Methotrexate metal coordination polymer and preparation method and application thereof
阅读说明：本技术 一种甲氨蝶呤金属配位聚合物及其制备方法和应用 (Methotrexate metal coordination polymer and preparation method and application thereof ) 是由 侯振清 范仲雄 王衍戈 朱富凯 于 2019-10-12 设计创作，主要内容包括：本发明公开了一种甲氨蝶呤金属配位聚合物及其制备方法和应用,其结构式为：<Image he="693" wi="700" file="DDA0002231149490000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R为功能金属离子。本发明通过在MTX的结构中引入可MRI成像的Gd<Sup>III</Sup>和Fe<Sup>III</Sup>得到MTX-Gd<Sup>III</Sup>和MTX-Fe<Sup>III</Sup>配位聚合物,此类聚合物在主动靶向(MTX与叶酸受体具有极强的亲和力)介导下可被高效递送至叶酸受体过表达的肿瘤细胞,进而降低给药剂量,实现对肿瘤病灶的精准高效诊疗；通过在MTX的结构中引入具有免疫促进作用的Zn<Sup>II</Sup>得到MTX-Zn<Sup>II</Sup>配位聚合物,此类聚合物有望高效治疗肿瘤及免疫疾病。(The invention discloses a methotrexate metal coordination polymer and a preparation method and application thereof, and the structural formula is as follows: wherein R is functional metal ion. The invention introduces Gd capable of being imaged by MRI into the structure of MTX III And Fe III Obtaining MTX-Gd III And MTX-Fe III Coordination polymers that can be efficiently delivered to under active targeting (MTX has a very strong affinity for folate receptors) mediationThe folic acid receptor over-expressed tumor cells further reduce the administration dosage and realize accurate and efficient diagnosis and treatment of tumor lesions; by introducing Zn with immune promoting effect into the structure of MTX II Obtaining MTX-Zn II Coordination polymers, which are expected to be highly effective in treating tumors and immune diseases.)
1. A methotrexate metal coordination polymer characterized in that: the structural formula is as follows:
2. The methotrexate metal coordination polymer of claim 1, wherein: r is GdIII、FeIIIOr ZnII。
3. A preparation method of methotrexate metal coordination polymer is characterized in that: the method comprises the following steps:
(1) mixing MTX and metal salt containing functional metal ions in a weak alkaline solution for reaction to obtain MTX metal coordination polymer mixed solution;
(2) removing impurities in the MTX metal coordination polymer mixed solution, and freeze-drying to obtain the methotrexate metal coordination polymer.
4. The method of claim 3, wherein: the functional metal ion is GdIII、FeIIIOr ZnII。
5. The method of claim 4, wherein: the metal salt is gadolinium chloride hexahydrate, ferric chloride hexahydrate or zinc chloride.
6. The use of the methotrexate metal coordination polymer of claim 1 or 2 in the preparation of a tumor-targeted diagnosis and treatment drug.
7. The use of claim 6, wherein: the functional metal ion is GdIIIOr FeIII。
8. Use of the methotrexate metal complex polymer of claim 1 or 2 for the preparation of a medicament for the treatment of immune disorders.
9. The use of claim 8, wherein: the functional metal ion is ZnII。
Technical Field
The invention belongs to the technical field of coordination chemistry, and particularly relates to a methotrexate metal coordination polymer and a preparation method and application thereof.
Background
Coordination chemistry is the interaction of metal atoms or ions with organic and inorganic ions and the formation of coordination complexes by coordinative bonding. With the progress of research on life sciences and diseases, it is found that many life phenomena include interactions between metal ions. In addition, designing new diagnostic agents based on coordination chemistry is also a major strategy to combat serious diseases. Therefore, in recent years, coordination chemistry has been widely used in the biomedical field. Some organic molecules and metals with diagnosis and treatment effects cannot be directly applied to clinic due to the defects of poor curative effect, large toxic and side effects, difficult absorption and the like, but if the organic molecules and the metals are modified into coordination compounds, the curative effect is expected to be improved, and the toxic and side effects are reduced. For example, various chelates of gadolinium (Gd) have extremely low toxic side effects and are widely used as Magnetic Resonance Imaging (MRI) contrast agents in clinical practice; the ferric citrate complex can be used for treating iron deficiency anemia; the copper coordination compound of aspirin and salicylic acid derivatives can greatly improve the anti-rheumatism effect; bleomycin has no tumor affinity, and the activity of a coordination compound formed by bleomycin and cobalt ions is greatly improved; the cis-palladium-platinum coordination compound has excellent anti-tumor effect; many ligands selectively form water-soluble chelates with harmful metals and metal ions, which are excreted via the kidney for detoxification. The above examples fully demonstrate that the development of novel biological diagnostic and therapeutic agents based on coordination chemistry design has great development prospects, and can be better applied to the field of biological medicine.
MTX (CAS number: 59-05-2) is a folic acid antimetabolite, can combine with folate receptors on the surfaces of tumor cells to play a good targeting role, and is commonly used for treating various malignant tumors. In addition, MTX is also one of the optional medicines for treating acute leukemia and autoimmune diseases. However, MTX still has many disadvantages in clinical application, such as difficulty in crossing the Blood Brain Barrier (BBB) in treating brain tumors. The medicine can increase the toxicity of liver and kidney functions, and has toxicity to normal biological cells because the medicine action mechanism is to inhibit the synthesis of tumor cell DNA by inhibiting dihydrofolate reductase. Researches find that the MTX prodrug modified by the amphiphilic polymer material has the advantages of improving the targeting property and bioavailability of the medicament, reducing the toxic and side effects of the medicament and the like. More importantly, the nano-drug formed by self-assembly enters into the body, and the phagocytosis of the RES system of the human body can be effectively reduced. The nano-drug system can control the drug release when reaching the target position, reduce the drug dosage, enhance the drug efficacy and reduce the drug toxicity. Meanwhile, the nano-drug system can avoid the loss of the activity of the drug and is beneficial to the storage and delivery of the drug. Virtually all nano-drug modified dosage forms also introduce undefined systemic toxicity in conjunction with the introduction of the carrier. In order to solve the problem, a carrier-free amphiphilic nano diagnosis and treatment system constructed by hydrophilic and hydrophobic diagnosis and treatment agents through methods such as chemical bonding, physical interaction force, metal coordination and the like is also concerned at present, but the stability of the nano diagnosis and treatment system is poorer than that of the traditional carrier-carrying nano diagnosis and treatment system.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a methotrexate metal coordination polymer.
Another object of the present invention is to provide a method for preparing the above-mentioned methotrexate metal complex polymer.
Still another object of the present invention is to provide the use of the above-mentioned methotrexate metal complex polymer.
The technical scheme of the invention is as follows:
the methotrexate metal coordination polymer has a structural formula as follows:
In a preferred embodiment of the present invention,r is GdIII、FeIIIOr ZnII。
The other technical scheme of the invention is as follows:
a preparation method of methotrexate metal coordination polymer comprises the following steps:
(1) mixing MTX and metal salt containing functional metal ions in a weak alkaline solution for reaction to obtain MTX metal coordination polymer mixed solution;
(2) removing impurities in the MTX metal coordination polymer mixed solution, and freeze-drying to obtain the methotrexate metal coordination polymer.
In a preferred embodiment of the present invention, the functional metal ion is GdIII、FeIIIOr ZnII。
Further preferably, the metal salt is gadolinium chloride hexahydrate (GdCl)3·6H2O, CAS number: 13450-84-5), ferric chloride hexahydrate (FeCl)3·6H2O, CAS number: 10025-77-1) or zinc chloride (ZnCl)2CAS number: 7646-85-7).
The invention adopts another technical scheme as follows:
the methotrexate metal coordination polymer is applied to the preparation of tumor targeted diagnosis and treatment medicines.
In a preferred embodiment of the present invention, the functional metal ion is GdIIIOr FeIII。
The methotrexate metal coordination polymer is applied to the preparation of immune disease treatment drugs.
In a preferred embodiment of the present invention, the functional metal ion is ZnII。
The invention has the beneficial effects that:
1. the invention introduces Gd capable of being imaged by MRI into the structure of MTXIIIAnd FeIIIObtaining MTX-GdIIIAnd MTX-FeIIIThe coordination polymer can be efficiently delivered to folate receptor over-expressed tumor cells under the mediation of active targeting (MTX has extremely strong affinity with folate receptor), so that the administration dosage is reduced, and the purpose of realizing the effectAccurate and efficient diagnosis and treatment of tumor lesions; by introducing Zn with immune promoting effect into the structure of MTXIIObtaining MTX-ZnIICoordination polymers, which are expected to be highly effective in treating tumors and immune diseases.
2. The synthesis process is extremely simple and easy to operate, the obtained product has excellent water solubility, other hydrophobic diagnosis and treatment agents can be efficiently loaded, a long-circulating self-assembly nano diagnosis and treatment system with good stability is easily prepared by a self-assembly technology, and the system can be efficiently delivered to the focus of tumor under the dual mediation of active targeting and passive targeting (tumor penetration and retention enhancement effect).
3. Experimental results prove that the MTX-Gd related to the inventionIIIAnd MTX-FeIIIThe coordination polymer has good tumor targeted diagnosis and treatment effects, particularly good relaxation enhancement capability when being used as an MRI contrast agent, can identify the tumor cells with over-expressed folate receptors with high selectivity, not only has strong targeted contrast effect, but also prolongs the imaging time of the contrast agent in vivo, thereby reducing the addition amount of the contrast agent and having strong practicability.
Drawings
FIG. 1 shows MTX and MTX-Gd prepared in example 1 of the present inventionIIIInfrared spectrum of coordination polymer.
FIG. 2 shows MTX-Gd prepared according to example 1 of the present inventionIIITransmission electron microscopy of coordination polymer.
FIG. 3 shows MTX and MTX-Fe obtained in example 2 of the present inventionIIIInfrared spectrum of coordination polymer.
FIG. 4 shows MTX-Fe obtained in example 2 of the present inventionIIITransmission electron microscopy of coordination polymer.
FIG. 5 shows MTX and MTX-Zn prepared in example 3 of the present inventionIIInfrared spectrum of coordination polymer.
FIG. 6 shows MTX-Zn prepared in example 3 of the present inventionIITransmission electron microscopy of coordination polymers.
FIG. 7 shows MTX-Gd prepared according to example 1 of the present inventionIIIOf coordination polymersLongitudinal relaxation (inset: T1 weighted MRI images).
FIG. 8 shows MTX-Fe obtained in example 2 of the present inventionIIITransverse relaxation of coordination polymers (inset: T2 weighted MRI picture).
FIG. 9 shows MTX-Gd prepared according to example 1 of the present inventionIIITumor targeting MRI experiments and result graphs of coordination polymers after BALB/C nude mice intravenous injection.
FIG. 10 shows MTX-Fe obtained in example 2 of the present inventionIIITumor targeting MRI experiments and result graphs of coordination polymers after BALB/C nude mice intravenous injection.
Detailed Description
The technical solution of the present invention is further illustrated and described by the following detailed description.
The most key concept of the invention is as follows: MTX and GdIII、FeIII、ZnIISeparately chelate-synthesizing MTX-Gd by coordination reactionIII、MTX-FeIII、MTX-ZnIIThree metal coordination polymers.
Referring to FIGS. 1 to 10, the present invention provides MTX-GdIII、MTX-FeIII、MTX-ZnIIThree coordination polymers having the following reaction formula:
the principle of the invention is as follows: MTX is taken as an aptamer (carboxyl and amino can give out lone pair electrons) and GdIII、FeIII、ZnII(easy to accept lone pair electrons) metal ions are synthesized into MTX-Gd through coordination reactionIII、MTX-FeIII、MTX-ZnIIThe three coordination polymers are used for diagnosing and treating tumors and immune diseases.
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