Preparation and application of breast cancer targeted liposome modified by biotin and glucose

Abstract

The invention discloses a novel lipid material for realizing the delivery of a breast cancer targeted drug. The novel lipid material takes lysine as a connecting group and is connected with a cholesteric part, a biotin part and a glucose part. The affinity between biotin and glucose in the novel lipid material and biotin transporter (SMVT) and glucose transporter (GLUT1) can be utilized to realizethe double targeting function to breast cancer and play a stronger breast cancer targeting therapeutic role, wherein the biotin transporter (SMVT) and the glucose transporter (GLUT1) are highly expressed on the surface of breast cancer cells. The novel lipid material can be used in different dosage forms comprising liposomes, nanoparticles, micelles and the like, and the prepared paclitaxel-loaded liposome has obvious breast cancer targeting property and a wide application prospect.

Description

technical field

[0001] The invention relates to a new type of lipid material and its application in drug delivery system, which has the function of breast cancer targeted drug delivery, including the preparation and characterization of the material, and its application as a drug carrier in drug delivery, belonging to field of medical technology. Background technique

[0002] For women, the three most common cancers are breast, lung and colorectal cancer, with breast cancer alone accounting for 30% of all newly diagnosed cancers in women, according to the 2018 Cancer Statistics. Breast cancer is a highly heterogeneous systemic disease with high morbidity and mortality.

[0003] The invention relates to a new type of lipid material and its application in drug delivery system, which has the function of breast cancer targeted drug delivery, including the preparation and characterization of the material, and its application as a drug carrier in drug delivery, belonging to field...

Examples

Embodiment 1

[0034] Preparation of compound 2

[0035] Benzyl alcohol (8.91 g, 82.44 mmol), succinic anhydride 1 (7.50 g, 74.94 mmol), 4-dimethylaminopyridine (91.5 mg, 0.75 mmol) were added to 60 ml tetrahydrofuran. After gradually raising the temperature to 50°C, the reaction was heated and stirred in an oil bath for 5 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in 150 ml ethyl acetate, washed successively with saturated sodium bicarbonate dilute hydrochloric acid (60 ml × 2), saturated aqueous sodium chloride solution (60 ml × 2), and dried over anhydrous sodium sulfate The organic layer was concentrated under reduced pressure and then recrystallized from isopropyl ether-acetone to obtain 9.5 g of white solid with a yield of 60.98%. Mp: 60-62°C.

Embodiment 2

[0037] Preparation of Compound 4

[0038] Anhydrous glucose 3 (9.01 g, 0.05 mol) was dissolved in 250 ml of pre-dried pyridine under ice bath conditions. Trimethylchlorosilane (38.03 ml, 0.30 mol) and hexamethyldisilazane (31.44 ml, 0.15 mol) were mixed, slowly added dropwise to the above pyridine solution containing glucose, and stirred at room temperature for 24 hours. Pyridine was evaporated under reduced pressure, 300 ml of water was added to the residue, the aqueous layer was extracted with ether (150 ml × 2), the organic layers were combined, washed with water and saturated aqueous sodium chloride solution (200 ml × 7), dried over anhydrous sodium sulfate, The solvent was removed under reduced pressure to obtain 25.38 g of a yellow oil with a yield of 93.80%. The product can be directly subjected to the next reaction without further purification.

Embodiment 3

[0040] Preparation of compound 5

[0041] Dissolve compound 4 (6.00 g, 11.09 mmol) in a mixed solution of acetone and methanol (5:8, 39 ml), and slowly add acetic acid (1.15 ml, 20.05 mmol) into acetone and methanol (v / v = 5 / 8, 3.9 ml) mixed solution. After dropping, the reaction solution was moved to room temperature and continued to stir for 2.5 hours. TLC monitored the completion of the reaction, and sodium carbonate powder (1.80 g, 17.00 mmol) was added to continue stirring at room temperature for 25 minutes. The white solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography to obtain 3.76 g of a colorless oil, with a yield of 72.38%. 1H NMR (400 MHz, CDCl 3 , ppm) δ:0.14-0.19 (m, 36 H), 3.35 (d, 1 H, Hz, J = 9.2 Hz), 3.66 (t, 1 H, J = 9.2Hz), 3.68 (dd, 1 H, J 1 = 4.8 Hz, J 2 = 12.0 Hz), 3.73-3.76 (m, 2H), 3.80 (t, 1H, J = 8.8 Hz), 5.16 (d, 1 H, J = 3.2 Hz).

technical field

[0001] The invention relates to a new type of lipid material and its application in drug delivery system, which has the function of breast cancer targeted drug delivery, including the preparation and characterization of the material, and its application as a drug carrier in drug delivery, belonging to field of medical technology. Background technique

[0002] For women, the three most common cancers are breast, lung and colorectal cancer, with breast cancer alone accounting for 30% of all newly diagnosed cancers in women, according to the 2018 Cancer Statistics. Breast cancer is a highly heterogeneous systemic disease with high morbidity and mortality.

[0003] The invention relates to a new type of lipid material and its application in drug delivery system, which has the function of breast cancer targeted drug delivery, including the preparation and characterization of the material, and its application as a drug carrier in drug delivery, belonging to field...

Examples

Embodiment 1

[0034] Preparation of compound 2

[0035] Benzyl alcohol (8.91 g, 82.44 mmol), succinic anhydride 1 (7.50 g, 74.94 mmol), 4-dimethylaminopyridine (91.5 mg, 0.75 mmol) were added to 60 ml tetrahydrofuran. After gradually raising the temperature to 50°C, the reaction was heated and stirred in an oil bath for 5 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in 150 ml ethyl acetate, washed successively with saturated sodium bicarbonate dilute hydrochloric acid (60 ml × 2), saturated aqueous sodium chloride solution (60 ml × 2), and dried over anhydrous sodium sulfate The organic layer was concentrated under reduced pressure and then recrystallized from isopropyl ether-acetone to obtain 9.5 g of white solid with a yield of 60.98%. Mp: 60-62°C.

Embodiment 2

[0037] Preparation of Compound 4

[0038] Anhydrous glucose 3 (9.01 g, 0.05 mol) was dissolved in 250 ml of pre-dried pyridine under ice bath conditions. Trimethylchlorosilane (38.03 ml, 0.30 mol) and hexamethyldisilazane (31.44 ml, 0.15 mol) were mixed, slowly added dropwise to the above pyridine solution containing glucose, and stirred at room temperature for 24 hours. Pyridine was evaporated under reduced pressure, 300 ml of water was added to the residue, the aqueous layer was extracted with ether (150 ml × 2), the organic layers were combined, washed with water and saturated aqueous sodium chloride solution (200 ml × 7), dried over anhydrous sodium sulfate, The solvent was removed under reduced pressure to obtain 25.38 g of a yellow oil with a yield of 93.80%. The product can be directly subjected to the next reaction without further purification.

Embodiment 3

[0040] Preparation of compound 5

[0041] Dissolve compound 4 (6.00 g, 11.09 mmol) in a mixed solution of acetone and methanol (5:8, 39 ml), and slowly add acetic acid (1.15 ml, 20.05 mmol) into acetone and methanol (v / v = 5 / 8, 3.9 ml) mixed solution. After dropping, the reaction solution was moved to room temperature and continued to stir for 2.5 hours. TLC monitored the completion of the reaction, and sodium carbonate powder (1.80 g, 17.00 mmol) was added to continue stirring at room temperature for 25 minutes. The white solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography to obtain 3.76 g of a colorless oil, with a yield of 72.38%. 1H NMR (400 MHz, CDCl 3 , ppm) δ:0.14-0.19 (m, 36 H), 3.35 (d, 1 H, Hz, J = 9.2 Hz), 3.66 (t, 1 H, J = 9.2Hz), 3.68 (dd, 1 H, J 1 = 4.8 Hz, J 2 = 12.0 Hz), 3.73-3.76 (m, 2H), 3.80 (t, 1H, J = 8.8 Hz), 5.16 (d, 1 H, J = 3.2 Hz).

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