CN117731637A

CN117731637A - MDP nano-particle and application thereof

Info

Publication number: CN117731637A
Application number: CN202311769854.1A
Authority: CN
Inventors: 杨兴东
Original assignee: Shanghai Amos Biotechnology Co ltd
Current assignee: Shanghai Amos Biotechnology Co ltd
Priority date: 2023-12-20
Filing date: 2023-12-20
Publication date: 2024-03-22

Abstract

The invention relates to MDP nano particles and application thereof, and relates to the technical field of modularized drug treatment, wherein the MDP nano particles are a nano particle technology for coupling and delivering drugs, and one or more drugs with diseases are coupled on a high polymer in a reasonable combination manner, so that the effects of treating or preventing the diseases more efficiently or simultaneously acting on various diseases are achieved, and the effects of treating or preventing the various diseases are improved. The invention relates to a general drug coupling and delivery nanoparticle platform, which plays a role in efficiently and accurately activating, inhibiting or regulating pathogenesis of one or more diseases, directly or assisting other drugs to achieve better prevention and treatment effects on the diseases, and solves the problems of poor targeting, short half-life, limited administration mode, safety and insufficient drug effect of various drugs at present, especially for some diseases with complex pathogenesis, such as metabolic diseases, cardiovascular system diseases, alzheimer disease and the like.

Description

MDP nano-particle and application thereof

Technical Field

The invention relates to the technical field of nanoparticle drug treatment, in particular to MDP nanoparticles and application thereof.

Background

At present, various medicines (chemical medicines, polypeptides, oligonucleotides, proteins, antibodies, cell therapies, polysaccharides, bacteria, viral vectors, gene therapies and the like) lack of cell or tissue targeting, have short half-life, are limited in administration modes (not suitable for oral administration, respiratory tract administration and the like), have low activation efficiency and have large side effects, and also lack a high-efficiency technical platform for treating and preventing diseases by drug combination. For example, the adjuvant molecule CpG ODN has the ability to activate the innate immune system by activating TLR9 receptors. CpG ODNs are classified into A, B, C, and D classes based on different sequence characteristics and activation of different immune responses. At present, cpG ODN is widely used for preventing and treating various diseases of different people and animals, including tumor, infectious disease, autoimmune and other diseases, alone or together with vaccine, immunotherapy, or other medicaments and treatment means. However, due to the small molecular weight, cpG ODNs are readily apparent in vivo, resulting in a short half-life and lack of cell or tissue targeting. This results in limited efficacy or high side effects of the drug. Meanwhile, most of the adjuvant administration modes are intramuscular injection or subcutaneous injection at present. Due to the specific physiological structure and environment of the digestive tract, respiratory tract, the adjuvant molecules cannot maintain stability and efficacy by oral or inhalation. The current solutions are topical administration, increasing the dosage, number of administrations, combination, different dosage forms, and mode of delivery. But the effect achieved by these means is still less than ideal. Similarly, many adjuvant molecules such as polypeptides, RNAs, DNAs, antibodies, proteins, cytokines, polysaccharides, small molecule adjuvants have the same problems of short half-life, lack of tissue or cell targeting, high side effects, and low potency. Meanwhile, the current application of the adjuvant is mainly single use or simple mixed use, has weak effect on the activation path of the immune system, and the activated immune system types (Th 1 vs Th2, cellular immune vs humoral immunity and IgA vs IgG) are unbalanced and cannot be regulated and controlled. For complex diseases such as tumors, cardiovascular diseases, respiratory diseases, neurodegenerative diseases, infectious diseases, metabolic diseases and the like, the single drug has limited treatment effect, and the trend is to use more and more drugs in combination, so that the treatment or prevention effect is improved through multiple action mechanisms. However, the mere mixing of multiple drugs results in limited effectiveness of the combination due to the inability to deliver the drugs to the same tissue or cell, or to the efficient activation of signaling pathways. For example, it is difficult to achieve the desired prophylactic or therapeutic effect by simply mixing the vaccine antigen with an adjuvant.

The problems of nanoparticle combination of various drugs at present include 1. Lack of high flux, modularized combination of various drugs, 2. Lack of large-scale production, 3. Poor biodegradability, 4. Complex combination steps of drugs and stent materials, 5. Low combination efficiency, 6. Poor stability, etc.

Disclosure of Invention

In order to solve the problems, the invention provides MDP nano-particles and application thereof. Specifically, the invention relates to a nanoparticle platform for coupling and delivering universal medicines, which plays a role in efficiently and accurately coupling and delivering various medicines, directly or assisting other medicines to achieve better prevention and treatment effects on diseases, and solves the problems of lack of cell or tissue targeting, short half-life, limitation of administration modes (unsuitable for oral administration, respiratory tract administration and the like), low activation efficiency and large side effects of the existing single medicine or combined medicine.

In a first aspect, the present invention provides an MDP nanoparticle, which is a nanoparticle coupled and delivered by a general drug, and is used for inhibiting immune checkpoint PD1 antibodies, ADCs, radioisotopes, covalent or non-covalent conjugates of various drugs, etc., by coupling one or more drugs, such as chemicals, cpG1018, MPL, mRNA, siRNA, ASO, PADRE, anti-CD 28 antibodies, inhibiting immune checkpoint PD1 antibodies, ADCs, radioisotopes, covalent or non-covalent conjugates of various drugs, etc., and reasonably combining a plurality of drug molecules on a polymer, and simultaneously regulating a plurality of pathways, improving the therapeutic or prophylactic effect of the drug on diseases, such as natural immune cells including DC, B, NK, macrophages, etc., or activating immune cells non-specifically. Etc.

Further, the MDP nanoparticle includes: (a) At least one or more drugs, such as CpG ODN sequences of any length; (b) a high molecular polymer; and or (c) a linker molecule such as strepavidin, neutravidin, rhizavidin and biotin, positively or negatively charged molecules such as polyamines, polypeptides, polysaccharides, and the like.

Further, the polymer includes dextran of any length, dextran of any length which is not modified or modified, other kinds of polysaccharides, nucleic acids, polymers containing different polymers such as PLGA, etc.

Further, the MDP nanoparticles may be a polymer or nanoparticle composed of dextran, or a polymer other than dextran.

Further, the MDP nanoparticles comprise the same drug, such as CpG ODN, or a mixture of two or more different drugs, such as CpG ODN and vaccine antigens.

Further, the MDP nanoparticles include the same drug, such as CpG ODN, or a mixture of two or more different drugs, such as a mixture of CpG ODNs of any length or type and vaccine antigens.

Further, each CpG molecule consists of a natural PE backbone or an artificial PS backbone to increase the stability of the CpG sequence.

Further, they are bound to other molecules and polymeric nanoparticles.

In a second aspect, the present invention provides the use of the MDP nanoparticles of any one of the first aspects, the use comprising:

(a) For the treatment or prophylaxis of diseases in humans or other mammals, including but not limited to cancer, infectious diseases, autoimmune diseases, allergies, metabolic-related diseases, cardiovascular diseases, CNS, aging, or other diseases;

(b) For in vitro stimulation of cells in vitro, such as dendritic cells, or for in vivo adoptive cell therapy of human or animal diseases;

(c) Alone or in combination with other vaccines or medicaments for the treatment or prophylaxis of human or animal diseases including, but not limited to, cancer, infectious diseases, autoimmune diseases, allergies or other immune mediated diseases;

(d) As a drug carrier, linking one or more other drugs such as antigens, adjuvants, immunostimulatory molecules, cell or tissue targeting molecules, immunomodulators, small molecule drugs, polypeptides, antibodies, proteins, polysaccharides, nucleic acid drugs (DNA, RNA, siRNA, ASO etc.), radioisotopes, ADCs, whole or partial cells or pathogens etc. by any means of covalent, non-covalent, biotin-avidin etc. for enhancing the prevention or treatment of human or animal diseases by the drug;

(e) For detecting a disease or diagnosing a disease in vitro.

In a third aspect, the present invention provides a pharmaceutical composition comprising the MDP nanoparticle of any one of the first aspects.

Further, the pharmaceutical composition also comprises pharmaceutically acceptable auxiliary materials.

Further, the pharmaceutical composition is a vaccine composition.

Further, the pharmaceutical composition is an aqueous solution or lyophilized.

Further, the pharmaceutical composition is for use in the treatment or prevention of diseases in humans or other mammals, including, but not limited to, cancer, infectious disease, autoimmune disease, allergy or other immune mediated disease.

Further, the pharmaceutical composition further comprises component (i): one or more additional bioactive molecules or components, including but not limited to the agents described in part (d) of the second aspect, such as PD1 or PD-L1 blockers, immunogenic proteins, cell lysates, or all or part of a pathogen.

Further, the route of administration of the pharmaceutical composition may be any oral or parenteral route including, but not limited to, oral, nasal, intramuscular, intravenous, subcutaneous, intradermal, intraperitoneal injection, and the like.

Further, the pharmaceutical composition may be delivered to the body in any dosage or formulation.

Further, the pharmaceutical composition may be used for in vitro stimulation of cells in vitro, such as dendritic cells, for in vivo adoptive cell therapy of human or animal diseases.

Compared with the prior art, the technical scheme provided by the embodiment of the invention has at least the following advantages:

the invention provides an MDP nanoparticle modularized drug coupling and delivery technology and application thereof, in particular to MDP nanoparticles provided by the invention, which have the following advantages:

1) Has high medicinal effect and long half-life period, and can stimulate multiple receptors simultaneously.

2) Safe, biodegradable, tissue or cell targeting.

3) Multifunctional, can combine with multiple adjuvant or drug molecules.

4) The production process is simple, easy to amplify and good in stability.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the invention and together with the description, serve to explain the principles of the invention.

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the description of the embodiments or the prior art will be briefly described below, and it will be obvious to those skilled in the art that other drawings can be obtained from these drawings without inventive effort.

FIG. 1 is a schematic diagram of the structure of the embodiment of the present invention directly bonded to Dextran functionalized with amine groups.

FIG. 2 is a schematic diagram of the indirect conjugation with amino-Dextran functionalized Dextran in an embodiment of the present invention.

Detailed Description

For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Unless otherwise specifically indicated, the various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or may be prepared by existing methods.

In a first aspect, the present invention provides an MDP nanoparticle that is a universal drug coupled and delivered nanoparticle that is coupled to one or more drugs, such as CpG1018, MPL, mRNA, siRNA, ASO, PADRE, anti-CD 28 antibodies, anti-immune checkpoint PD1 antibodies, etc., via direct or indirect, covalent or non-covalent means, such as biotin and avidin, via a rational combination of multiple drugs and their combination on a polymer while modulating multiple receptors or pathways, enhancing the effect, safety, half-life, or number of disease categories. For example, enhancing the response of natural immune cells such as DC, B, NK, macrophages, etc. or nonspecifically activating immune cells such as PADRE activates most MHC II subtypes on T helper cells.

The MDP (MDP letter meaning: universal modular drug coupling and delivery nanoparticle technology) provided by the invention relates to a universal modular drug coupling and delivery nanoparticle platform. For example, TLR9 is a pathogen-associated molecular pattern recognition receptor that recognizes unmethylated CpG motifs (CpG motif) on viral and bacterial DNA that are not present in human DNA; its recognition of pathogen DNA triggers and activates signal pathways in antigen presenting cells (such as DCs and macrophages), recruiting cytokines and chemokines, and thereby regulating innate and adaptive immune responses. Previous studies have shown that the TLR9 agonist CpG ODN has a powerful immunopotentiating effect on cancer and infectious diseases. TLR9 agonist polymers have also been shown to increase TLR9 contact and activation of the immune response. The present invention may link a plurality of natural immunostimulatory molecules such as oligonucleotide molecules like CpG ODN (a, B, C, D classes, cpG1018, cpG2395, cpG1086 etc.), RNA molecules, siRNA, ASO, polypeptide molecules like PADRE, polysaccharides, MPL molecules, a-Gal etc., proteins, anti-CD 28, OX40, PD1 antibodies etc. by non-covalent (biotin and Neutravidin, avidin, strepitavidin) or covalent means; also included are immune cell targeting molecules (polypeptides, proteins, polysaccharides, etc.); disease tissue microenvironment-regulating molecules (e.g., tumor microenvironment); forming a nano-polymer or nano-particle.

In the present invention, MDP consists of dextran polymers directly or indirectly coupled to several to thousands of CpG ODN molecules, which significantly enhances innate or adaptive immune responses in comparison to CpG monomers. MDP has the advantage of low amounts of drug required by the organism with increased safety and efficacy, increased throughput and reduced production costs.

MDP nanoparticles can be used alone or in combination with other pharmaceutical ingredients for the treatment and prevention of human or animal diseases. .

As an implementation of the examples of the present application, the MDP nanoparticle includes: (a) At least one drug, such as a CpG ODN sequence of any length; (b) a high molecular polymer; and or (c) a linker molecule, such as SA and biotin.

In the present invention, the effect of any one of the drugs for treating or preventing diseases, such as CpG ODN sequences, is to bind to TLR9 receptor of antigen presenting cells, activate the natural immune system, thereby finally activating the acquired immune system, and the prophylactic and therapeutic effects of the direct or auxiliary vaccine or drug on diseases can be specifically adopted, such as CpG1018, cpG2395, cpG2006, etc.

In the present invention, (b) the high molecular polymer serves to provide a scaffold and shape for binding the pharmaceutical ingredient, and specifically, dextran, other polysaccharide molecules, DNA or RNA nucleic acids, polymer PLGA of different high molecular materials, etc. of any length can be used.

In the present invention, (c) the linking molecule serves to link the drug molecule with the polymer, and specifically, SA, biotin, etc. can be used.

For example, as shown in fig. 1-2, it can be seen from fig. 1-2: the 5' -biotinylated a, B, C CpG ODN forms MDP nanoparticles by the combination of the linker strepitavidins and biotinylated 500K molecular weight Dextran molecules (Dextran).

In some embodiments, the high molecular weight polymer comprises dextran of any length.

In some embodiments, the MDP nanoparticles may be dextran-based polymers or nanoparticles, or polymers other than dextran.

In some embodiments, the MDP nanoparticles comprise the same CpG ODN or a mixture of two or more different CpG ODNs.

In some embodiments, the MDP nanoparticles comprise the same CpG ODN or a mixture of two or more different CpG ODNs, with CpG ODNs of any length or type.

In some embodiments, each CpG molecule consists of a natural PE backbone or an artificial PS backbone to increase the stability of the CpG sequence.

In some embodiments, they are bound to other molecules and polymeric nanoparticles. In particular, "they are bound to other molecules and polymeric nanoparticles" refers to other polysaccharide polymeric materials, single or double stranded nucleic acids, polypeptides, and derivatives or modifications of these materials.

In some embodiments, the MDP nanoparticles have a particle size of 1 to 100,000 nm, preferably 50 to 100nm.

In some embodiments, the preparation method of the MDP nanoparticle comprises the following process 1. Mixing biotinylated drug molecules such as CpG ODN, a linker such as strepitavidin and biotinylated dextran polymer material uniformly according to a certain molar ratio, and incubating at room temperature, 37 ℃ or 4 ℃ for 30 min-24 h;2. purifying to remove unbound monomer molecules or incompletely bound nanoparticles; 3. and (5) ultrafiltration and concentration.

In a second aspect, based on the same inventive concept, the present invention provides the use of the MDP nanoparticles of any one of the first aspects, the use comprising:

(a) For the treatment or prophylaxis of diseases in humans or other mammals, including but not limited to cancer, infectious diseases, autoimmune diseases, allergies or other immune-mediated diseases;

(d) As a drug carrier, linking one or more other drugs such as adjuvants, immunostimulatory molecules, cell or tissue targeting molecules, immunomodulators, small molecule drugs, polypeptides, antibodies, various antigens, pMHC complexes, proteins, polysaccharides, nucleic acid drugs (DNA, RNA, siRNA, ASO, etc.), radioisotopes, ADCs, whole or partial cells or pathogens, or covalent or non-covalent combinations of multiple types of drugs, etc. by any means such as covalent, non-covalent, biotin-avidin, etc. for enhancing the prevention or treatment of human or animal diseases with drugs;

(e) For detecting a disease or diagnosing a disease in vitro.

In the present invention, the "application" includes use for preparing products in the above application fields, such as medicines, test kits, test devices, and the like.

In a third aspect, based on the same inventive concept, the present invention provides a pharmaceutical composition comprising the MDP nanoparticle according to any one of the first aspects.

In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant. The adjuvants may include "drug carriers" (specifically, a system capable of changing the mode and distribution of a drug into a human body, controlling the release rate of the drug and delivering the drug to a targeted organ), "excipients" (e.g., physiological saline, glucose, vitamin C, amino acids, etc., refer to additives other than the main drug in a pharmaceutical preparation; e.g., binders in tablets, fillers, disintegrants, lubricants, wines, vinegar, juices, etc., in a traditional Chinese medicine pill; semi-solid preparation ointments, matrix portions in creams; preservatives, antioxidants, flavoring agents, fragrances, co-solvents, emulsifiers, solubilizing agents, osmotic pressure regulators, colorants, etc., in a liquid preparation) etc., and the like.

In some embodiments, the pharmaceutical composition is a vaccine composition.

In some embodiments, the pharmaceutical composition is an aqueous solution or lyophilized.

In some embodiments, the pharmaceutical composition is for use in treating or preventing a disease in a human or other mammal, including but not limited to cancer, infectious disease, autoimmune disease, allergy, or other immune-mediated disease.

In some embodiments, the route of administration of the pharmaceutical composition may be any oral or parenteral route including, but not limited to, oral, nasal, intramuscular, intravenous, subcutaneous, intradermal, intraperitoneal injection, and the like.

In some embodiments, the pharmaceutical composition may be delivered to the body in any dosage or formulation. Preferably, the body is delivered in an effective amount of dosage or formulation, "effective amount" may also be referred to as "therapeutically effective amount" meaning an amount of agent sufficient to provide the desired biological result. The result may be a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, a "therapeutically effective amount" of a pharmaceutical composition of the invention refers to the amount of the composition required to clinically significantly reduce the disease. In any case, an appropriate "effective" amount can be determined by one of ordinary skill in the art using routine experimentation. Thus, the expression "effective amount" generally refers to the amount of active substance that has a therapeutic effect.

In some embodiments, the pharmaceutical composition may be used to stimulate in vitro cells, such as dendritic cells, in vitro, for adoptive cell therapy in vivo for human or animal diseases.

In some embodiments, the pharmaceutical composition further comprises component (i): one or more additional bioactive molecules or components, including but not limited to an immunomodulatory agent, such as a PD1 or PD-L1 blocker, an immunogenic protein, a polypeptide, a cell lysate, or all or part of a pathogen.

In summary, the present invention provides an MDP nanoparticle and application thereof, and in particular, the MDP nanoparticle provided by the present invention has the following advantages:

1) The medicine has high disease treating or preventing effect and long half life and may be used in stimulating several receptors simultaneously.

2) Safe, biodegradable, tissue or cell targeting.

3) Multifunctional, can combine with multiple adjuvant or drug molecules.

4) The production process is simple, easy to amplify and good in stability.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which are not specified in the following examples, are generally determined according to national standards. If the corresponding national standard does not exist, the method is carried out according to the general international standard, the conventional condition or the condition recommended by the manufacturer.

Example 1

The present example provides an MDP nanoparticle comprising: biotin-CpG1018, strepitavidin, biotin-Dextran 500kd.

The preparation method of the MDP nano-particles comprises the following steps:

1. Biotin-CpG1018 and strepitavidin were mixed at 1:0.1-10:1, and incubating for 30 minutes to 24 hours at room temperature.

2. Biotin-Dextran 500kd was combined with the solution obtained in step 1 as Dextran 500: strepitavidins in a molar ratio of 1:1-1:1000 and incubated at room temperature for 30 minutes to 24 hours.

3. And (5) chromatographic purification.

4. And (5) ultrafiltration and concentration.

Example 2

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the linker is Neutravidin; the rest steps and parameters are the same.

Example 3

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the linker is Rhizavidin; the rest steps and parameters are the same.

Example 4

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the polymer material is Dextran 2000Kd; the rest steps and parameters are the same.

Example 5

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the polymer material is Dextran200Kd; the rest steps and parameters are the same.

Example 6

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the polymer material is Dextran100Kd; the rest steps and parameters are the same.

Example 7

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the polymer material is Dextran 70Kd; the rest steps and parameters are the same.

Example 8

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the polymer material is Dextran10Kd; the rest steps and parameters are the same.

Example 9

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the high polymer material is mannose Mannan; the rest steps and parameters are the same.

Example 10

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG2395; the rest steps and parameters are the same.

Example 11

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: adjuvant molecules are CpG2395 and CpG1018; the rest steps and parameters are the same.

Example 12

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: adjuvant molecules are CpG2395 and PADRE; the rest steps and parameters are the same.

Example 13

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: adjuvant molecules are CpG2395 and PADRE; and has additional DC cell targeting molecule polypeptide VSY, and the other steps and parameters are the same.

Example 14

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: adjuvant molecules are CpG2395 and PADRE; and has additional DC cell targeting molecule polysaccharide Mannose, and the rest steps and parameters are the same.

Example 15

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG1018; and HAs vaccine antigens such as influenza HA, and the rest steps and parameters are the same.

Example 16

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG1018; and has vaccine antigen such as tumor related antigen HER2, and the rest steps and parameters are the same.

Example 17

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG1018; and has vaccine antigen such as tumor neoantigen KRAS G12D, and the rest steps and parameters are the same.

Example 18

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG1018; and has vaccine antigen such as tumor neoantigen KRAS G12D and PDL1 antigen, and the rest steps and parameters are the same.

Example 19

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG1018; and has vaccine antigen such as tumor neoantigen KRAS G12D and IDO protein antigen, and the rest steps and parameters are the same.

Example 20

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG1018; and has vaccine antigens such as Alzheimer's antigen beta-amylase protein, and the rest steps and parameters are the same.

Example 21

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG1018; and has vaccine antigens such as hyperlipidemia antigen Lipoprotein a protein, and other steps and parameters are the same.

Example 22

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG1018; and has anti-CD 19 monoclonal antibody and cytotoxic drug Topoisomerase Inhibitor, and the rest steps and parameters are the same.

Example 23

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG1018; and has anti-TNFR monoclonal antibody, and the rest steps and parameters are the same.

Example 24

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG1018; and ASO nucleic acid medicine with KRAS G12D resistance, and the rest steps and parameters are the same.

Example 25

This example provides MDP nanoparticles and a method for preparing the same, which differ from example 1 only in that: the adjuvant molecule is CpG1018; and HAs influenza HA mRNA sequence antigen, and other steps and parameters are the same.

Test case

The MDP nanoparticles obtained in examples 1 to 23 were tested in this example.

1) DNA electrophoresis test, test result shows that: the CpG1018 molecular band was located near the loading well of the gel.

2) Heat denatured SDS-PAGE test, test results indicated: neutravidin protein bands are around 60 kd.

3) Heat denatured SDS-PAGE test, test results show that: the Rhizavidin protein band is about 30 kd.

12 Heat denaturing SDS-PAGE test, test results indicate: the PADRE peptide band was around 2 kd.

13 Heat denaturing SDS-PAGE test, test results indicate: PADRE and VSY peptide bands were around 1-3 kd.

15 Heat denaturing SDS-PAGE test, test results indicate: the HA protein band was around 60 kd.

18 Heat denaturing SDS-PAGE test, test results indicate: KRAS G12D and PDL1 protein bands at 20kd

And about 30 kd.

25 Heating denatured DNA molecular gel test, test results indicate: mRNA nucleic acid molecule bands are near the gel loading wells.

In summary, the present invention relates to an MDP nanoparticle and an application thereof, wherein the MDP nanoparticle is a nanoparticle technology of drug coupling and delivery, and by coupling one or more drugs for treating or preventing diseases, the reasonable combination of one or more drugs on a polymer, the result of treating or preventing diseases can be achieved more efficiently, or the effect of treating or preventing various diseases can be improved by acting on various diseases simultaneously. The invention relates to a general drug coupling and delivery nanoparticle platform, which plays a role in efficiently and accurately activating, inhibiting or regulating pathogenesis of one or more diseases, directly or assisting other drugs to achieve better prevention and treatment effects on the diseases, and solves the problems of poor targeting, short half-life, limited administration mode, safety and insufficient drug effect of various drugs (micromolecules, radiotherapy, proteins, antibodies, mRNA, cell therapy, oncolytic viruses, bacterial drugs and the like), especially the problems of complex pathogenesis of some diseases such as tumors, autoimmune diseases, infectious diseases, metabolic diseases such as obesity and diabetes, cardiovascular system diseases, alzheimer's disease, aging and the like.

Various embodiments of the invention may exist in a range of forms; it should be understood that the description in a range format is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the invention; it is therefore to be understood that the range description has specifically disclosed all possible sub-ranges and individual values within that range. For example, it should be considered that a description of a range from 1 to 6 has specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as single numbers within the range, such as 1, 2, 3, 4, 5, and 6, wherever applicable. In addition, whenever a numerical range is referred to herein, it is meant to include any reference number (fractional or integer) within the indicated range.

The foregoing is only a specific embodiment of the invention to enable those skilled in the art to understand or practice the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. An MDP nanoparticle, wherein the MDP nanoparticle is a nanoparticle capable of treating or preventing a human or other mammalian disease, and is capable of activating a natural immune system or a non-antigen specific molecule, such as a natural immune system or a non-antigen specific molecule, through modularized and rational coupling and delivery, and a plurality of immune activating molecules and rational combination on a high molecular polymer, and simultaneously modulate a plurality of receptors or disease pathways, thereby improving targeting, half-life, administration mode diversity, safety and drug efficacy of the drug.

2. The MDP nanoparticle of claim 1, wherein the MDP nanoparticle comprises: (a) At least one drug, such as a CpG ODN sequence of any length; (b) a high molecular polymer of any length; and or (c) one or more covalent or non-covalent linking molecules;

wherein the high molecular polymer comprises dextran of any length; the linker molecule includes Neutravidin, strepitavidin, avidin, or Rhizavidin and biotin.

3. The MDP nanoparticle according to any one of claims 1-2, wherein the MDP nanoparticle comprises the same drug, such as CpG ODN, or two or more different drugs, such as a mixture of CpG ODNs.

4. The MDP nanoparticle of any one of claims 1 to 3, wherein the MDP nanoparticle comprises the same drug, such as CpG ODN, or a mixture of two or more different drugs, such as CpG ODN, having any length or type of CpG ODN.

5. The MDP nanoparticle according to claims 1 to 4, wherein each CpG molecule consists of a natural PE backbone or an artificial PS backbone to increase the stability of the CpG sequence.

6. MDP nanoparticles according to any one of claims 1 to 5, characterized in that they are bound to other molecules and polymeric nanoparticles.

7. The use of MDP nanoparticles according to any one of the claims 1 to 6, characterized in that said use comprises:

(a) For the treatment or prophylaxis of diseases in humans or other mammals, including but not limited to cancer, infectious diseases, autoimmune diseases, allergies, metabolic diseases, aging, cardiovascular diseases, CNS diseases or other diseases;

(d) As a drug carrier, linking one or more other drugs such as antigens, adjuvants, immunostimulatory molecules, cell or tissue targeting molecules, immunomodulators, small molecule drugs, polypeptides, antibodies, proteins, polysaccharides, nucleic acid drugs (DNA, RNA, siRNA, ASO etc.), radioisotopes, ADCs, CAR-T, oncolytic viruses, bacterial carrier drugs etc. or covalent or non-covalent combinations of different drugs etc. by any means such as covalent, non-covalent, biotin-avidin etc. for enhancing the prevention or treatment of human or animal diseases with drugs;

(e) For detecting a disease or diagnosing a disease in vitro.

8. A pharmaceutical composition comprising the MDP nanoparticle of any one of claims 1 to 7.