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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  • Summary
  • 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

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
Comparison scheme
Effect test

Example Embodiment

[0032] Example 1: Synthesis of folic acid coupled polyethylene glycol monostearate

[0033] Accurately weigh 0.5 g of folic acid, 0.5 mL of triethylamine, and 15 mL of DMSO to dissolve it, add 0.6 g of dicyclohexylcarbodiimide (DCC), 0.26 g of N-hydroxysuccinimide (NHS), and stir at room temperature away from light. Overnight, filter to remove by-products. Then add 5g polyethylene glycol (molecular weight 4000) monostearate, heat to 35°C to dissolve, and react at 35°C overnight to obtain a crude product. Pour it into a dialysis bag with a molecular retention of 3,500, place it in a 500 mL beaker filled with water, stir, dialyze for two days, and freeze-dry it.

[0034] The synthetic route is as follows:

[0035]

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

Example Embodiment

[0037] Example 2: Oxaliplatin folic acid targeting 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 minutes, sonicate for 20 minutes, and remove organic solvents by rotary evaporation at 40°C until the gel collapses. Then, add 50 mL of an aqueous solution containing 580 mg of folic acid-polyethylene glycol monostearate and 400 mg of F68 according to the components, continue to evaporate for 30 minutes, homogenize under high pressure at 400 bar, 5 minutes, and dilute to 100 mL with water, then The tangential flow ultrafiltration method was used to separate free oxaliplatin, and the tangential flow membrane bag with a molecular retention of 10K was used for ultrafiltration. Water was used as the replacement liquid. The ultrafiltration was repeated 3 times, and the bag was measured by the ultrafiltration centrifuge tube method. The final drug concentra...

Example Embodiment

[0039] Example 3: Investigation of the particle size and pH value of the oxaliplatin folate targeting liposome obtained in Experimental Example 2

[0040] In this study, a laser particle size analyzer was used to determine the particle size and distribution of the oxaliplatin folic acid targeting liposomes in Example 2, 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. Image 6 . After the sample is diluted, the variability is small, the particle size range is still narrow, and the distribution is unimodal. The pH value of the oxaliplatin folic acid targeting liposome solution measured with a pH meter was 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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