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Calcium phosphate-lipid nano-drug co-delivery system composed of low molecular weight heparin and natural drug prodrug

A low-molecular-weight heparin and natural medicine technology, applied in the field of pharmaceutical preparations, can solve the problems that chemotherapy drugs cannot effectively enter tumor tissues, chemotherapy drugs have systemic toxicity, and cannot be targeted.

Active Publication Date: 2022-03-18
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Traditional chemotherapy drugs such as cisplatin, doxorubicin and other drugs can not play a targeted role in the above two pathways because of their direct killing of proliferating cells, and chemotherapy drugs generally have systemic toxicity after long-term use, which leads to patients in the course of treatment. Need to endure a lot of pain; not only that, traditional chemotherapy drugs cannot effectively enter the tumor tissue, and it is difficult to effectively enter the tumor parenchyma to inhibit tumor metastasis

Method used

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  • Calcium phosphate-lipid nano-drug co-delivery system composed of low molecular weight heparin and natural drug prodrug
  • Calcium phosphate-lipid nano-drug co-delivery system composed of low molecular weight heparin and natural drug prodrug
  • Calcium phosphate-lipid nano-drug co-delivery system composed of low molecular weight heparin and natural drug prodrug

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Example 1: Synthesis and characterization of PIC-POOH

[0042]PIC-POOH was synthesized using a two-step chemistry. The first step, weigh 200mg of PIC solid powder, 780mg of 4-dimethylaminopyridine (DMAP), and take 0.89ml of triethylamine in anhydrous 20ml of tetrahydrofuran with a syringe, add 3ml of dichlorophosphoric acid dropwise after stirring Ethyl ester, nitrogen protection after adding, heated to 70 ℃ reflux, terminated the reaction after 24h, and then purified by silica gel column chromatography to remove reaction impurities and by-products to obtain the intermediate product phosphorylated piceatanol (PIC-POOET ); second step, weigh 50mg of PIC-POOET, dissolve in 5ml of dichloromethane, add 0.33ml of bromotrimethylsilane dropwise after stirring, stir at room temperature for 4h, and remove dichloromethane by rotary evaporation, add methanol and stir for 30min Finally, the reaction is terminated, and then purified by a semi-preparative chromatographic column to r...

Embodiment 2

[0044] Example 2: Preparation of calcium phosphate-lipid nanoparticles encapsulated by low molecular weight heparin

[0045] Calcium phosphate nano-cores were prepared by reverse microemulsion method in which PIC-POOH solution and calcium chloride solution were combined in oil phase. Calcium phosphate-lipid nanoparticles were prepared by film hydration method containing calcium phosphate nano-cores: Weigh 16.8mg of DSPE-PEG2000, 8.6mg of cationic lipid material DOTAP and 4.6mg of cholesterol, add 2ml of chloroform to dissolve them Dissolve, add 0.7ml of calcium phosphate nano-precipitate dispersed in chloroform, mix well and add to a 500ml round bottom flask, remove chloroform by rotary evaporation, add 6ml of distilled water to hydrate the lipids attached to the inner wall of the bottle, ice bath Ultrasound for 2.4 minutes under the condition of ultrasonic power 240W, interval 2S, that is to make Ca-P, take it out for use;

[0046] The LMWH was wrapped on the outside of Ca-P...

Embodiment 3

[0048] Example 3: Evaluation of Drug Co-delivery System for Inhibiting Tumor Angiogenesis

[0049] Tubule formation experiments were used to simulate tumor angiogenesis in vivo. After the Matrigel was thawed at 4°C, 50uL was added to a pre-cooled 96-well plate in an ice bath, transferred to 37°C and incubated for 30min until the Matrigel was polymerized. Add 1×10 per well 4 1 HUVEC cells were centrifuged to remove the supernatant, and then resuspended with DMEM solution containing PIC, LMWH, Ca-P, and H-Ca-P (the concentration of PIC and PIC-POOH was 5 μmol / L, and the concentration of LMWH was 3.5 μmol / L). Suspended and inoculated into 96-well plates precoated with Matrigel. The control group used DMEM solution without drugs. After co-incubating for 12 hours, observe and take pictures under a phase-contrast microscope, and use Image J 1.46version software to quantify the number of lumens of tubules formed in each group in the field of view;

[0050] The results showed that...

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Abstract

The field of pharmaceutical preparations of the present invention relates to a calcium phosphate-lipid nano-drug co-delivery system composed of low-molecular-weight heparin and natural drug prodrugs and a preparation method thereof. The present invention uses nanoparticles prepared from biodegradable lipid materials as a carrier , and physically encapsulates the phosphorylated prodrug PIC-POOH of the natural drug PIC, and electrostatically adsorbs LMWH on the outer layer, and utilizes the long-circulation properties of nano-preparations and the EPR effect of solid tumor tissues to enrich in tumor sites, thereby regulating tumor cell metastasis-related pathways , inhibit angiogenesis, anti-tumor metastasis. Experiments show that the drug co-delivery system can inhibit the EMT process of tumor cells, and can significantly inhibit tumor angiogenesis through tubule formation experiments. and prolong the survival period of tumor-bearing mice; it has obvious anti-tumor metastasis effect, especially reduces triple-negative breast cancer metastasis, and has good safety.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to making a prodrug from a natural drug monomer with a short half-life by a chemical synthesis method and encapsulating it in a biodegradable lipid nanostructure with long circulation function, and at the same time adsorbing low molecular weight on its surface Heparin, to co-deliver the two drugs into the tumor and achieve the purpose of enhancing anti-metastasis. Background technique [0002] Breast cancer is a kind of multiple malignant tumors all over the world, which has the characteristics of high clinical incidence, high degree of malignancy and poor prognosis. Especially for triple-negative breast cancer, the treatment effect and prognosis are poor, because this type of breast cancer cells have a high degree of migration and invasion characteristics, which makes them prone to metastasize to distant sites after forming a solid tumor in the body. 90% of patients with t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/51A61K47/36A61K47/02A61K9/127A61K47/24A61K47/28A61K47/10A61K31/05A61P35/00
CPCA61K9/5161A61K9/5115A61K9/127A61K47/24A61K47/28A61K47/10A61K31/05A61P35/00
Inventor 陈钧胥敏俊
Owner FUDAN UNIV
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