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Targeted drug delivery system for brain glioma as well as preparation method and use thereof

A glioma and nano-drug delivery system technology is applied to the glioma targeted drug delivery system modified by nucleic acid aptamer AS1411 and the field of preparation thereof, and can solve the problem of low drug loading, neurotoxicity and side effects, and excipients. Problems such as large injection dose to achieve the effect of inhibiting tumor growth and enhancing the inhibitory effect

Inactive Publication Date: 2016-12-14
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this preparation still has the disadvantages of low drug loading and large injection dose of excipients, which leads to strong systemic toxicity and side effects, and its curative effect needs to be further improved.
At present, there are still many problems in the treatment of brain tumors in the paclitaxel nano-delivery system: due to the hindering effect of the blood-brain barrier, it is difficult for 98% of small-molecule drugs and almost all macromolecular drugs to enter the central nervous system; distribution, it is difficult to concentrate to the lesion, and it may also cause toxic side effects on the normal nerve center
However, although the polymer bonded PGG-PTX has good water solubility, its drug loading capacity cannot meet the clinical needs of high drug loading capacity. Increasing the drug dose to increase the efficacy of the drug will also increase the systemic side effects of the drug.

Method used

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  • Targeted drug delivery system for brain glioma as well as preparation method and use thereof
  • Targeted drug delivery system for brain glioma as well as preparation method and use thereof
  • Targeted drug delivery system for brain glioma as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Preparation of polyglutamyl glutamic acid PGG:

[0051] 1) Sodium polyglutamate cPGA-Na (molecular weight 35000, 10g), tert-butyl butyl glutamate hydrochloride H-Glu (otBu) 2 HCl (38.3g, 0.148mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDC HCl (37.0g, 0.193mol), 1-hydroxybenzo Triazole HOBt (10.6 g, 0.074 mol) was dissolved in 500 mL of anhydrous N,N-dimethylformamide DMF, magnetically stirred at 700 rpm at 25°C for 24 h, and protected by argon. The reacted solution was slowly poured into 3 L of deionized water, and a white precipitate was precipitated, filtered, washed three times with 250 mL of deionized water, and freeze-dried for 15 hours to obtain a white solid.

[0052] 2) Transfer the product (60 g) obtained in step 1) to a 1 L round bottom flask, add 480 mL of trifluoroacetic acid TFA, and stir magnetically at 25° C. and 700 rpm for 4 h. TFA was removed by vacuum rotary evaporation at 40°C to obtain a yellow oily substance. After repeatin...

Embodiment 2

[0054] Preparation of polyglutamyl glutamic acid PGG-PTX:

[0055] Add polyglutamine glutamic acid PGG (10g) into 500mL of anhydrous N,N-dimethylformamide DMF, stir magnetically at 25°C and 700rpm for 30min until completely dissolved, then add 1-(3-dimethylaminopropyl base)-3-ethylcarbodiimide hydrochloride EDC·HCl (9.4g, 0.049mol) and 4-lutidine (2.6g), and continued to stir for 15min. Add paclitaxel PTX (5.4g) into the reaction bottle, and stir magnetically at 25°C and 700rpm for 26-28h. After the reaction is complete, slowly pour the reaction solution into 1.5L hydrochloric acid aqueous solution (0.2M) in an ice-bath environment, and a white precipitate precipitates, 5000rpm After centrifugation for 10 min, the resulting white precipitate was dissolved in 1.5 L of sodium bicarbonate (0.5 M) aqueous solution, and then transferred to a dialysis bag (MWCO 10,000) for dialysis for 24 h, during which all deionized water was replaced every 4 hours. When the resistivity of the so...

Embodiment 3

[0058] Preparation of polyglutamine glutamic acid-paclitaxel covalent bond AS1411-PGG-PTX modified by nucleic acid aptamer AS1411:

[0059] 1) Dissolve 8mg (10nmol) of polyglutamine glutamic acid-paclitaxel covalent bond PGG-PTX in 1mL of 2-(N-morpholine)ethanesulfonic acid buffer solution MES buffer (pH 6.0, 0.1M) , where the concentration of PGG-PTX was 10 μM. Then add 200mM 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDC·HCl and 200mM N-hydroxysuccinimide NHS in sequence, stir at 25°C and 400rpm After 30 minutes, the carboxyl groups on the surface of PGG-PTX were activated, and the mixed solution changed from transparent and clear to white and turbid.

[0060] 2) Transfer the solution obtained in step 1) to a 4mL ultrafiltration tube (molecular weight cut-off: 30000), wash with DNA / RNase-free distilled water DNase / RNase free water, remove EDC / NHS, and use 4mL of DNase / RNase free water / time, the centrifugal force is 2500g, 5min / time, repeat this step 4 tim...

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Abstract

The invention discloses a targeted drug delivery system for a brain glioma, as well as a preparation method and use of the targeted drug delivery system for the brain glioma. The drug delivery system comprises targeting molecules, a polymer carrier and a drug, wherein the targeting molecules are aptamers AS1411, the polymer carrier is PGG (polyclonal gamma globulin), and the drug is PTX (paclitaxel); PGG and PTX are combined to a PGG-PTX covalent bond complex through a covalent bond; the aptamers AS1411 are covalently linked with carboxyls on the surface of PGG-PTX through primary amino modified by the 5'ends of the aptamers AS1411 to form an AS1411-PGG-PTX covalent bond complex modified by the aptamers AS1411 which has a structure of the following formula. The targeted drug delivery system disclosed by the invention can target brain glioma tissues and neovascular endothelial cells simultaneously to effectively improve the drug accumulation in tumor sites and increase the drug concentration in tumor cells so as to enhance the antitumor treatment effect of the drug. The targeted drug delivery system is easily and automatically assembled into nanoparticles to improve the accuracy of PTX chemotherapy and reduce side effects of PTX in clinical application.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a brain-targeted drug delivery system, in particular to a brain glioma-targeted drug delivery system modified by nucleic acid aptamer AS1411 and a preparation method thereof. The drug delivery system can target brain glioma tissue and neovascular endothelial cells at the same time, effectively improve the accumulation of drugs in the tumor site, thereby improving the effect of chemotherapy. Background technique [0002] According to the statistics of the World Health Organization, the global incidence of malignant brain tumors is 3.5 / 100,000, among which Glioblastoma multiforme (GBM) is one of the most common primary malignant tumors with the highest mortality in the brain , accounting for about 40% of the incidence of brain tumors, the average survival period is only 14 months. The traditional clinical treatment method is surgical resection, but because the brain tumor ...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/337A61P35/00
CPCA61K31/337
Inventor 俞磊罗子淼庞志清闫志强王镜朱建中王依婷
Owner EAST CHINA NORMAL UNIVERSITY
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