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Preparation method and application of a metal-organic framework drug-loading system based on a small-molecule prodrug of cytarabine

A metal-organic framework and cytarabine technology, which is applied in the field of medicine, can solve the problems of difficult encapsulation, small molecular structure of anticancer drug cytarabine, leakage, etc. Effect

Active Publication Date: 2020-12-15
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the stability of the MOF material's own structure and the specificity of the molecular structure of different drugs, the currently known types of drugs that can be entrapped by the MOF material are very limited. Leaking from the pores of MOFs makes it difficult to achieve encapsulation. Therefore, it is urgent to develop a metal-organic framework drug-loaded delivery system with high loading of small-molecule drugs.

Method used

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  • Preparation method and application of a metal-organic framework drug-loading system based on a small-molecule prodrug of cytarabine
  • Preparation method and application of a metal-organic framework drug-loading system based on a small-molecule prodrug of cytarabine
  • Preparation method and application of a metal-organic framework drug-loading system based on a small-molecule prodrug of cytarabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0045] Embodiment 1Ara-IR820 prodrug molecular synthesis

[0046] Accurately weigh a certain amount of IR820 with an analytical balance, dissolve it in anhydrous DMF and place it in a round bottom flask, accurately weigh a certain amount of 6-aminocaproic acid with an analytical balance, dissolve it in anhydrous DMF, and add it to the above IR820 under stirring conditions DMF solution, added triethylamine under stirring condition, and reacted for 4h under nitrogen protection and 85°C oil bath condition. The molar amount is IR820: triethylamine: 6-aminocaproic acid = 1:5:5, and the reaction progress is monitored by a thin-layer plate. After the reaction was completed, the anhydrous DMF was removed by rotary evaporation under reduced pressure, and the crude product was obtained by vacuum drying overnight. Dissolve the crude product in methanol, mix the sample with a little column chromatography on silica gel, purify by silica gel column chromatography, gradient elution with eth...

Embodiment 2

[0048] Embodiment 2 proton nuclear magnetic resonance spectrum ( 1 H-NMR) identification of IR820-COOH and Ara-IR820 prodrug chemical structure

[0049] Weigh about 5 mg of IR820-COOH and Ara-IR820 prodrugs respectively, dissolve them in deuterated dimethyl sulfoxide (DMSO-d6) and place them in NMR tubes, and measure their H NMR spectra by using 400 MHz H NMR spectrum. Silane was used as an internal standard, and the chemical shift values ​​(ppm) of the compounds were recorded. The result is as figure 1 As shown, the NMR results can confirm that the molar ratio of cytarabine and IR820 in the newly synthesized molecule is close to 1:1, and the appearance of the characteristic peak of H on the amide bond at the same time proves the synthesis of the amide bond. pass 1 H-NMR spectrum can confirm the successful synthesis of Ara-IR820 prodrug.

Embodiment 3

[0050] Example 3 Preparation of metal organic framework drug delivery system with active targeting function based on cytarabine and new indocyanine green small molecule prodrug (Ara-IR820) as an intravenous preparation

[0051] Accurately weigh about 50 mg of the Ara-IR820 prodrug molecule, dissolve it in 2 mL of water, and add 0.5 mL of Zn(NO 3 ) 2 ·6H 2 O aqueous solution, and then drop the above suspension into 5 mL of 2-methylimidazole aqueous solution under the condition of stirring, the drug-loaded MOF nanoparticles formed spontaneously, the suspension was centrifuged, washed with water, the supernatant was discarded, and vacuum-dried to obtain blue Color solid Ara-IR820@ZIF-8.

[0052] Disperse Ara-IR820@ZIF-8 in a 3 mg / mL hyaluronic acid (HA) aqueous solution and stir at room temperature for 48 hours; centrifuge the formed suspension, wash with water, and dry to obtain a blue solid, which is dispersed in water by ultrasonic That is, the target intravenous injection ...

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Abstract

The invention discloses a preparation method and application of metal organic framework drug carrier system based on drug cytosine arabinoside micromolecule prodrug. The preparation method disclosed by the invention comprises the steps: choosing molecules which can generate coordination reaction with metal ions to be covalently combined with cytosine arabinoside to synthesize novel multifunctionalmicromolecule prodrug; carrying the prodrug on the metal organic framework through a simple environment-friendly one-step entrapment method to form medicine carrying nanoparticles; centrifuging, washing and drying to obtain a cytosine arabinoside micromolecule prodrug carrying MOF intravenous injection preparation. Taking synthesized Ara-IR820@ZIF-8 as an example, a mouse in-vivo antitumor pharmacological result shows that HA / Ara-IR820@ZIF-8 nano water solution has a good antitumor effect and lower system toxicity. The intravenous injection preparation has the advantages of high medicine carrying amount, simple and economic preparation process, batch production, small toxicity, good safety and wide application prospect in achieving high medicine carrying amount of the cytosine arabinosidein the metal organic framework and applying intravenous injection dosage to treat solid tumors.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the design and synthesis of a novel cytarabine small-molecule prodrug, and also to the preparation and evaluation of a metal-organic framework drug delivery system based on the small-molecule prodrug of the drug. Background technique [0002] With the increasing morbidity and mortality, cancer has become the primary factor threatening public health, and the treatment of cancer is urgent. Chemotherapy is a means of inhibiting tumor cell proliferation and promoting tumor cell apoptosis through the use of chemical drugs, and is currently the most widely used treatment. As a typical pyrimidine anti-metabolite, cytarabine is one of the most commonly used chemotherapeutic drugs in clinic, and is widely used in the treatment of various acute and chronic leukemias. However, due to its high molecular polarity, low fat solubility, and poor membrane permeability; in addition, the NH on th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K41/00A61K31/7068A61K9/14A61K47/36A61K47/22A61K47/55A61P35/02A61P35/00C07H19/09C07H1/00
CPCA61K9/0019A61K9/145A61K9/146A61K31/7068A61K41/0052A61K47/55A61P35/00A61P35/02C07H1/00C07H19/09A61K2300/00
Inventor 栾玉霞张会苑
Owner SHANDONG UNIV
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