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

A low-molecular-weight heparin and natural drug technology, applied in the field of pharmaceutical preparations, can solve the problems of chemotherapy drugs cannot effectively enter tumor tissue, chemotherapy drugs have systemic toxicity, and cannot be targeted, and can reduce the formation of lung metastases, inhibit the The effect of tumor angiogenesis and prolongation of survival

Active Publication Date: 2020-04-07
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 consisting of low molecular weight heparin and prodrug of natural drug
  • Calcium phosphate-lipid nano-drug co-delivery system consisting of low molecular weight heparin and prodrug of natural drug
  • Calcium phosphate-lipid nano-drug co-delivery system consisting of low molecular weight heparin and prodrug of natural drug

Examples

Experimental program
Comparison scheme
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 invention relates to the field of pharmaceutical preparations, and relates to a calcium phosphate-lipid nano-drug co-delivery system consisting of low molecular weight heparin and a prodrug of a natural drug and a preparation method for the nano-drug co-delivery system. According to the nano-drug co-delivery system, nanoparticles prepared from a biodegradable lipid material are taken as carriers, and the phosphorylated prodrug PIC-POOH of the natural drug piceatannol (PIC) is physically entrapped, and the low molecular weight heparin (LMWH) adsorbs on the outer layers of the carriers by static electricity; and a nano preparation concentrates at a tumor site by utilizing the long circulating performance of the nano preparation and the enhanced permeability and retention (EPR) effect ofa solid tumor tissue, a related pathway for tumor cell metastasis is then regulated, angiogenesis is inhibited, and the anti-tumor metastasis action is exerted. Proved by assays, the nano-drug co-delivery system can inhibit the epithelial-mesenchymal transition (EMT) progress of tumor cells; proved by a tube formation assay, the nano-drug co-delivery system can significantly inhibit tumor angiogenesis; proved by in vivo administration evaluation, the nano-drug co-delivery system can reduce formation of lung metastasis on a mice model, and prolongs the survival time of tumor-bearing mice; and the nano-drug co-delivery system has an obvious anti-tumor metastasis effect, especially reduces triple negative breast cancer metastasis, and has high 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 Applications(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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