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WO2012034379A1 - Méthode de préparation d'un polymère de coordination organométallique sensible au ph - Google Patents

Méthode de préparation d'un polymère de coordination organométallique sensible au ph Download PDF

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Publication number
WO2012034379A1
WO2012034379A1 PCT/CN2011/071361 CN2011071361W WO2012034379A1 WO 2012034379 A1 WO2012034379 A1 WO 2012034379A1 CN 2011071361 W CN2011071361 W CN 2011071361W WO 2012034379 A1 WO2012034379 A1 WO 2012034379A1
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solution
organic coordination
coordination polymer
preparing
metal
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PCT/CN2011/071361
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Chinese (zh)
Inventor
车顺爱
邢磊
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Shanghai Jiao Tong University
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Shanghai Jiao Tong University
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Priority claimed from CN201010283898XA external-priority patent/CN101927006B/zh
Priority claimed from CN2010102839376A external-priority patent/CN101947324B/zh
Application filed by Shanghai Jiao Tong University filed Critical Shanghai Jiao Tong University
Publication of WO2012034379A1 publication Critical patent/WO2012034379A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • the invention relates to a method in the field of nano drug technology, in particular to a method for preparing a pH-responsive metal organic coordination polymer.
  • the pH-responsive drug delivery system is a class of intelligent drug release systems that provide controlled release of the drug based on its pH.
  • the extracellular environment of the human tumor (pH 5.7-7.8) is more acidic than normal blood or tissue (pH 7.4), and the pH of the cell endosomes and lysosomes are as low as 5.0 and 4.5, respectively. Therefore, pH-responsive drug delivery systems have broad application prospects in the fields of biomedicine, especially in the field of anti-tumor. Book
  • Metal organic framework complexes are useful materials for drug delivery.
  • the article reports the first use of metal backbone complexes in drug delivery systems. Mirkin, CA et al., "Nature” (Nature), No. 7068, pp. 651-654, published “Chemically tailorable colloidal particles from infinite coordination polymers” (chemically tailored infinitely coordinated polymers to colloidal particles) In the article, the paper first reported the preparation of metal-organic complexes into colloidal spherical particles.
  • the present invention provides a method for preparing a pH-responsive metal organic coordination polymer according to the above-mentioned deficiencies of the prior art, and the drug forms a nano-scale metal organic coordination polymer by using a biocompatible polymer or a drug and a metal ion. Controllable release of the drug based on subtle changes in pH.
  • the present invention is achieved by the following technical solutions.
  • the present invention obtains a pH-responsive metal organic by mixing and reacting a biocompatible polymer solution and/or a drug solution with a metal salt solution and a poor solvent in a stirred environment. Coordination polymer.
  • the biocompatible polymer solution refers to: an aqueous solution of polyethylene glycol, chitosan, and F127;
  • alcohol is of the formula R-OH, wherein, R is ⁇ ⁇ ⁇ 4 linear Or branched chain thiol;
  • the drug contained includes: an organic compound containing a hydroxyl group, a carbonyl group, a thiol group, an amino group, a nitro group, a carboxyl group, a thiol group, a sulfonic acid group or a phosphate group, preferably daunorubicin hydrochloride, CAS number: 23541-50-6), Doxorubicin hydrochloride, CAS No.: 2531640-9, Idarubicin hydrochloride, CAS No.: 57852-57-0, Epirubicin Hydrochloride
  • the metal salt solution refers to: a mixture of a copper nitrate solution, a cobalt nitrate solution or a zinc nitrate solution mixed with an aqueous sodium sulfate solution in a mixing ratio of 1.42:1 by volume, and a ferric nitrate solution.
  • the mixed reaction refers to: acting with a copper nitrate solution, a poor solvent, or acting with a ferric nitrate solution, a poor solvent, or a solution of copper nitrate, cobalt nitrate or zinc nitrate, a biocompatible polymer, Poor solvent and sodium nitrate water
  • the solution works.
  • the mixing reaction it is preferred to react with any of the copper nitrate solution, the cobalt nitrate solution or the zinc nitrate solution, and the biocompatible polymer, and then adjust the pH to neutral with a base, and then carry out the reaction with a poor solvent and a sodium sulfate aqueous solution. reaction.
  • the base is potassium hydroxide, sodium hydroxide, lithium hydroxide, aqueous ammonia, ethanolamine, diethanolamine, triethanolamine or dC 4 linear, branched chain fluorenyl short-chain amine.
  • the ratio of the loaded drug to the metal salt is 1:0.5 to 1:10; (only when the drug reacts with the metal salt) the metal salt and the biocompatible polymer in the drug and metal salt solution
  • the dosage ratio is 1: 0.5 ⁇ 10: 0.01 ⁇ 100.
  • the stirring environment refers to: magnetic stirring in an environment of 0 ° C to 50 ° C;
  • the poor solvent is an organic solvent for burning a hydrocarbon, an ether, an alcohol, an aldehyde or a ketone, preferably petroleum ether, diethyl ether, dichloromethane, trichloromethane, tetrahydrofuran, hydrazine, hydrazine dimethylformamide, ethyl acetate. Or acetone.
  • novel pH-responsive drug delivery system based on metal-organic coordination bond prepared by the invention can release the drug in a controlled manner according to the slight change of pH, especially in the weakly acidic diseased tissue and in the near-neutral normal tissue. Less release, has broad application prospects in the field of drug delivery.
  • Figure 1 is a SEM image of daunorubicin-copper nanoparticles prepared based on metal-organic coordination bonds prepared in Example 1.
  • Figure 2 is a stepwise release profile of daunorubicin at different pH for a pH-responsive drug delivery system based on metal-organic coordination bonds prepared in Example 1.
  • Figure 3 is an ultraviolet absorption spectrum of daunorubicin-copper nanoparticles and daunorubicin prepared by the metal-organic coordination bond prepared in Example 1.
  • Example 4 is an infrared spectrum of daunorubicin-copper nanoparticles and daunorubicin prepared by the metal-organic coordination bond prepared in Example 1.
  • Figure 5 is a SEM image of a polyethylene glycol-copper-mitoxantrone prepared based on a metal organic coordination bond prepared in Example 5.
  • Figure 6 is a stepwise release profile of a medicinal system based on a metal-organic coordination bond prepared in Example 5 for pH responsiveness at different pH.
  • Figure 7 is a graph showing the ultraviolet absorption spectrum of polyethylene glycol-copper-mitoxantrone nanoparticles and mitoxantrone prepared based on metal organic coordination bonds prepared in Example 5.
  • Figure 8 is an infrared spectrum of a polyethylene glycol-copper-mitoxantrone-based nanoparticle prepared by the metal-organic coordination bond prepared in Example 5 and mitoxantrone.
  • the pH responsiveness of the metal organic coordination polymer was evaluated as follows.
  • the obtained purple-red solid powder was dispersed in 50 mM phosphate buffer pH 7.4, stirred at room temperature, and the pH of the solution was adjusted to pH 6.0 with dilute hydrochloric acid. , pH 5.0, pH 4.0, timed sampling, centrifugation, supernatant was diluted with 1N HC1 and quantified by UV.
  • the results were as follows: only 3% was released in the pH 7.4 solution, 72% was released in the pH 6.0 solution, 79% was released in the pH 5.0 solution, and 84% was released in the pH 4.0 solution.
  • the pH response of metal-organic coordination polymers differs from previous pH-responsive release systems, which are pH-responsiveness based on coordination bonds. And its responsiveness is very sensitive. The physiological environment is almost not released at pH 7.4, and 72% has been released under pH 6.0.
  • the SEM image of the pH-responsive metal organic coordination polymer prepared in the present example shows that the obtained spherical particles have a particle diameter of 50 nm.
  • the pH-responsive metal-organic coordination polymer prepared in this example has a stepwise release curve of daunorubicin at different pHs, and it can be seen that: the obtained daunorubicin-copper coordination polymer Only 3.0% was released within 24 hours in physiological environment pH 7.4; when the pH of the solution was adjusted to 6.0, the release amount rapidly increased to 72%. This indicates that this coordination polymer has good pH sensitivity.
  • the ultraviolet absorption spectrum of the pH-responsive metal organic coordination polymer and daunorubicin prepared in the present example can be seen in the figure: the ultraviolet spectrum shows that when the copper ion acts with daunorubicin, it is soft. The maximum absorption of erythromycin redshifted from 500 nm to 550 nm, indicating that a coordination bond was formed between copper ions and daunorubicin.
  • the infrared spectrum of the pH-responsive metal-organic coordination polymer and daunorubicin prepared in the present example can be seen in the figure: the infrared spectrum shows that 1618 (3 ⁇ of the erythromycin oxime)
  • the oxy group also forms a coordinate bond with the copper ion.
  • the pH responsiveness of the metal organic coordination polymer was evaluated as follows, and the obtained purple-black solid powder was dispersed at 50 mM pH 7.4.
  • the phosphate buffer was stirred at room temperature, and the pH of the solution was adjusted to pH 6.0, pH 5.0, pH 4.0 with dilute hydrochloric acid, timed, and centrifuged.
  • the supernatant was diluted with 1 N HCl and quantified by UV.
  • the results were as follows: 15% in the pH 7.4 solution, 42% in the pH 6.0 solution, 49% in the pH 5.0 solution, and 57% in the pH 4.0 solution.
  • the pH response of metal-organic coordination polymers differs from previous pH-responsive release systems, which are pH-responsiveness based on coordination bonds. And its responsiveness is very sensitive. The physiological environment releases very little at pH 7.4, and it has been released 42% under pH6.0.
  • doxorubicin 0.22 mg was dissolved in 2 mL of ethanol to form a drug solution, and then 40 L of 0.02 mol/L copper nitrate in ethanol solution was added to the drug solution under stirring at room temperature; then 10 mL of ethyl acetate was added dropwise. After stirring for 15 hours, centrifugation, washing, and vacuum drying at room temperature, a purple-red solid powder material was obtained.
  • the pH responsiveness of the metal organic coordination polymer was evaluated as follows.
  • the obtained purple-red solid powder was dispersed in 50 mM phosphate buffer pH 7.4, stirred at room temperature, and the pH of the solution was adjusted to pH 6.0 with dilute hydrochloric acid.
  • pH 5.0, pH 4.0 timed sampling, centrifugation, supernatant was diluted with IN HC1 and quantified by UV.
  • the results were as follows: 1% in the pH 7.4 solution, 6% in the pH 6.0 solution, 23% in the pH 5.0 solution, and 48% in the pH 4.0 solution.
  • the pH response of metal-organic coordination polymers differs from previous pH-responsive release systems, which are pH-responsiveness based on coordination bonds. And its responsiveness is sensitive, the physiological environment is almost not released under pH 7.4, and 48% has been released under pH 4.0 conditions.
  • the pH responsiveness of the metal organic coordination polymer was evaluated as follows.
  • the obtained purple black solid powder was dispersed in 50 mM phosphate buffer pH 7.4, stirred at room temperature, and the pH of the solution was adjusted to pH 6.0 with dilute hydrochloric acid.
  • pH 5.0, pH 4.0 timed sampling, centrifugation, supernatant was diluted with 1N HC1 and quantified by UV.
  • the results were as follows: 13% in the pH 7.4 solution, 16% in the pH 6.0 solution, 24% in the pH 5.0 solution, and 40% in the pH 4.0 solution.
  • the pH response of metal-organic coordination polymers differs from previous pH-responsive release systems, which are pH-responsiveness based on coordination bonds. And its responsiveness is not released in the physiological environment at pH 7.4, and 40% has been released under pH 4.0 conditions.
  • the pH responsiveness of the metal organic coordination polymer was evaluated as follows, and the obtained blue-black solid powder was dispersed at 50 mM pH 7.4.
  • the phosphate buffer was stirred at room temperature, and the pH of the solution was adjusted to pH 6.0, pH 5.0, pH 4.0 with dilute hydrochloric acid, timed, and centrifuged.
  • the supernatant was diluted with 1 N HCl and quantified by UV. The results were as follows: only 4% was released in the pH 7.4 solution, 18% in the pH 6.0 solution, 46% in the pH 5.0 solution, and 98% in the pH 4.0 solution.
  • the pH response of metal-organic coordination polymers differs from previous pH-responsive release systems, which are pH-responsiveness based on coordination bonds. And its responsiveness is very sensitive, the physiological environment is almost not released at pH 7.4, and almost completely released under pH 4.0 conditions.
  • an SEM image of the pH-responsive metal organic coordination polymer prepared in the present example shows that the obtained spherical particles have a particle diameter of 30 to 50 nm.
  • the pH-responsive metal-organic coordination polymer prepared in the present example has a stepwise release curve of mitoxantrone at different pHs, and it can be seen that: the obtained polyethylene glycol-copper-mitoxantrone The ruthenium coordination polymer released only 4.0% within 24 hours of physiological environment pH 7.4; when the pH of the solution was adjusted to 4.0, it was almost completely released. This indicates that this coordination polymer has good pH sensitivity.
  • the ultraviolet absorption spectrum of the pH-responsive metal-organic coordination polymer and mitoxantrone prepared in the present example can be seen in the figure: the ultraviolet spectrum shows that when the copper ion and the mitoxantrone act, the meter The maximum absorption of the sputum was red-shifted from 620 nm to 670 nm, and the two absorption peaks merged into a broad peak, indicating that a coordination bond was formed between the copper ion and the mitoxantrone.
  • C-0- of the polyethylene glycol C stretching vibration has at least three absorption peaks 1148, 1113, and 1061 cm 1 , and the peak intensity weakens after coordination, and shifts to 1100 and 1039 01 ⁇ .
  • the pH responsiveness of the metal organic coordination polymer was evaluated as follows.
  • the obtained blue-black solid powder was dispersed in 50 mM phosphate buffer pH 7.4, stirred at room temperature, and the pH of the solution was adjusted to pH 6.0 with dilute hydrochloric acid. , pH 5.0, pH 4.0, timed sampling, centrifugation, supernatant was diluted with 1N HC1 and quantified by UV.
  • the results were as follows: only 11% was released in the pH 7.4 solution, 17% was released in the pH 6.0 solution, 23% was released in the pH 5.0 solution, and 31% was released in the pH 4.0 solution.
  • Ethanol solution Add 50 ⁇ , 0.2 mol/L cobalt nitrate in ethanol, add 300 0.1 mol/L sodium hydroxide solution to adjust the pH of the solution to 7, then add 10 mL of acetone, stir for 10 minutes, then add ⁇ , 1% The aqueous sodium sulfate solution was stirred for further 30 minutes, centrifuged, washed, and lyophilized to obtain a purple-red solid powder material.
  • the pH responsiveness of the metal organic coordination polymer was evaluated as follows.
  • the obtained purple-red solid powder was dispersed in 50 mM phosphate buffer pH 7.4, stirred at room temperature, and the pH of the solution was adjusted to pH 6.0 with dilute hydrochloric acid.
  • pH 5.0, pH 4.0 timed sampling, centrifugation, supernatant was diluted with 1N HC1 and quantified by UV.
  • the results were as follows: only 3% was released in the pH 7.4 solution, 3.5% in the pH 6.0 solution, 51% in the pH 5.0 solution, and 65% in the pH 4.0 solution.
  • the pH response of metal-organic coordination polymers differs from previous pH-responsive release systems, which are pH-responsiveness based on coordination bonds. And its responsiveness is very sensitive, the physiological environment is almost not released under pH 7.4, and 65% is released under pH 4.0 conditions.
  • Ethanol solution Add 50 ⁇ , 0.2 mol/L zinc nitrate in ethanol, add 500 ⁇ , 0.1 mol/L sodium hydroxide solution to adjust the pH of the solution to 7, then add 10 mL of acetone, stir for 10 minutes, then add ⁇ , A 1% aqueous solution of sodium sulfate was stirred for further 30 minutes, centrifuged, washed, and lyophilized to obtain a purple-red solid powder material.
  • the pH responsiveness of the metal organic coordination polymer was evaluated as follows.
  • the obtained purple-red solid powder was dispersed in 50 mM phosphate buffer pH 7.4, stirred at room temperature, and the pH of the solution was adjusted to pH 6.0 with dilute hydrochloric acid.
  • pH 5.0, pH 4.0, timed sampling, centrifugation, supernatant was diluted with 1N HC1 and quantified by UV.
  • the results were as follows: only 3.5% was released in the pH 7.4 solution, 11% was released in the pH 6.0 solution, 37% was released in the pH 5.0 solution, and 98% was released in the pH 4.0 solution.
  • the pH response of metal-organic coordination polymers differs from previous pH-responsive release systems, which are pH-responsiveness based on coordination bonds. And its responsiveness is very sensitive, the physiological environment is almost not released at pH 7.4, and almost completely released under pH 4.0 conditions.
  • Ethanol solution Add 50 ⁇ , 0.2 mol/L copper nitrate in ethanol, add 350 ⁇ , 0.1 mol/L sodium hydroxide solution to adjust the pH of the solution to 7, then add 6 mL of acetone, stir for 10 minutes, then add ⁇ , 1% aqueous sodium sulfate, stirring for another 30 minutes, centrifuging, washing, lyophilization Thereafter, a blue solid powder material was obtained.
  • the pH response of the metal organic coordination polymer was evaluated as follows.
  • the obtained blue solid powder was dispersed in 50 mM phosphate buffer pH 7.4, stirred at room temperature, and the pH of the solution was adjusted to pH 6.0 with dilute hydrochloric acid.
  • pH 5.0, pH 4.0 timed sampling, centrifugation, supernatant was diluted with 1N HC1 and quantified by UV.
  • the results were as follows: only 4% was released in the pH 7.4 solution, 12% in the pH 6.0 solution, 25% in the pH 5.0 solution, and 76% in the pH 4.0 solution.
  • the pH response of metal-organic coordination polymers differs from previous pH-responsive release systems, which are pH-responsiveness based on coordination bonds. And its responsiveness is very sensitive, the physiological environment is almost not released at pH 7.4, and 76% is released under pH 4.0 conditions.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une méthode de préparation d'un polymère de coordination organométallique sensible au pH, impliquant le mélange d'une solution de polymère biocompatible et/ou une solution médicamenteuse avec une solution de sel métallique et un mauvais solvant avec agitation, centrifugation, lavage et séchage, pour obtenir le polymère de coordination. Le polymère de coordination à l'échelle nanométrique préparé par cette méthode peut libérer de façon contrôlée le médicament en fonction de petits changements du pH.
PCT/CN2011/071361 2010-09-17 2011-02-28 Méthode de préparation d'un polymère de coordination organométallique sensible au ph Ceased WO2012034379A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201010283898XA CN101927006B (zh) 2010-09-17 2010-09-17 基于药物的pH响应金属有机配位聚合物的制备方法
CN201010283898.X 2010-09-17
CN201010283937.6 2010-09-17
CN2010102839376A CN101947324B (zh) 2010-09-17 2010-09-17 基于高分子的pH响应金属有机配位聚合物的制备方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112870355A (zh) * 2021-01-28 2021-06-01 中山大学 一种复合纳米多孔的铂基配位聚合物及其制备方法和应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1673258A (zh) * 2005-02-25 2005-09-28 复旦大学 一种金属配位聚合物纳米结构材料的制备方法
WO2009117410A2 (fr) * 2008-03-17 2009-09-24 Board Of Regents, The University Of Texas System Formation de particules nanostructurées de médicaments médiocrement solubles dans l'eau et récupération par des techniques mécaniques
CN101721707A (zh) * 2009-11-30 2010-06-09 上海交通大学 基于配位键制备pH响应的药物释放载体的制备方法
CN101927006A (zh) * 2010-09-17 2010-12-29 上海交通大学 基于药物的pH响应金属有机配位聚合物的制备方法
CN101947324A (zh) * 2010-09-17 2011-01-19 上海交通大学 基于高分子的pH响应金属有机配位聚合物的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1673258A (zh) * 2005-02-25 2005-09-28 复旦大学 一种金属配位聚合物纳米结构材料的制备方法
WO2009117410A2 (fr) * 2008-03-17 2009-09-24 Board Of Regents, The University Of Texas System Formation de particules nanostructurées de médicaments médiocrement solubles dans l'eau et récupération par des techniques mécaniques
CN101721707A (zh) * 2009-11-30 2010-06-09 上海交通大学 基于配位键制备pH响应的药物释放载体的制备方法
CN101927006A (zh) * 2010-09-17 2010-12-29 上海交通大学 基于药物的pH响应金属有机配位聚合物的制备方法
CN101947324A (zh) * 2010-09-17 2011-01-19 上海交通大学 基于高分子的pH响应金属有机配位聚合物的制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112870355A (zh) * 2021-01-28 2021-06-01 中山大学 一种复合纳米多孔的铂基配位聚合物及其制备方法和应用
CN112870355B (zh) * 2021-01-28 2022-04-01 中山大学 一种复合纳米多孔的铂基配位聚合物及其制备方法和应用

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