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Folate-conjugated polyethylene glycol monostearate, and preparation method and application thereof

A technology of polyethylene glycol monostearate and folic acid, which is applied in pharmaceutical formulations, liposome delivery, medical preparations of non-active ingredients, etc., can solve folic acid leakage and affect the tumor cell targeting effect of folic acid To achieve the effect of increasing peak plasma concentration, improving anti-tumor efficacy, and accelerating cell uptake

Active Publication Date: 2013-06-12
HANGZHOU NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of these carriers for simple physical encapsulation of folic acid, on the one hand, will cause a large amount of folic acid leakage during the rotation process in the body, on the other hand, it may also be encapsulated in the carrier material or distributed in the carrier, thereby affecting the tumor cells of folic acid. targeted effect

Method used

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  • Folate-conjugated polyethylene glycol monostearate, and preparation method and application thereof
  • Folate-conjugated polyethylene glycol monostearate, and preparation method and application thereof
  • Folate-conjugated polyethylene glycol monostearate, and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Embodiment 1: the synthesis of folic acid coupling polyethylene glycol monostearate

[0033] Precisely weigh 0.5 g of folic acid, 0.5 mL of triethylamine, and 15 mL of DMSO to dissolve, add 0.6 g of dicyclohexylcarbodiimide (DCC), 0.26 g of N-hydroxysuccinimide (NHS), and stir at room temperature in the dark. Overnight, by-products were removed by filtration. Then add 5g of polyethylene glycol (molecular weight: 4000) monostearate, heat to 35°C to dissolve, and react overnight at 35°C to obtain a crude product. Pour it into a dialysis bag with a molecular cut-off of 3500, place it in a 500 mL beaker filled with water, stir, dialyze for two days, and freeze-dry to obtain it.

[0034] Its synthetic route is as follows:

[0035]

[0036] After synthesis, the infrared spectrum and hydrogen nuclear magnetic resonance spectrum of folic acid-coupled polyethylene glycol monostearate were investigated to study its structure. figure 1 It is the red absorption spectrum of po...

Embodiment 2

[0037] Example 2: Oxaliplatin Folate Targeted Liposomes

[0038] Dissolve 4 g of phospholipids and 667 mg of cholesterol in 60 mL of dichloromethane, add 20 mL of an aqueous solution containing 80 mg of oxaliplatin, stir for 30 min, sonicate for 20 min, and remove the organic solvent by rotary evaporation at 40°C until the gel collapses Finally, according to the components, add 50 mL of an aqueous solution containing 580 mg of folic acid-polyethylene glycol monostearate and 400 mg of F68, continue to evaporate for 30 min, homogenize under high pressure at 400 bar for 5 min, and dilute to 100 mL with water, then Use tangential flow ultrafiltration to separate free oxaliplatin, use a tangential flow membrane bag with a molecular cut-off of 10K to carry out ultrafiltration, use water as the replacement liquid, repeat the ultrafiltration 3 times, and use the ultrafiltration centrifuge tube method to measure its content. The encapsulation efficiency and high performance liquid chro...

Embodiment 3

[0039] Embodiment 3: The particle diameter of the oxaliplatin folic acid targeting liposome obtained in Experimental Example 2, pH value investigation

[0040] In this study, the particle size and distribution of the oxaliplatin folic acid-targeted liposomes of Example 2 were measured by a laser particle size analyzer, and the samples were directly measured. The results are shown in Figure 5 ; After diluting 100 times with water, the laser particle size analyzer measures the particle size of the sample, and the results are shown in Figure 6 . After sample dilution, the variability is small, and the particle size range is still narrow and unimodal. The pH value of the oxaliplatin folic acid-targeted liposome solution was measured with a pH meter to be 6.53±0.05 (n=5).

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Abstract

The invention discloses folate-conjugated polyethylene glycol monostearate, and a preparation method and application thereof. The folate-conjugated polyethylene glycol monostearate has a structure shown as below, wherein n equals to 45-136. The preparation method of the folate-conjugated polyethylene glycol monostearate comprises the following steps: weighing folic acid and triethylamine; adding dimethylsulfoxide for dissolution; adding dicyclohexylcarbodiimide and N-hydroxy succinimide; stirring at room temperature by avoiding light; standing for overnight; filtering to remove by-products; then adding polyethylene glycol monostearate; heating to dissolve; reacting overnight to obtain a coarse product; placing the coarse product in a dialysis bag; dialyzing with water; and conducting freeze-drying to obtain the folate-conjugated polyethylene glycol monostearate. The folate-conjugated polyethylene glycol monostearate can be applied to preparation of a folic acid modified antitumor drug delivery system, improve drug targeting, efficacy and pharmacokinetics, and reduce toxicity.

Description

(1) Technical field [0001] The present invention relates to folic acid-coupled polyethylene glycol monostearate and its preparation method and preparation of folic acid-modified liposomes, polymer nanoparticles or solid liposome nanoparticles and other nano drug carriers and anti-tumor drug-loaded Application in nano preparations such as folic acid modified liposomes, polymer nanoparticles or solid liposome nanoparticles. (2) Background technology [0002] Tumor has always been a major disease that directly threatens human health. Due to the lack of molecular targeting of the drug itself, tumor chemotherapy has major treatment problems such as low cure rate and huge toxic side effects. Directly targeting drugs to diseased tissues (organs) and cells through appropriate carrier technology is one of the important means to solve the low cure rate and toxic side effects of cancer chemotherapy. At present, scientists at home and abroad have made some progress in the composition (...

Claims

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Application Information

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IPC IPC(8): C08G65/00C08G65/48A61K47/34A61K9/127A61K9/14A61P35/00A61K47/22
Inventor 曾昭武肖人钟王小丽王俊洁周广林刘星言
Owner HANGZHOU NORMAL UNIVERSITY
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