[go: up one dir, main page]

WO2012034379A1 - Ph响应金属有机配位聚合物的制备方法 - Google Patents

Ph响应金属有机配位聚合物的制备方法 Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
solution
organic coordination
coordination polymer
preparing
metal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2011/071361
Other languages
English (en)
French (fr)
Inventor
车顺爱
邢磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Jiao Tong University
Original Assignee
Shanghai Jiao Tong University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • 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)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

pH响应金属有机配位聚合物的制备方法 技术领域
本发明涉及的是一种纳米药物技术领域的方法， 具体是一种 pH响应金属有机配位聚合物 的制备方法。
背景技术
pH响应的药物释放系统是一类智能说药物释放系统，它能根据所处环境的酸碱度对药物进行 可控性的释放。人体的肿瘤胞外环境 (pH 5.7-7.8) 比正常血液或组织（pH约 7.4)显酸性， 而 且细胞内涵体和溶酶体的 pH更分别低至 5.0和 4.5。因此， pH响应的药物释放系统在生物医药 等领域尤其是抗肿瘤领域具有广泛的应用前景。 书
经对现有技术的文献检索发现， Yatvin, M. B.等人在《Science》（科学） 1980年第 210期 1253-1255页上发表了《pH-Sensitive liposomes: possible clinical implications》（pH-敏感性脂质体： 可能的临床含义）一文， 文中提出了一种通过在脂质体中掺杂 pH敏感性的磷脂分子实现药物 的 pH响应性释放的方法，通过 pH敏感性的磷脂分子的水解作用破坏脂质体的稳定性从而达到 药物释放的目的。 Hudson, S. M.等人在《Progress in Polymer Science》（聚合物科学进展） 2004 年第 29期 1173-1222页上发表了《Stimuli-responsive polymers and their bioconjugates》（剌激响 应性聚合物及其生物轭合物）一文， 文中综述了基于聚合物的 pH响应体系的实现方法， 通过 不同 pH下静电作用引起的"溶胀-收缩"效应和聚合物的降解等实现药物对 pH的响应性释放。 F6rey, G.等人在《Angewandte Chemie International Edition》（德国应用化学（英文版））2006年 第 45期 5974-5978页上发表了《Metal-Organic Frameworks as Efficient Materials for Drug Delivery》
(金属有机骨架配合物用于药物投递的有效材料）一文， 文中报道了首次将金属骨架配合物用 于药物投递系统。 Mirkin, C. A.等人在《Nature》（自然 )2005年第 7068期 651-654页上发表了 《 Chemically tailorable colloidal particles from infinite coordination polymers》 (将无限配位聚合物 用化学方法裁制成胶态颗粒） 一文， 文中报道了首次将金属有机配合物制备成胶态球状颗粒。 Lin, W. B.等人在《 Journal of the American Chemical Society》（美国化学会杂志) 2008年第 35期 11584-11585页上发表了《Nanoscale Coordination Polymers for Platinum-Based Anticancer Drug Delivery》（用于铂类抗癌药物投递的纳米尺度的配位聚合物）一文， 文中报道了将铂类抗肿瘤 药物包含于纳米配位聚合物中，外层再用氧化硅壳保护来实现铂类抗肿瘤药物的可控释放。 osi, N. L.等人在《 Journal of the American Chemical Society》（美国化学会杂志) 2009年第 35 期 8376-8377 页上发表了 《 Cation-Triggered Drug Release from a Porous Zinc-Adeninate Metal-Organic Framework》（阳离子触发药物释放的多孔锌-腺嘌呤金属有机骨架配合物）一文， 文中报道了一种生物型金属有机骨架配合物具有阳离子触发释放药物的性质。
但是， 药物在近中性的正常组织 "零释放"、 在弱酸性病变组织大量释放的 pH敏感性药物 释放系统仍是科学界的一个难题。 pH响应的药物释放系统仍需继续探索合适的策略和方法。
发明内容
本发明针对现有技术存在的上述不足，提供一种 pH响应金属有机配位聚合物的制备方法， 药物借助生物相容性高分子或搭载药物与金属离子形成纳米级金属有机配位聚合物，能根据 pH 的细微变化对药物进行可控的释放。
本发明是通过以下技术方案实现的，本发明通过将生物相容性高分子溶液和 /或药物溶液在 搅拌环境下与金属盐溶液和不良溶剂混合反应， 经过离心洗涤干燥后得到 pH响应金属有机配 位聚合物。
所述的生物相容性高分子溶液是指： 聚乙二醇、 壳聚糖、 F127的水溶液；
所述的药物溶液是指： 浓度为 2.0xlO_5〜2.0xlO_2 mol/L的溶解于醇的搭载药物， 其中： 醇 的化学式为 R-OH，其中， R为 <^〜< 4的直链或分支链垸基；搭载药物包括：含有羟基、羰基、 巯基、氨基、硝基、羧基、胍基、磺酸基或磷酸基的有机化合物、优选盐酸柔红霉素（daunorubicin hydrochloride、 CAS号： 23541-50-6)、 盐酸阿霉素 （Doxorubicin hydrochloride、 CAS号： 2531640-9)、 盐酸伊达比星 (Idarubicin hydrochloride、 CAS号： 57852-57-0)、 盐酸表阿霉素
( Epirubicin hydrochloride、 CAS号： 56390-09-1 )、盐酸阿柔比星（ Aclarubicin hydrochloride、 CAS号： 75443-99-1 )、盐酸佐柔比星 (Daunorubicin hydrochloride、 CAS号： 23541-50-6)、 吡 柔比星（Pirarubicin、 CAS号： 72496414)、 依索比星（Esorubicin、 CAS号： 63521-85-7)、 卡柔比星（Carubicin、 CAS号： 64241-34-5)、奈莫柔比星（Nemorubicin、 CAS号： 108852-90-0)、 戊柔比星（Valrubicin、 CAS号： 56124-62-0)、地托比星（Detorubicin、 CAS号： 66211-92-5)、 罗多比星（Rodorubicin、 CAS号： 96497-67-5)、美多比星（Medorubicin、 CAS号： 64314-52-9)、 达佐霉素（Duazomycin、 CAS号： 140347-0)、 丝裂霉素（Mitomycin C、 CAS号： 50-07-7)、 博莱霉素（Bleomycin, CAS号： 11056-06-7)、平阳霉素（Bleomycin A5、 CAS号： 5565847-4)、 米托蒽醌（Mitoxantrone、 CAS号： 65271-80-9)、茜素红（ Alizarin Red S、 CAS号： 130-22-3)、 邻菲啰啉（l,10-Phenanthroline、 CAS号： 66-71-7)。
所述的金属盐溶液是指： 硝酸铜溶液、 硝酸钴溶液或硝酸锌溶液中的一种与硫酸钠水溶液 的混合， 其混合比例为体积比 1.42:1， 以及硝酸铁溶液。
所述的混合反应是指： 与硝酸铜溶液、 不良溶剂进行作用或与硝酸铁溶液、 不良溶剂进行 作用或与硝酸铜、 硝酸钴或硝酸锌溶液中的一种、 生物相容性高分子、 不良溶剂以及硝酸钠水 溶液进行作用。
所述的混合反应中优选与硝酸铜溶液、 硝酸钴溶液或硝酸锌溶液中任一种、 生物相容性高 分子反应后， 采用碱调节 pH至中性， 再与不良溶剂以及硫酸钠水溶液进行反应。
所述的碱为氢氧化钾、氢氧化钠、氢氧化锂、氨水、 乙醇胺、二乙醇胺、三乙醇胺或 d-C4 直链， 分支链垸基的短链胺。
所述的搭载药物与金属盐的用量比例为 1 ： 0.5〜1： 10； (仅药物与金属盐反应时） 所述的搭载药物与金属盐溶液中的金属盐以及生物相容性高分子的用量比为 1 ： 0.5〜10： 0.01〜100。 （生物相容性高分子参与反应时）
所述的搅拌环境是指： 在 0°C〜50°C的环境下磁力搅拌；
所述的不良溶剂为烧烃、 醚、 醇、 醛、 酮的有机溶剂， 优选石油醚、 乙醚、 二氯甲垸、 三 氯甲垸、 四氢呋喃、 Ν,Ν二甲基甲酰胺、 乙酸乙酯或丙酮。
本发明制备的基于金属有机配位键的新颖 pH响应的药物释放系统能根据 pH的细微变化对 药物进行可控的释放， 尤其能在弱酸性病变组织中释放而在近中性正常组织中极少释放， 在药 物投递领域具有广阔的应用前景。
附图说明
图 1是实施例 1制备的基于金属有机配位键制备的柔红霉素-铜的纳米颗粒的 SEM图。 图 2是实施例 1制备的基于金属有机配位键制备 pH响应的药物释放系统对柔红霉素在不 同 pH下的台阶式释放曲线。
图 3是实施例 1制备的基于金属有机配位键制备的柔红霉素-铜的纳米颗粒和柔红霉素的 紫外吸收光谱
图 4是实施例 1制备的基于金属有机配位键制备的柔红霉素-铜的纳米颗粒和柔红霉素的 红外光谱
图 5是实施例 5制备的基于金属有机配位键制备的聚乙二醇-铜-米托蒽醌的纳米颗粒的 SEM图。
图 6是实施例 5制备的基于金属有机配位键制备 pH响应的药物释放系统对米托蒽醌在不 同 pH下的台阶式释放曲线。
图 7是实施例 5制备的基于金属有机配位键制备的聚乙二醇-铜 -米托蒽醌的纳米颗粒和米 托蒽醌的紫外吸收光谱。
图 8是实施例 5制备的基于金属有机配位键制备的聚乙二醇-铜 -米托蒽醌的纳米颗粒和米 托蒽醌的红外光谱。
具体实施方式 下面对本发明的实施例作详细说明， 本实施例在以本发明技术方案为前提下进行实施， 给 出了详细的实施方式和具体的操作过程， 但本发明的保护范围不限于下述的实施例。
实施例 1
将 1.05 mg柔红霉素溶解于 lmL乙醇中形成药物溶液，然后在室温搅拌下， 向药物的溶液 中加入 20 L 0.2 mol/L的硝酸铜的乙醇溶液； 然后滴加 6 mL乙酸乙酯， 搅拌 30分钟， 离心， 洗涤， 室温真空干燥后， 得到紫红色固体粉末材料。
如下评估金属有机配位聚合物的 pH响应性，将得到的紫红色固体粉末分散于 50 mM pH7.4 的磷酸缓冲液中， 在室温下搅拌， 溶液的 pH值用稀盐酸调节至 pH6.0， pH5.0， pH4.0， 定时取 样， 离心， 上清液用 1N HC1稀释后紫外定量测定。结果如下： pH7.4溶液中只释放 3%， pH6.0 溶液中释放 72%, pH5.0溶液中释放 79%, pH4.0溶液中释放 84%。
金属有机配位聚合物的 pH响应性不同以往的 pH响应性释放系统， 它是一种基于配位键 的 pH响应性。 并且其响应性非常敏感， 生理环境 pH7.4下几乎不释放， pH6.0条件下已释放 72%。
如图 1所示， 为本实施例制备的 pH响应金属有机配位聚合物的 SEM图， 图中可见：所得 到的球形颗粒， 粒径在 50nm。
如图 2所示， 为本实施例制备的 pH响应金属有机配位聚合物对柔红霉素在不同 pH下的 台阶式释放曲线， 图中可见： 所得柔红霉素 -铜配位聚合物在生理环境 pH7.4中 24小时内仅释 放 3.0%; 当溶液 pH调节至 6.0时，释放量迅速增至 72%。这说明此配位聚合物具有良好的 pH 敏感性。
如图 3所示，为本实施例制备的 pH响应金属有机配位聚合物和柔红霉素的紫外吸收光谱， 图中可见：紫外图谱显示，当铜离子与柔红霉素作用后，柔红霉素最大吸收发生红移，由 500nm 移至 550nm， 这说明铜离子与柔红霉素之间形成了配位键。
如图 4所示， 为本实施例制备的 pH响应金属有机配位聚合物和柔红霉素的红外光谱， 图 中可见：红外图谱显示， 1618(3^处的柔红霉素的蒽醌羰基（C=0)伸缩振动位移至 1551«^， 这表明蒽醌羰基与铜离子形成配位键， 12860^处的蒽醌苯酚氧 (C-0)伸缩振动位移至 ΒΠαηΛ 这表明蒽醌苯酚氧基也与铜离子形成配位键。
实施例 2
将 1.05 mg柔红霉素溶解于 lmL乙醇中形成药物溶液，然后在室温搅拌下， 向药物的溶液 中加入 30 L 0.2 mol/L的硝酸铁的乙醇溶液； 然后滴加 6 mL乙酸乙酯， 搅拌 30分钟， 离心， 洗涤， 室温真空干燥后， 得到紫黑固体粉末材料。
如下评估金属有机配位聚合物的 pH响应性， 将得到的紫黑固体粉末分散于 50 mM pH7.4 的磷酸缓冲液中， 在室温下搅拌， 溶液的 pH值用稀盐酸调节至 pH6.0， pH5.0， pH4.0， 定时取 样， 离心， 上清液用 1N HC1稀释后紫外定量测定。 结果如下： pH7.4溶液中释放 15%， pH6.0 溶液中释放 42%, pH5.0溶液中释放 49%, pH4.0溶液中释放 57%。
金属有机配位聚合物的 pH响应性不同以往的 pH响应性释放系统， 它是一种基于配位键 的 pH响应性。并且其响应性非常敏感，生理环境 pH7.4下释放很少， pH6.0条件下已释放 42%。
实施例 3
将 0.22 mg阿霉素溶解于 2 mL乙醇中形成药物溶液， 然后在室温搅拌下， 向药物的溶液 中加入 40 L 0.02 mol/L的硝酸铜的乙醇溶液；然后滴加 10 mL乙酸乙酯，搅拌 15小时，离心， 洗涤， 室温真空干燥后， 得到紫红色固体粉末材料。
如下评估金属有机配位聚合物的 pH响应性，将得到的紫红色固体粉末分散于 50 mM pH7.4 的磷酸缓冲液中， 在室温下搅拌， 溶液的 pH值用稀盐酸调节至 pH6.0， pH5.0， pH4.0， 定时取 样， 离心， 上清液用 IN HC1稀释后紫外定量测定。 结果如下： pH7.4溶液中释放 1%， pH6.0 溶液中释放 6%, pH5.0溶液中释放 23%, pH4.0溶液中释放 48%。
金属有机配位聚合物的 pH响应性不同以往的 pH响应性释放系统， 它是一种基于配位键 的 pH响应性。并且其响应性敏感，生理环境 pH7.4下几乎不释放， pH4.0条件下已释放 48%。
实施例 4
将 0.22 mg阿霉素溶解于 lmL乙醇中形成药物溶液，然后在室温搅拌下， 向药物的溶液中 加入 60 L 0.02 mol/L的硝酸铁的乙醇溶液； 然后滴加 10 mL乙酸乙酯， 搅拌 15小时， 离心， 洗涤， 室温真空干燥后， 得到紫黑固体粉末材料。
如下评估金属有机配位聚合物的 pH响应性， 将得到的紫黑固体粉末分散于 50 mM pH7.4 的磷酸缓冲液中， 在室温下搅拌， 溶液的 pH值用稀盐酸调节至 pH6.0， pH5.0， pH4.0， 定时取 样， 离心， 上清液用 1N HC1稀释后紫外定量测定。 结果如下： pH7.4溶液中释放 13%， pH6.0 溶液中释放 16%, pH5.0溶液中释放 24%, pH4.0溶液中释放 40%。
金属有机配位聚合物的 pH响应性不同以往的 pH响应性释放系统，它是一种基于配位键的 pH响应性。 并且其响应性敏感， 生理环境 pH7.4下释放不多， pH4.0条件下已释放 40%。
实施例 5
将 0.20 mg米托蒽醌溶解于 lmL乙醇中形成药物的溶液，然后在室温搅拌下， 向药物的溶 液中加入 10 L 0.2 mol/L的硝酸铜的乙醇溶液和 100 L 20 g/L的聚乙二醇 4000的乙醇溶液； 加入 25 L 0.1 mol/L氢氧化钠溶液， 然后滴加 3 mL乙酸乙酯， 搅拌 30分钟， 离心， 洗漆， 室 温真空干燥后， 得到蓝黑色固体粉末材料。
如下评估金属有机配位聚合物的 pH响应性，将得到的蓝黑色固体粉末分散于 50 mM pH7.4 的磷酸缓冲液中， 在室温下搅拌， 溶液的 pH值用稀盐酸调节至 pH6.0， pH5.0， pH4.0， 定时取 样， 离心， 上清液用 1N HC1稀释后紫外定量测定。结果如下： pH7.4溶液中只释放 4%， pH6.0 溶液中释放 18%, pH5.0溶液中释放 46%, pH4.0溶液中释放 98%。
金属有机配位聚合物的 pH响应性不同以往的 pH响应性释放系统， 它是一种基于配位键 的 pH响应性。并且其响应性非常敏感， 生理环境 pH7.4下几乎不释放， pH4.0条件下几乎完全 释放。
如图 5所示， 为本实施例制备的 pH响应金属有机配位聚合物的 SEM图， 图中可见：所得 到的球形颗粒， 粒径在 30〜50nm。
如图 6所示， 为本实施例制备的 pH响应金属有机配位聚合物对米托蒽醌在不同 pH下的 台阶式释放曲线， 图中可见： 所得聚乙二醇-铜 -米托蒽醌配位聚合物在生理环境 pH7.4中 24小 时内仅释放 4.0%; 当溶液 pH调节至 4.0时， 几乎完全释放。 这说明此配位聚合物具有良好的 pH敏感性。
如图 7所示，为本实施例制备的 pH响应金属有机配位聚合物和米托蒽醌的紫外吸收光谱， 图中可见：紫外图谱显示，当铜离子与米托蒽醌作用后，米托蒽醌最大吸收发生红移，由 620nm 移至 670nm， 并且两个吸收峰融合成一个宽峰， 这说明铜离子与米托蒽醌之间形成了配位键。
如图 8所示， 为本实施例制备的 pH响应金属有机配位聚合物和米托蒽醌的红外光谱， 图 中可见：红外图谱显示， WlOcnT1处的米托蒽醌的蒽醌羰基（C=0)伸缩振动位移至 1575«^， 这表明蒽醌羰基与铜离子形成配位键， 1220(3^处的蒽醌苯酚氧（C-0) 峰强变弱， 这表明蒽 醌苯酚氧基也与铜离子形成配位键。 3315(3^处的米托蒽醌的 NH伸缩振动消失， 这说明米托 蒽醌上的 NH也参与配位。聚乙二醇的 C-0-C伸缩振动至少有三个吸收峰 1148, 1113,和 1061 cm 1, 配位后峰强变弱， 并且位移至 1100和 1039 01^。
实施例 6
将 0.20 mg米托蒽醌溶解于 lmL乙醇中形成药物的溶液，然后在室温搅拌下， 向药物的溶 液中加入 18 L 0.2 mol/L的硝酸铁的乙醇溶液和 200 L 20 g/L的聚乙二醇 4000的乙醇溶液； 然后滴加 3 mL乙酸乙酯， 搅拌 30分钟， 离心， 洗漆， 室温真空干燥后， 得到蓝黑色固体粉末 材料。
如下评估金属有机配位聚合物的 pH响应性，将得到的蓝黑色固体粉末分散于 50 mM pH7.4 的磷酸缓冲液中， 在室温下搅拌， 溶液的 pH值用稀盐酸调节至 pH6.0， pH5.0， pH4.0， 定时取 样，离心，上清液用 1N HC1稀释后紫外定量测定。结果如下： pH7.4溶液中只释放 11%， pH6.0 溶液中释放 17%, pH5.0溶液中释放 23%, pH4.0溶液中释放 31%。
金属有机配位聚合物的 pH响应性不同以往的 pH响应性释放系统， 它是一种基于配位键 的 pH响应性。并且其响应性非常敏感，生理环境 pH7.4下释放很少， pH4.0条件下释放 31%。 实施例 7
将 10 mg壳寡糖（3000)和 100 mg F127溶解于 5mL去离子水中形成高分子的溶液，然后 在室温搅拌下， 向上述溶液中加入 lmL 2.0X 10"3 mol/L的茜素红的乙醇溶液； 加入 50 μΐ, 0.2 mol/L硝酸鈷的乙醇溶液， 加入 300 0.1 mol/L氢氧化钠溶液调节溶液 pH为 7， 然后滴加 10 mL丙酮， 搅拌 10分钟后加入 ΙΟΟμΙ^, 1%硫酸钠水溶液， 再搅拌 30分钟， 离心， 洗漆， 冷冻 干燥后， 得到紫红色固体粉末材料。
如下评估金属有机配位聚合物的 pH响应性，将得到的紫红色固体粉末分散于 50 mM pH7.4 的磷酸缓冲液中， 在室温下搅拌， 溶液的 pH值用稀盐酸调节至 pH6.0， pH5.0， pH4.0， 定时取 样， 离心， 上清液用 1N HC1稀释后紫外定量测定。结果如下： pH7.4溶液中只释放 3%， pH6.0 溶液中释放 3.5%, pH5.0溶液中释放 51%, pH4.0溶液中释放 65%。
金属有机配位聚合物的 pH响应性不同以往的 pH响应性释放系统， 它是一种基于配位键 的 pH响应性。并且其响应性非常敏感，生理环境 pH7.4下几乎不释放， pH4.0条件下释放 65%。
实施例 8
将 10 mg壳寡糖（3000)和 100 mg F127溶解于 5mL去离子水中形成高分子的溶液，然后 在室温搅拌下， 向上述溶液中加入 lmL 2.0X 10"3 mol/L的茜素红的乙醇溶液； 加入 50 μΐ, 0.2 mol/L硝酸锌的乙醇溶液， 加入 500 μΐ, 0.1 mol/L氢氧化钠溶液调节溶液 pH为 7， 然后滴加 10 mL丙酮， 搅拌 10分钟后加入 ΙΟΟμΙ^, 1%硫酸钠水溶液， 再搅拌 30分钟， 离心， 洗漆， 冷冻 干燥后， 得到紫红色固体粉末材料。
如下评估金属有机配位聚合物的 pH响应性，将得到的紫红色固体粉末分散于 50 mM pH7.4 的磷酸缓冲液中， 在室温下搅拌， 溶液的 pH值用稀盐酸调节至 pH6.0， pH5.0， pH4.0， 定时取 样，离心，上清液用 1N HC1稀释后紫外定量测定。结果如下： pH7.4溶液中只释放 3.5%， pH6.0 溶液中释放 11%, pH5.0溶液中释放 37%, pH4.0溶液中释放 98%。
金属有机配位聚合物的 pH响应性不同以往的 pH响应性释放系统， 它是一种基于配位键 的 pH响应性。并且其响应性非常敏感， 生理环境 pH7.4下几乎不释放， pH4.0条件下几乎完全 释放。
实施例 9
将 10 mg壳寡糖（3000)和 100 mg F127溶解于 5mL去离子水中形成高分子的溶液，然后 在室温搅拌下， 向上述溶液中加入 lmL 2.0X 10"3 mol/L的邻菲啰啉的乙醇溶液； 加入 50 μΐ, 0.2 mol/L硝酸铜的乙醇溶液，加入 350 μΐ, 0.1 mol/L氢氧化钠溶液调节溶液 pH为 7，然后滴加 6 mL 丙酮， 搅拌 10分钟后加入 ΙΟΟμΙ^, 1%硫酸钠水溶液， 再搅拌 30分钟， 离心， 洗漆， 冷冻干燥 后， 得到蓝色固体粉末材料。
如下评估金属有机配位聚合物的 pH响应性， 将得到的蓝色固体粉末分散于 50 mM pH7.4 的磷酸缓冲液中， 在室温下搅拌， 溶液的 pH值用稀盐酸调节至 pH6.0， pH5.0， pH4.0， 定时取 样， 离心， 上清液用 1N HC1稀释后紫外定量测定。结果如下： pH7.4溶液中只释放 4%， pH6.0 溶液中释放 12%, pH5.0溶液中释放 25%, pH4.0溶液中释放 76%。
金属有机配位聚合物的 pH响应性不同以往的 pH响应性释放系统，它是一种基于配位键的 pH响应性。 并且其响应性非常敏感， 生理环境 pH7.4下几乎不释放， pH4.0条件下释放 76%。

Claims

权 利 要 求 书
1、 一种 pH响应金属有机配位聚合物的制备方法， 其特征在于， 通过将生物相容性高分子 溶液和 /或药物溶液在搅拌环境下与金属盐溶液和不良溶剂混合反应，经过离心洗涤干燥后得到 pH响应金属有机配位聚合物。
2、 根据权利要求 1所述的 pH响应金属有机配位聚合物的制备方法， 其特征是， 所述的生 物相容性高分子溶液是指： 聚乙二醇、 壳寡糖、 F127的水溶液。
3、 根据权利要求 1所述的 pH响应金属有机配位聚合物的制备方法， 其特征是， 所述的生 物相容性高分子溶液的浓度为： 2-20 g L。
4、 根据权利要求 1所述的 pH响应金属有机配位聚合物的制备方法， 其特征是， 所述的药 物溶液是指： 浓度为 2.0xl0_5〜2.0xl0_2 mol/L的溶解于醇的搭载药物。
5、 根据权利要求 4所述的 pH响应金属有机配位聚合物的制备方法， 其特征是， 醇的化学 式为 R-OH， 其中， R为 <^〜< 4的直链或分支链垸基。
6、 根据权利要求 4所述的 pH响应金属有机配位聚合物的制备方法， 其特征是， 所述的搭 载药物包括： 含有羟基、 羰基、 巯基、 氨基、 硝基、 羧基、 胍基、 磺酸基或磷酸基的有机化合 物。
7、 根据权利要求 4或 6所述的 pH响应金属有机配位聚合物的制备方法， 其特征是， 所述 的搭载药物为盐酸柔红霉素、 盐酸阿霉素、 盐酸伊达比星、 盐酸表阿霉素、 盐酸阿柔比星、 盐 酸佐柔比星、吡柔比星、依索比星、卡柔比星、奈莫柔比星、戊柔比星、地托比星、罗多比星、 美多比星、 达佐霉素、 丝裂霉素、 博莱霉素、 平阳霉素、 米托蒽醌、 茜素红或邻菲啰啉或其组 合。
8、 根据权利要求 1所述的 pH响应金属有机配位聚合物的制备方法， 其特征是， 所述的金 属盐溶液是指： 硝酸铜溶液、 硝酸钴溶液或硝酸锌溶液中的一种与硫酸钠水溶液的混合， 其混 合比例为体积比 1.42:1。
1
9、 根据权利要求 1所述的 pH响应金属有机配位聚合物的制备方法， 其特征是， 所述的混 合反应是指：与硝酸铜溶液、不良溶剂进行作用或与硝酸铁溶液不良溶剂进行作用或与硝酸铜、 硝酸钴或硝酸锌溶液中的一种、 生物相容性高分子、 不良溶剂以及硝酸钠水溶液进行作用。
10、 根据权利要求 9所述的 pH响应金属有机配位聚合物的制备方法， 其特征是， 所述的 混合反应中： 与硝酸铜溶液、 硝酸钴溶液或硝酸锌溶液中任一种、 生物相容性高分子进行反应 后， 采用碱调节 pH至中性， 再与不良溶剂以及硫酸钠水溶液进行反应。
11、根据权利要求 10所述的 pH响应金属有机配位聚合物的制备方法， 其特征是， 所述的 碱为氢氧化钾、 氢氧化钠、 氢氧化锂、 氨水、 乙醇胺、 二乙醇胺、 三乙醇胺或 d-c4直链， 分 支链垸基的短链胺。
2
Figure imgf000013_0001
图 4
替换页 （细则第 26条)
Figure imgf000014_0001
Figure imgf000014_0002
波长 (nm) 波数（ατΓ1) 图 7 图 8
替换页 （细则第 26条)
PCT/CN2011/071361 2010-09-17 2011-02-28 Ph响应金属有机配位聚合物的制备方法 Ceased WO2012034379A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201010283937.6 2010-09-17
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
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
CN201010283898.X 2010-09-17

Publications (1)

Publication Number Publication Date
WO2012034379A1 true WO2012034379A1 (zh) 2012-03-22

Family

ID=45830963

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2011/071361 Ceased WO2012034379A1 (zh) 2010-09-17 2011-02-28 Ph响应金属有机配位聚合物的制备方法

Country Status (1)

Country Link
WO (1) WO2012034379A1 (zh)

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 (en) * 2008-03-17 2009-09-24 Board Of Regents, The University Of Texas System Formation of nanostructured particles of poorly water soluble drugs and recovery by mechanical techniques
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 (en) * 2008-03-17 2009-09-24 Board Of Regents, The University Of Texas System Formation of nanostructured particles of poorly water soluble drugs and recovery by mechanical techniques
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

Similar Documents

Publication Publication Date Title
CN101927006B (zh) 基于药物的pH响应金属有机配位聚合物的制备方法
Mi et al. New synthetic adriamycin-incorporated chitosan nanoparticles with enhanced antioxidant, antitumor activities and pH-sensitive drug release
CN112546027B (zh) 载脂溶性色素纳米粒及其制备方法
Chaudhary et al. Assessing the effect of different shapes of glyco-gold nanoparticles on bacterial adhesion and infections
Chu et al. Synthesis and application of a series of amphipathic chitosan derivatives and the corresponding magnetic nanoparticle-embedded polymeric micelles
CN112618514B (zh) 氨硼烷/中空介孔聚多巴胺/聚乙二醇纳米复合粒子及其制备与应用
Pan et al. Fabrication and characterization of taurine functionalized graphene oxide with 5-fluorouracil as anticancer drug delivery systems
CN106362162A (zh) ZnO@PMAA‑b‑PHPMA 量子点纳米材料及其制备和作为药物载体的应用
Benyettou et al. Microwave assisted nanoparticle surface functionalization
CN112546026B (zh) 中空介孔聚多巴胺载脂溶性色素纳米粒及其制备方法
Verma et al. Novel hydrophilic drug polymer nano-conjugates of cisplatin showing long blood retention profile-its release kinetics, cellular uptake and bio-distribution
Nayak et al. Design and evaluation of antibacterials crosslinked chitosan nanoparticle as a novel carrier for the delivery of metronidazole to treat bacterial vaginosis
CN108310397B (zh) 一种具有sers/荧光双模态靶向肿瘤细胞成像的诊疗试剂及其制备方法
CN111588690B (zh) 一种响应性透明质酸荧光纳米凝胶、制备方法和应用
Hatamiazar et al. Chitosan-albumin nanocomposite as a promising nanocarrier for efficient delivery of fluconazole against vaginal candidiasis
CN101947324B (zh) 基于高分子的pH响应金属有机配位聚合物的制备方法
CN107224590B (zh) 一种可降解聚合物磁性纳米粒子及其制备方法
CN113712939B (zh) 一种阿霉素偶联壳寡糖的纳米粒子
Teng et al. pH-responsive nanoparticles based on sodium dodecylbenzene sulfonate and polyamine-modified cyclodextrins for controlled release of metformin hydrochloride
CN108126211A (zh) 一种纳米杂化颗粒的制备方法以及由此得到的纳米杂化颗粒和纳米药物
CN107970224B (zh) 一种脂质修饰磁性氧化石墨烯复合材料的制备方法及应用
CN109953974B (zh) 一种酶-还原双响应性透明质酸-聚硫化丙烯共聚物纳米胶囊的制备方法
Bae et al. Pluronic/chitosan shell cross-linked nanocapsules encapsulating magnetic nanoparticles
WO2012034379A1 (zh) Ph响应金属有机配位聚合物的制备方法
CN110448698B (zh) 一种药物控释介孔硅纳米颗粒及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11824450

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 12/08/13)

122 Ep: pct application non-entry in european phase

Ref document number: 11824450

Country of ref document: EP

Kind code of ref document: A1