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Preparation and application methods of difunctional naonparticle preparation entrapping vincristine sulphate

A vincristine sulfate and nanoparticle technology, applied in the field of medicine, can solve the problems of wide particle size distribution, no significant improvement in curative effect, and low targeting

Inactive Publication Date: 2010-12-29
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] After searching the prior art, it was found that there are several PEGylated vincristine sulfate liposomes (Rodriguez M.A., Pytlik R., Kozak T., et al. Cancer 2009, 115:3475-3482; Thomas D.A., Sarris A.H., Cortes J., et al.Cancer 2006, 106:120-127) have entered the stage of preclinical experiments, although this type of liposome can achieve long-term circulation in vivo, but the particle size is relatively large, generally above 500nm , some particles have a particle size as high as tens or even hundreds of microns, and the particle size distribution is very wide
After such large particles enter the body, due to the lack of vascular permeability, they are easily swallowed by the reticuloendothelial system and difficult to reach the tumor site, resulting in low targeting. Therefore, compared with the traditional vincristine sulfate injection, The curative effect was not significantly improved (Tokudome Y., Oku N., Doi K., et al. Biochim. Biophys. Acta. 1996, 1279: 70-74)

Method used

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  • Preparation and application methods of difunctional naonparticle preparation entrapping vincristine sulphate
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  • Preparation and application methods of difunctional naonparticle preparation entrapping vincristine sulphate

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Embodiment 1

[0034]Polymers PLGA-PEG-folate and PLGA-PEG-R 7 synthesis, such as figure 1 As shown, it specifically includes the following steps:

[0035] 1) Starting from HO-PEG-OH, through three steps, the polymer NH 2 -PEG-NH 2 ;

[0036] 2) Using chloroform as a solvent, NHS as an activation reagent, and DIC as a condensation agent to make NH 2 -PEG-NH 2 Conjugate with PLGA-COOH to get PLGA-PEG-NH 2 , the above synthesis process see figure 1 A;

[0037] 3) Using chloroform as a solvent, DIC as a condensation agent, and 4-dimethylaminopyridine (DMAP) as a catalyst, succinic anhydride and PLGA-PEG-NH 2 Condensation to obtain PLGA-PEG-succinate;

[0038] 4) using DMF as a solvent, the heptameric arginine (R 7 -NH 2 ) reacted with PLGA-PEG-succinate to obtain cell-penetrating peptide modified PLGA-PEG (PLGA-PEG-R 7 ); 1 See HNMR figure 2 c. In the second step reaction, the molar ratio of PLGA-COOH / NHS / DIC is: 1 / 5 / 5~1 / 10 / 10. 3) and 4) step synthesis process see figure 1 b. ...

Embodiment 2

[0041] The preparation of the PLGA-PEG bifunctional nanoparticles modified by folic acid / cell penetrating peptide comprises the following steps:

[0042] (1) Dissolve vincristine sulfate in Tris-HCl buffer solution with pH (5-7.4) to form a concentrated solution (referred to as phase I). The three polymer carriers PLGA-mPEG, PLGA-PEG-folate and PLGA-PEG-R 7 (mass ratio 7 / 2 / 1) dissolved in an organic solvent (dichloromethane, or chloroform, or ethyl acetate) (referred to as phase II). The ratio of the buffer solution to the organic solvent is 1 / 10-1 / 30. Theoretically, the dosage of vincristine sulfate is 4-9% (w / w);

[0043] (2) Ultrasound, under the condition of ice-water bath, add phase I dropwise to phase II to obtain colostrum;

[0044] (3) Ultrasound, under the condition of ice-water bath, add the above-mentioned colostrum dropwise to the Tris-HCl buffer solution containing 0.6-2.5% PVA (w / v), pH 5-7.4, to obtain w / o / w double emulsion ;

[0045] (4) stirring at room t...

Embodiment 3

[0052] Release of folate / cell-penetrating peptide-modified PLGA-PEG bifunctional nanoparticles

[0053] Take 0.5mL of the bifunctional nanoparticle solution, put it in a dialysis bag (5000-10000Da), put it in a release medium (phosphate buffer or Tris-HCl buffer) with a volume of 30mL, shake it on a constant temperature shaker at 37°C, and use it for regular sampling. The content of VCR in the release medium was determined by high performance liquid chromatography, and the cumulative release percentage was calculated. see release curve Figure 4 .

[0054] Through the study of the release properties of the samples in two release media, the results showed that, in the first 8 hours, VCR appeared burst release in phosphate buffer (pH 6.8); in 8-20 hours, VCR showed a steady release; but after more than 20 hours, due to VCR has poor stability in phosphate buffered saline, but the concentration decreases slowly, and the cumulative release decreases accordingly ( Figure 4 A). ...

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Abstract

The invention relates to a preparation method of a difunctional naonparticle preparation entrapping vincristine sulphate, which belongs to the technical field of medicine. The difunctional naonparticle preparation is prepared by entrapping the vincristine sulphate in a PLGA-PEG polymer carrier modified by folic acid / cell-penetrating peptide through a multiple emulsion method. The difunctional naonparticle preparation shows favorable pharmacokinetic behaviors in vitro and vivo. The diameter of the prepared PLGA-PEG difunctional naonparticle modified by folic acid / cell-penetrating peptide is 287.2+ / -0.8nm, and the difunctional naonparticle preparation has high drug loading rate, high entrapment rate and good stability.

Description

technical field [0001] The invention relates to a preparation in the technical field of medicine and a preparation and application method thereof, in particular to a preparation and application method of a bifunctional nanoparticle preparation carrying vincristine sulfate. Background technique [0002] Vincristine is an active ingredient extracted from the vinca flower of the Apocynaceae plant. Its free form is extremely unstable, so it often exists in its sulfate form (vincristine sulfate, VCR). The target of anti-tumor effect is microtubules. In the S phase of the cell cycle, VCR binds to tubulin, thereby stopping the cell division in the metaphase, resulting in a significant increase in the cell population in mitosis, and stopping the cell division in the M phase, so it is the M phase Cell Cycle Specific Drugs. It can also interfere with protein metabolism and inhibit the activity of RNA polymerase, and inhibit the synthesis of cell membrane lipids and the transport of ...

Claims

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Application Information

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IPC IPC(8): A61K9/14A61K47/42A61K47/34A61K31/475A61P35/00
Inventor 沈琦李绍顺陈家念
Owner SHANGHAI JIAO TONG UNIV
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