mimetic design, PPS-b-PEI can be targeted to foam cells in atherosclerotic plaques, enhancing the targeting and safety of drug delivery;

[0013] 4. The PEI outer layer is easy to be surface-modified. It can not only enhance the targeting ability by coating with macrophage cell membranes, enabling the macrophage cell membranes to specifically recognize and target atherosclerotic plaques and foam cells within the plaques, but also achieve targeting of sepsis-related encephalopathy or other lesions by covalently modifying polysialic acid or other target molecules;

[0014] 5. As a drug delivery system, PPS-b-PEI has ROS responsiveness, dual drug-loading ability, and adjustable surface modification functions, providing an effective strategy for the treatment of atherosclerosis and related cardiovascular and cerebrovascular diseases. Brief Description of the Drawings

[0015] Figure 1 It is the schematic diagram of the action principle of the amphiphilic block polymer polypropylene sulfide-polyethyleneimine PPS-b-PEI in the embodiments of the present invention. Detailed Embodiments

[0016] In order to enable those skilled in the art to better understand the solution of the present invention, the technical solution of the present invention will be further described in detail below in combination with the embodiments and drawings of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0017] It should be noted that, without conflict, the embodiments in the present invention and the features in the embodiments can be combined with each other. The present invention will be described in detail below in combination with the embodiments.

[0018] Embodiment:

[0019] The solution provided by the embodiments of the present invention is as described in the above-mentioned invention content, which provides an amphiphilic block polymer and its application. The amphiphilic block polymer is polypropylene sulfide-polyethyleneimine PPS-b-PEI. The preparation method of the amphiphilic block polymer is as follows: a fragment of ROS-sensitive polypropylene sulfide PPS is used to covalently connect polyethyleneimine PEI to form an amphiphilic block polymer: polypropylene sulfide-polyethyleneimine PPS-b-PEI.

[0020] Polypropylene sulfide-polyethyleneimine PPS-b-PEI can co-load small molecule hydrophobic drugs and gene drugs. That is, polypropylene sulfide-polyethyleneimine PPS-b-PEI can self-assemble into nanoparticles. The PPS part forms a hydrophobic core to load curcumin, and PEI forms a hydrophilic layer in the aqueous phase and loads anti-miR-33 antisense oligonucleotide (anti-miR-33ASO) by means of electrostatic interaction; the nanoparticles enhance the targeting ability by coating macrophage cell membranes, enabling the macrophage cell membranes to specifically recognize and target atherosclerotic plaques and foam cells within the plaques.

[0021] By forming ROS-sensitive macrophage cell membrane biomimetic nanoparticles, curcumin and anti-miR-33ASO are co-delivered to synergistically inhibit the formation of foam cells and inflammatory responses during the atherosclerotic process. Among them, PPS serves as a hydrophobic core to load drugs (such as curcumin), and PEI serves as a hydrophilic outer layer to load genes (anti-miR-33ASO) through electrostatic interaction. The surface of the nanoparticles is further coated with macrophage cell membranes to achieve targeted delivery to atherosclerotic plaques and the foam cells therein. When the nanoparticles enter the foam cells in atherosclerotic plaques, the PPS core will respond to the high level of ROS in this area and undergo a transformation from "hydrophobic" to "hydrophilic", resulting in the diffusion of the nanoparticles and promoting the release of drugs. Curcumin inhibits the formation of foam cells and inflammatory responses by inhibiting the expression of macrophage surface receptors CD36 and SR-A1, inhibiting lipid uptake by foam cells, and promoting the expression of ABCA1 (ATP-binding cassette subfamily A member 1). At the same time, anti-miR-33ASO promotes the efflux of cholesterol in foam cells and further promotes the lipid efflux of foam cells by upregulating the expression of ABCA1 and ABCG1 (ATP-binding cassette subfamily G member 1), ultimately reversing the formation of foam cells.

[0022] The present invention provides a new treatment option for the clinical treatment of atherosclerotic-related cardiovascular diseases by jointly applying curcumin and anti-miR-33ASO and adopting a "two-in-one" strategy, that is, simultaneously inhibiting the formation of foam cells and anti-inflammatory effects, controlling atherosclerosis and delaying the atherosclerotic process.

[0023] The above specific embodiments are only explanations of the present invention, and they are not limitations on the present invention. After reading this specification, those skilled in the art can make modifications to these embodiments that do not contribute creatively as needed, but as long as they are within the scope of the claims of the present invention, they are protected by the patent law.

Claims

1. An amphiphilic block polymer and its application, characterized in that: The amphiphilic block polymer is polypropylene sulfide-polyethyleneimine PPS-b-PEI.

2. The amphiphilic block polymer and its application according to claim 1, characterized in that: The preparation method of the amphiphilic block polymer is as follows: a ROS-sensitive fragment of polypropylene sulfide PPS is used to covalently link polyethyleneimine PEI to form an amphiphilic block polymer: polypropylene sulfide-polyethyleneimine PPS-b-PEI.

3. An amphiphilic block polymer and its application according to claim 1, characterized in that: The polypropylene sulfide-polyethyleneimine PPS-b-PEI can co-load small molecule hydrophobic drugs and gene drugs.

4. The amphiphilic block polymer and its application according to claim 1, characterized in that: The polypropylene sulfide-polyethyleneimine PPS-b-PEI can be used for the treatment of atherosclerosis, sepsis-related encephalopathy and inhibition of blood-brain barrier damage.

5. The amphiphilic block polymer and its application according to claim 4, characterized in that: The polypropylene sulfide-polyethyleneimine PPS-b-PEI self-assembles to form nanoparticles. The PPS part forms a hydrophobic core to load small molecule hydrophobic drugs, and the PEI forms a hydrophilic layer in the aqueous phase and loads gene drugs by means of electrostatic interaction; The surface of the nanoparticles is easy to modify. The targeting property can be enhanced by coating macrophage cell membranes, enabling the nanoparticles to specifically recognize and target atherosclerotic plaques and foam cells within the plaques; It can also be covalently modified with polysialic acid or other target molecules to achieve targeting of sepsis-related encephalopathy or other lesions.

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