PEG (polyethylene glycol)-polylysine/isothiocyanate bonding compound and application thereof as drug carrier

A technology of isothiocyanate and polyethylene glycol, which is applied in the field of anti-tumor nano-drugs, can solve the problems of poor stability of micelles and short half-life, and achieve enhanced anti-tumor effect, stability in vivo, and high drug loading rate Effect

Active Publication Date: 2019-07-23
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the pharmacokinetic evaluation shows that the Genexol-PM micelles have a short half-life in vivo, which is due to the poor stability of the micelles in the body, and in the circulation process in the body, various proteins dissociate the micelles, resulting in The loaded drug is released into the blood and eliminated

Method used

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  • PEG (polyethylene glycol)-polylysine/isothiocyanate bonding compound and application thereof as drug carrier
  • PEG (polyethylene glycol)-polylysine/isothiocyanate bonding compound and application thereof as drug carrier
  • PEG (polyethylene glycol)-polylysine/isothiocyanate bonding compound and application thereof as drug carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Embodiment 1: the synthesis of polyethylene glycol-polylysine polymer

[0070] The synthetic method of polyethylene glycol-dendritic polylysine polymer is as follows:

[0071] N,N'-di-tert-butoxycarbonyl-L-lysine (Boc-Lys(Boc)-OH, 25g, 72.2mmol) and 2,3,4,5,6-pentafluorophenol (PFP, 15.9g , 86.6mmol) was dissolved in dioxane, and N,N'-dicyclohexylcarbodiimide (DCC, 17.8g, 86.6mmol) was added at 0°C, and the reaction solution gradually rose to room temperature, stirred overnight, iso Recrystallized in propyl ether to obtain white solid N,N'-di-tert-butoxycarbonyl-L-lysine pentafluorophenol ester (Boc-Lys(Boc)-OPFP, 28.6g);

[0072] Methoxy polyethylene glycol amino (PEG 5k -NH 2 , 1g, 0.2mmol), Boc-Lys(Boc)-OPFP (0.31g, 0.6mmol) and N,N-diisopropylethylamine (DIPEA, 0.2mL, 0.6mmol) were dissolved in 20mL dry dichloro In methane, stirred overnight under the protection of nitrogen at room temperature, concentrated the reaction solution, and precipitated in glacial ethe...

Embodiment 2

[0076] Embodiment 2: Preparation of polyethylene glycol-polylysine / phenylethyl isothiocyanate linkage

[0077] Taking the preparation of the third-generation polyethylene glycol-dendritic polylysine / phenylethyl isothiocyanate bond (PEG-G3-PEITC) as an example, the amino molarity of PEG-G3 and styrene The molar ratio of phenylethyl isothiocyanate is 1:1. Feeding: PEG-G3 (500mg, 0.073mmol) and phenylethyl isothiocyanate (PEITC, 100mg, 0.613mmol) are dissolved in 4mL of dimethyl sulfoxide , add 120 μL of triethylamine (Triethylamine, TEA, Mw=101.19), and react at 45° C. for 12 h. The reaction solution was put into a dialysis bag (molecular weight cut-off 3500), dialyzed against methanol for 24 hours, the methanol was removed by rotary evaporation under reduced pressure, and precipitated in ether to obtain a white powder, which was designated as PEG-G3-PEITC. Using deuterium band dimethyl sulfoxide as a solvent, the structure of the bond was characterized by NMR, 1 H NMR spectru...

Embodiment 3

[0084] Example 3: Polyethylene glycol-polylysine / phenylethyl isothiocyanate bonded paclitaxel

[0085] Encapsulation of anti-tumor drugs by thin film hydration method:

[0086] PEG-G3-PEITC (7.5 mg) and paclitaxel (2.5 mg) were dissolved in 1 mL of acetonitrile, and rotovaped at 40° C. under reduced pressure to form a film. Then, isothermal deionized water (2.5 mL) was slowly added dropwise while stirring to form nanomicelles, which were denoted as PEG-G3-PEITC / PTX, and its dynamic light scattering pattern in water (the content of PTX 1mg / mL) was as figure 2 As shown in (a), it can be seen from the figure that the particle size distribution of nano micelles is 0.130, the potential is -6.69mV, and the average size is 31.03nm. PEG-G4-PEITC-loaded paclitaxel micelles were prepared in the same way.

[0087] The morphology of PEG-G3-PEITC / PTX micelles was observed by transmission electron microscope (TEM). image 3 As shown in (left), spherical particles with a diameter of abou...

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Abstract

The invention discloses a PEG (polyethylene glycol)-polylysine / isothiocyanate bonding compound and further provides a preparation method of the bonding compound. The preparation method comprises stepsas follows: (1), a PEG-polylysine block polymer is prepared by ring opening polymerization, or PEG-dendritic polylysine is prepared by a condensation reaction; (2), PEG-polylysine prepared in step (1) is subjected to a reaction with isothiocyanate compounds, and the PEG-polylysine / isothiocyanate bonding compound is prepared. The prepared bonding compound is good in biocompatibility and high in bio-safety, has controllable hydrophilcity and hydrophobicity and can be taken as a drug delivery carrier with hydrogen bond interaction, and nanomicelles which are distributed uniformly and coated tightly can be prepared from the carrier, are high in drug loading ratio, small in particle size and stable in vivo and have low systemic toxicity and long cycling time.

Description

technical field [0001] The invention belongs to the technical field of anti-tumor nano-medicine, and in particular relates to a polyethylene glycol-polylysine / isothiocyanate bond and its application as a drug carrier. Background technique [0002] Clinical anti-tumor chemotherapy drugs such as paclitaxel, vincristine, doxorubicin and camptothecin have problems such as poor water solubility, high toxicity and side effects, and no targeting. Nano drug delivery system can solve the above problems, prolong the half-life of drugs in the blood circulation system, improve drug targeting and reduce drug side effects. Commonly used nano-drug systems include polymer micelles, polymer-drug conjugates, liposome nanoparticles, protein nanoparticles, etc. At present, a variety of nano-drugs have been approved for marketing or clinical research. [0003] Paclitaxel antineoplastic drugs can inhibit tubulin depolymerization, thereby inhibiting cell mitosis, and have been used in the treatme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G69/48C08G69/40C08G83/00A61K9/107
CPCA61K9/1075A61K47/34C08G69/40C08G69/48C08G83/004
Inventor 申有青吴碧寒相佳佳朴莹
Owner ZHEJIANG UNIV
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