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Biotin and cell-penetrating peptide co-mediated breast cancer targeted intelligent liposome material

A technology targeting liposomes and breast cancer, applied in the field of medicine, can solve problems such as high cell and tissue toxicity

Inactive Publication Date: 2020-05-19
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its non-specific affinity to different cells, the R8-mediated breast cancer-targeted drug delivery system exhibits high cytotoxicity in vivo after systemic administration, and is prone to erythrocyte lysis and Hemoglobin release, etc. are not widely used

Method used

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  • Biotin and cell-penetrating peptide co-mediated breast cancer targeted intelligent liposome material
  • Biotin and cell-penetrating peptide co-mediated breast cancer targeted intelligent liposome material
  • Biotin and cell-penetrating peptide co-mediated breast cancer targeted intelligent liposome material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Preparation of Compound 2

[0034]

[0035] Weigh monobenzyl succinate (2.84 g, 13.62 mmol) into a double-necked flask, replace argon three times, dissolve with 55 mL of anhydrous dichloromethane, stir at -5°C, and add chloroformic acid under argon protection After addition of isobutyl ester (IBCF, 1.86 g, 13.62 mmol) and N-methylmorpholine (NMM, 1.38 g, 13.62 mmol), the activation was continued for 30 min. Compound 1 (1.50 g, 11.35 mmol) was dissolved in 2.5 mL of anhydrous dichloromethane and added dropwise to the above reaction solution. After the dropwise addition was completed, the reaction was carried out at room temperature for 3 h, and the completion of the reaction was monitored by TLC. The solvent in the reaction system was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 2.77 g of a colorless transparent oil, with a yield of 75.70%. ...

Embodiment 2

[0036] Example 2 Preparation of Compound 3

[0037]

[0038] Compound 2 (2.25 g, 6.98 mmol) was dissolved in 16 mL of degassed methanol, 330 mg of palladium on carbon was added, hydrogen was replaced 5 times, and stirred at room temperature. The completion of the reaction was monitored by TLC. The reaction liquid was filtered through diatomaceous earth, and the diatomaceous earth was washed 2-3 times with methanol. The filtrate was collected and concentrated under reduced pressure to remove the solvent to obtain 1.60 g of a colorless oil with a yield of 98.70%. The product was directly carried on to the next step without purification. 1 H-NMR (400 MHz, DMSO- d 6 , ppm) δ : 1.38 (s, 9H), 2.29 (t, J = 6.0 Hz, 2H), 2.41 (t, J = 6.0 Hz, 2H), 8.68 (s, 1H), 9.52 (s, 1H), 11.0 (brs, 1H).

Embodiment 3

[0039] Example 3 Preparation of Compound 5

[0040]

[0041] Cholesterol 4 (30.00 g, 77.59 mmol) was dissolved in 100 mL of anhydrous pyridine, and a pyridine solution (50 mL) of p-toluenesulfonyl chloride (TsCl, 23.67 g, 124.14 mmol) was slowly added dropwise at 0 °C. After the dropwise addition was completed, the reaction solution was moved to 55° C. to react overnight. TCL monitored the completion of the raw material reaction, and distilled off pyridine under reduced pressure, dissolved the residue with ethyl acetate (300 mL), and washed it with dilute hydrochloric acid (1 N, 100 mL × 2), saturated aqueous sodium chloride solution (100 mL × 2 ), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain 37.79 g of a white solid, with a yield of 90.06%. The product was directly subjected to the next reaction without purification. Mp: 129-132°C (Literature Mp: 130-132°C).

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Abstract

The invention discloses a biotin and cell-penetrating peptide co-mediated breast cancer targeted intelligent liposome material. The intelligent liposome material is prepared by the following steps: 1,modifying biotin on a PEG long chain, and connecting the biotin with cholest through an acid-sensitive bond (a general formula I, a ligand material a); and 2, connecting cell-penetrating peptide R8 with phospholipid through Michael addition reaction (a formula II and a ligand material b). After the two ligand materials are combined to prepare a liposome, the biotin exposed on the surface of the liposome can specifically recognize an overexpressed SMVT transporter on the surface of a breast cancer cell; and after the liposome reaches the breast tumor part, a PEG long chain connected with a hydrazone bond is broken and separated, and the R8 connected with a short chain is mediated, passes through membrane and enters the cell, so that the effect of strongly treating the breast cancer is realized. The novel intelligent liposome material can be used for different dosage forms including liposome, nanoparticles, micelles and the like, and a prepared paclitaxel-loaded liposome has strong breast cancer penetrability and treatment effect and has a wide application prospect.

Description

technical field [0001] The invention relates to the preparation and characterization of a novel biotin and membrane-penetrating peptide co-mediated targeted intelligent lipid material for breast cancer, and its application as a drug carrier in drug delivery, belonging to the technical field of medicine. Background technique [0002] Breast cancer is a major public health problem in today's society and a major disease that endangers women's physical and mental health. It is called "the number one beauty killer". In January 2019, the National Cancer Center released the latest national cancer statistics, in which breast cancer ranks first among female malignant tumors. Moreover, on a global scale, the incidence of breast cancer among women in both developed and developing countries ranks first. So far, various treatment methods such as surgery, radiation therapy, chemotherapy, endocrine therapy, small molecule targeted therapy and immunotherapy have been widely used clinically...

Claims

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Application Information

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IPC IPC(8): A61K47/28A61K47/22A61K47/10A61K47/42A61K9/127A61K31/337A61K49/00A61P35/00A61P15/14C08G65/334C08G65/332C08G65/333
CPCA61K9/1272A61K9/1277A61K31/337A61K47/10A61K47/22A61K47/28A61K47/42A61K49/0054A61K49/0056A61K49/0084A61P15/14A61P35/00C08G65/3326C08G65/33396C08G65/3348
Inventor 海俐吴勇郭丽卢润鑫刘启俊周琳杨春艳王思琪
Owner SICHUAN UNIV
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