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Multivalent cell-penetrating peptide biological macromolecule delivery vector and application thereof

A biomacromolecule and delivery carrier technology, applied in the field of a series of multivalent penetrating peptide delivery carriers and their complexes, and the multivalent penetrating peptide biomacromolecule delivery carrier field, can solve the problems of ocular tissue toxicity and low delivery efficiency. , to achieve the effect of strong ability to carry biological macromolecules, good biological safety, and high biological safety

Pending Publication Date: 2019-03-05
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The purpose of the present invention is to provide a class of artificially synthesized multivalent membrane-penetrating peptide biomacromolecule delivery in order to overcome the problems of low delivery efficiency and easy ocular tissue toxicity of polymer biomacromolecule delivery carriers in the prior art. Carrier and its preparation method

Method used

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  • Multivalent cell-penetrating peptide biological macromolecule delivery vector and application thereof
  • Multivalent cell-penetrating peptide biological macromolecule delivery vector and application thereof
  • Multivalent cell-penetrating peptide biological macromolecule delivery vector and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Preparation of multivalent peptide (multi-valent peptide): from 4-arm polyethylene glycol maleimide derivatives (4-arm PEG, molecular weight 5000±500Da) or 8-arm polyethylene glycol maleimide The amine derivative (8-arm PEG, molecular weight 10000±1000Da) is obtained by one-step reaction with N-terminal modified cysteine ​​penetratin (Cys-penetratin). Specifically, 4-arm PEG (1.0mg) was dissolved in phosphate buffer solution (10mM, pH7.2), Cys-penetratin (2.0mg) dissolved in the same medium was added under stirring, and stirring was continued overnight to allow the reaction completely. After the reaction was finished, the resulting mixture was dialyzed for 2 days under ice-bath conditions, and freeze-dried to obtain white floc 4-valent penetratin (4-valent penetratin, 4VP). 8-valent penetratin (8-valent penetratin, 8VP) was prepared by the same synthesis method;

[0068] The preparation method of other multivalent membrane-penetrating peptides is the same, which is ob...

Embodiment 2

[0073] Characterization of multivalent penetratin: Utilize high-performance liquid chromatography to carry out characterization, select Sepax Bio-C4 column (4.6 * 150mm, 5 μ m); Column temperature 25 ℃; Mobile phase acetonitrile (0.1% trifluoroacetic acid): water (0.1% trifluoroacetic acid) Acetic acid), 5-65% acetonitrile gradient, 30min; flow rate 0.8mL / min; detection wavelength 214nm; injection volume 20μL; sample concentration 5mg / mL;

[0074] The results showed that, compared with the multi-arm polyethylene glycol maleimide derivatives, the peak eluting time of multivalent penetratin was about 2min earlier, indicating that the polarity of the product increased. In addition, the liquid chromatogram also shows that the purity of the obtained product is above 95%;

[0075] In the proton nuclear magnetic spectrum characterization, the multi-arm polyethylene glycol maleimide derivative and the multivalent penetratin were dissolved in heavy water respectively, with a concentrat...

Embodiment 3

[0078] Cytotoxicity evaluation of multivalent penetratin: Take HCEC and NHC cells with good logarithmic phase growth state and press 5×10 3 cells / cm 2 Concentrations were placed in the middle 60 wells of a 96-well plate, and the edges were filled with sterile PBS buffer solution, at 37°C, 5% CO 2 Cultivate under certain conditions until the cell monolayer covers the bottom of the plate, discard the culture medium, wash with sterile PBS buffer 3 times, add 200 μL of culture medium containing different concentrations of multivalent penetratin, incubate in the cell culture box for 12 hours, discard the medicine solution, washed 3 times with sterile PBS buffer, and then added complete medium to continue culturing for 12 h. Then add 20 μL of MTT solution (5 mg / mL) to each well, continue to culture for 4 hours, carefully discard the liquid, wash with PBS buffer three times, add 150 μL DMSO to each well, shake at low speed on a shaker for 20 min, and place the plate at OD490nm on a ...

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Abstract

The invention belongs to the field of pharmaceutical preparations, and relates to a series multivalent cell-penetrating peptide delivery vector and a complex thereof, wherein the vector is built by the aid of multi-arm polyethylene glycol and cell-penetrating peptides or cell-penetrating peptide derivatives. The multivalent cell-penetrating peptide delivery vector has an octopus-like flexible structure, can be self-assembled with biological macromolecules, particularly genes to form the non-covalent complex and has strong biological macromolecule carrying, biological macromolecule delivery andocular tissue penetrating capacity, ocular tissue toxicity is avoided, biological macromolecule drugs can be effectively delivered to an intraocular portion or ocular fundus in a noninvasive way, andbiological macromolecule drug uptake by ocular tissues is increased. The complex formed by self-assembling the multivalent cell-penetrating peptide delivery vector with the biological macromoleculescan be used for eye drop administration, intraocular injection administration with poor compliance to patients can be replaced, and intraocular and ocular fundus disease treatment convenience and safety are enhanced.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a multivalent membrane-penetrating peptide biomacromolecule delivery carrier, in particular to a series of multivalent membrane-penetrating peptide delivery carriers constructed by using multi-arm polyethylene glycol and membrane-penetrating peptide or membrane-penetrating peptide derivatives and its compound. The multivalent membrane-penetrating peptide delivery carrier has an octopus-like flexible structure, can self-assemble with biomacromolecules, especially genes, to form non-covalent complexes, and has a strong ability to carry biomacromolecules, deliver biomacromolecules and ocular tissues Penetration ability, without ocular tissue toxicity, can realize the effective delivery of biomacromolecular drugs to the eye or fundus through non-invasive ways, and increase the uptake of biomacromolecular drugs by ocular tissues. technical background [0002] According to dat...

Claims

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Application Information

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IPC IPC(8): A61K47/42A61K47/10A61K48/00A61K39/395A61K38/21A61P27/02
CPCA61K38/212A61K39/395A61K47/10A61K47/42A61K48/0025A61K9/0048
Inventor 魏刚江宽陆伟跃高欣
Owner FUDAN UNIV
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