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Glucose and H2O2 dual-response double-layer cross-linked polymer nano drug delivery system as well as preparation method and application thereof

A nano-drug delivery system and cross-linked polymer technology, applied in biochemical equipment and methods, pharmaceutical formulations, medical preparations of non-active ingredients, etc., can solve the problem of weakening long-term circulation, hypoglycemia, low drug loading, etc. question

Pending Publication Date: 2022-06-28
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the above-mentioned insulin delivery systems often have problems such as low drug loading, slow response, complex preparation process, and unstable carrier released in multiple cycles, which weakens the effect of long-acting circulation, and the resulting large amount of insulin burst release may adverse consequences such as severe hypoglycemia

Method used

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  • Glucose and H2O2 dual-response double-layer cross-linked polymer nano drug delivery system as well as preparation method and application thereof
  • Glucose and H2O2 dual-response double-layer cross-linked polymer nano drug delivery system as well as preparation method and application thereof
  • Glucose and H2O2 dual-response double-layer cross-linked polymer nano drug delivery system as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The synthesis of PEG-b-PAC and PEG-b-P (AC-co-MPA), the synthetic route and process are as follows:

[0041]

[0042] In a dry glove box under nitrogen protection, 0.67g polyethylene glycol (PEG, 8000Da, 0.084mmol) and 0.5g acryloyl carbonate (AC, 2.5mmol) were added to the sealed reaction flask, and 4mL of dichloromethane was added to dissolve After that, 50 mg of bis(bistrimethylsilyl)amine zinc (Zn[N(SiMe 3 )i] 2 ) (0.13 mmol). The reaction vessel was sealed and placed in an oil bath, and stirred at 45 °C for 72 h. After the polymerization reaction, the solution was dropped into ice ether for precipitation, and dried in vacuo to obtain 0.97 g of white solid powder PEG-b-PAC with a yield of 83%. . Take 1.18g PEG-b-PAC (0.1mmol), 0.148mg mercaptopropionic acid (MPA, 1.4mmol), 100μL Et 3 N (0.72 mmol) was dissolved in 10 mL of DMF, and the carbon-carbon double bond and thiol molar ratio was 4:3 at room temperature for overnight reaction, and the white solid PEG-P...

Embodiment 2

[0046] The synthesis of PEG-b-P (AC-co-MAPBA), the synthetic route and the process are as follows:

[0047]

[0048] Accurately weigh 0.876g PEG-b-P(AC-co-MPA) (0.067mmol) and dissolve it in 10mL N,N-dimethylformamide (DMF), add 0.46g EDC·HCl (2.4mmol) and 0.276g NHS (2.4mmol) After activation, the reaction was stirred for 30 min, and then 0.50 g of m-aminophenylboronic acid (APBA, 3.2 mmol) was added to continue the reaction overnight. Dialysis was performed in methanol for 12 h with a dialysis bag with a molecular weight cut-off (MWCO) of 3500 Da. Methanol was removed by vacuum rotary evaporation. The solution was dialyzed against water and dried in vacuo to give the product PEG-b-P(AC-co-MAPBA).

[0049] H NMR characterization of PEG-b-P(AC-co-MAPBA) is attached image 3 , 1H NMR (400MHz, MeOD)δ1.05(s, 3H), 2.39-3.14(m, 3H), 2.83-3.09(m, 4H), 3.63(s, 52H), 3.95-4.35(m, 6H) , 5.56-6.71 (m, 1H), 7.13-8.05 (m, 3H).

Embodiment 3

[0051] The synthesis, synthetic route and process of GOx-MAA-MPD are as follows:

[0052]

[0053] 8 μL of α-methacrylic acid (MAA) was added to 400 μL of DMF, and then EDC·HCl and NHS were added sequentially. After half an hour, 3 mL of PB (pH 7.4, 5 mmol) containing 12 mg of GOx was added. The mixture was dialyzed against MWCO 3500Da dialysis bag for 24 h in deionized water to remove unreacted MAA. Vacuum drying gave solid GOx-MAA. Subsequently, GOx-MAA was treated with 1-thioglycerol (MPD) and triethylamine (Et 3 N) Reaction for 12h. The solution was dialyzed for 24 h and dried under vacuum.

[0054] Hydrogen NMR characterization of GOx-MAA-MPD is attached Figure 4 , 1 H NMR (400MHz, D 2 O)δ1.08(t, 1H), 1.29(t, 3H), 2.37-2.49(m, 1H), 2.65(s, 1H), 2.87(s, 2H), 3.07-3.28(m, 4H), 3.71(s, 1H).

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Abstract

The invention discloses a glucose and H2O2 dual-response double-layer cross-linked polymer nano drug delivery system as well as a preparation method and application thereof. Polyethylene glycol, functionalized carbonic ester and sulfydryl-containing carboxylic acid are sequentially subjected to ring-opening polymerization reaction to form an amphiphilic triblock polymer skeleton, and the amphiphilic triblock polymer skeleton is modified by a phenylboronic acid derivative to form an amphiphilic polymer; gOx is sequentially modified by carboxylic acid containing double bonds and vicinal diol substances, and then the modified GOx is mixed with the amphiphilic polymer. The novel biodegradable polymer auxiliary material is designed and synthesized by organically combining GOx serving as a glucose oxidation mechanism, a competitive mechanism between sugar molecules and acyclic diol and gel ultraviolet crosslinking for the first time. GOx and phenylboronic acid ester act together to enhance glucose sensitivity and H2O2 sensitivity; the phenylboronic acid derivative and the vicinal diol compound form phenylboronic acid ester, and the phenylboronic acid ester and the polymer nanoparticles are subjected to ultraviolet crosslinking to form a double-layer cross-linked structure, so that the stability is improved, and long-acting circulation of insulin in vivo is realized.

Description

technical field [0001] The present invention relates to polymer material science and medicament and its preparation method and application, in particular to a kind of glucose and H 2 O 2 Dual-responsive bilayer cross-linked polymer nano-drug delivery system and preparation method and application thereof. Background technique [0002] Exogenous insulin is the most direct drug for the treatment of diabetes. However, there are some problems with direct injection of insulin. If the injection dose is not enough, it will lead to poor blood sugar reduction and induce a series of complications; if the injection dose is too high, the blood sugar will be lowered too quickly, which can easily lead to hypoglycemia symptoms and cannot achieve the expected therapeutic effect. . Nanocarriers prepared by using the glucose response principle can complete an intelligent blood glucose regulation system, which to a certain extent can solve the disadvantages and limitations of traditional ins...

Claims

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Application Information

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IPC IPC(8): A61K9/51A61K38/28A61K38/44A61K47/59A61K47/34A61P3/10C08G64/18C08G64/30C08G64/42
CPCA61K9/5146A61K47/59A61K38/28A61P3/10A61K38/443C12Y101/03004C08G64/42C08G64/305C08G64/183A61K2300/00
Inventor 钱红亮冯婕杨静如陈维钟伊南黄德春
Owner CHINA PHARM UNIV
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