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Preparation method and application of stimuli-responsive poly-zwitterionic nanogel

A technology of polyzwitterion and nanogel, which is applied to medical preparations with non-active ingredients, medical preparations containing active ingredients, and pharmaceutical formulas, etc., which can solve the problem of reduced drug treatment effect, increased normal tissue toxicity, and nano-carrier drugs. Kinetic advantage loss and other problems, to achieve high-efficiency enrichment and long-term retention, rapid response release of high-efficiency drugs, and prolong the effect of in vivo circulation time

Pending Publication Date: 2022-05-31
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the process of in vivo circulation, premature or too fast drug release will cause the loss of nanocarrier pharmacokinetic advantages or increase the toxicity to normal tissues, while too late or too slow drug release after reaching the target site will make the drug Reduced Healing Effect

Method used

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  • Preparation method and application of stimuli-responsive poly-zwitterionic nanogel
  • Preparation method and application of stimuli-responsive poly-zwitterionic nanogel
  • Preparation method and application of stimuli-responsive poly-zwitterionic nanogel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: preparation MEL / HA@NG (initiator is riboflavin)

[0047] Step 1: Preparation of MEL / HA Complex

[0048] 1 mg melittin (MEL, 0.35 μmol) was dissolved in 1 mL deionized water, mixed with 500 μL hyaluronic acid (HA, 10 mg / mL, 1.92 μmol), and stirred for 1 h. Before preparation, the HA solution was sonicated for 5 min due to the viscosity of HA making it difficult to disperse uniformly. The MEL / HA complex was dialyzed against deionized water (MWCO: 7000Da) for 12 hours to remove free HA and MEL.

[0049] Step 2: Preparation of MEL / HA@NG

[0050] 2mL of the above-prepared MEL / HA complex (MEL, 0.5mg / mL) was continuously stirred, followed by adding 2-methacryloyloxyethylphosphorylcholine (MPC, 10mg, 34μmol), N , N'-bis(acryloyl)cystamine (CBA, 5mg, 19μmol), initiator riboflavin (VB2, 0.2mg, 0.5μmol), catalyst N, N, N', N'-tetramethylethylenedi Amine (TEMED, 1.574 mg, 13.5 μmol). After passing nitrogen gas for 10 minutes, use an ultraviolet lamp (20mW / cm 2 )...

Embodiment 2

[0051] Embodiment 2: preparation MEL / HA@NG (initiator is ammonium persulfate)

[0052] Step 1: Preparation of MEL / HA Complex

[0053] 1 mg melittin (MEL, 0.35 μmol) was dissolved in 1 mL deionized water, mixed with 500 μL hyaluronic acid (HA, 10 mg / mL, 1.92 μmol), and stirred for 1 h. Before preparation, the HA solution was sonicated for 5 min due to the viscosity of HA making it difficult to disperse uniformly. The MEL / HA complex was dialyzed against deionized water (MWCO: 7000Da) for 12 hours to remove free HA and MEL. The average particle diameter of this nanogel recorded by the dynamic light scattering instrument is 116nm, and the particle size distribution index is 0.19 ( figure 2 ).

[0054] Step 2: Preparation of MEL / HA@NG

[0055] 2mL of the above-prepared MEL / HA complex (MEL, 0.5mg / mL) was continuously stirred, followed by adding 2-methacryloyloxyethylphosphorylcholine (MPC, 10mg, 34μmol), N , N'-bis(acryloyl)cystamine (CBA, 5mg, 19μmol), initiator ammonium pers...

Embodiment 3

[0057] Example 3: Preparation of polyzwitterion-coated multi-drug nanocrystals MDNCs@NG (initiator is riboflavin)

[0058] Weigh methotrexate (MTX, 0.3 mg, 6.6 μmol) and 3-bromopyruvate (3-BP, 0.9 mg, 5.4 μmol) and mix them ultrasonically, and slowly drip the mixture drop by drop with a syringe under ice bath conditions into 10mL of water, stirred rapidly at 1000rpm for 5min, then adjusted the rotational speed to 300rpm, and added acrylamide carboxybetaine (CBAA, 4.8mg, 20.9μmol), N,N'-bis(acryloyl)cystamine (CBA , 2.4mg, 9.2μmol) and riboflavin (VB2, 0.1mg, 0.25μmol). After passing nitrogen gas for 10 minutes, use an ultraviolet lamp (20mW / cm 2 ) was irradiated for 30 min, and then dialyzed against deionized water (MWCO: 7000 Da) for 24 h to remove free drugs, zwitterions and cross-linking agents, and obtain multi-drug nanocrystals MDNCs@NG coated with polyzwitterions.

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Abstract

The invention discloses a preparation method and application of stimuli-responsive poly-zwitter-ion nanogel, which comprises the following steps: modifying double bonds by hyaluronic acid or derivatives and analogues thereof, and then forming a compound with a positively charged drug, or modifying double bonds by polyethyleneimine, and then forming a compound with a negatively charged drug, so as to prepare the stimuli-responsive poly-zwitter-ion nanogel. And forming a poly-zwitterionic nanogel through double bonds, zwitterions with double-bond structures at one end and a response type cross-linking agent with double-bond structures at two ends in an in-situ free radical polymerization manner, so as to obtain the poly-zwitterionic nanocage coated with protein polypeptide drugs or nucleic acid drugs. The nanogel has excellent anti-fouling performance, can resist adsorption of non-specific biomacromolecules and remarkably prolong the blood circulation time, and can be split under specific stimulation of tumors, so that targeted delivery of therapeutic drugs is realized. The carrier has the characteristics of good biocompatibility, high drug loading rate, efficient enrichment of tumor sites, controllable drug release and the like, and achieves the purpose of efficiently treating tumors.

Description

technical field [0001] The invention relates to a preparation method and application of a medicinal polymer material, in particular to a preparation method and application of a stimulus-responsive polyzwitterion nanogel. Background technique [0002] With the maturity of biotechnology and peptide synthesis technology, more and more macromolecular drugs such as peptides, nucleic acids, and proteins have been developed and applied clinically. Protein polypeptide drugs refer to protein or polypeptide fragments that can treat or control diseases, mainly including enzymes, cytokines, hormones, etc., and can be used to treat cancer, metabolic and autoimmune diseases, etc. Compared with small molecule drugs, protein peptide drugs have the advantages of low toxicity, targeting, and specificity. However, this class of drugs also has the disadvantages of being easily degraded by proteases in the blood, fast elimination speed, and poor stability (Tiwari G, Tiwari R, SriwastawaB, et al...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/06A61K45/00A61K47/59A61K47/61A61P35/00C08F251/00C08F230/02C08F222/38
CPCA61K9/06A61K47/61A61K47/59A61K45/00A61P35/00C08F251/00C08F230/02C08F222/385
Inventor 钟伊南王慧陈小钰蒋林洋黄德春陈维
Owner CHINA PHARM UNIV
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