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Nanoparticle compound with tumor microenvironment responsive deformation

A combination and drug technology, applied in anti-tumor drugs, drug combinations, drug delivery, etc., can solve the problem of poor tumor site retention time, and achieve the effects of stable structure, small side effects, and high drug loading.

Active Publication Date: 2020-11-17
NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are certain risks in the intravenous injection of nanofibers and nanogels, and it is difficult to be used clinically for intravenous administration
[0004] Nanoparticles or micelles can often be used for systemic drug delivery. Due to the EPR effect at the tumor site, nanoparticles or micelles can penetrate the capillaries well into tumor cells, but their residence time in the tumor site is far less than that of nanofibers.

Method used

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  • Nanoparticle compound with tumor microenvironment responsive deformation
  • Nanoparticle compound with tumor microenvironment responsive deformation
  • Nanoparticle compound with tumor microenvironment responsive deformation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Preparation of Amphiphilic Oligomeric Polypeptide Drug Conjugate Dox-Suc-KIGLFRWR

[0040] 1. Materials

[0041] 9-Wat methoxycarbonyl (Fmoc) protected glycine (G), Fmoc protected phenylalanine (F), Fmoc and tert-butoxycarbonyl (Boc) protected tryptophan (W), Fmoc protected leucine Amino acid (L), Fmoc and 2,2,4,6,7-pentamethyl-2H-benzofuran-5-sulfonyl (Pbf) protected arginine (R), Fmoc protected isoleucine Acid (I), Fmoc and 2-(4,4-dimethyl-2,6-dioxocyclohexylmethylene)ethyl protected lysine (K), Rink Amide-AM Resin (100 -200 mesh, substitution coefficient: 0.486mmol / g), O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU, 99%); N,N-diisopropylethylamine (DIEA, 99 %); piperidine (Piperidine, 99%), N,N-dimethylformamide (DMF, 99%), triethylamine; triisopropylsilane (Tis, 99%); trifluoroacetic acid (TFA, 99%).

[0042] 2. Preparation method

[0043] Using conventional solid-phase synthesis methods, oligomeric polypeptides are synthesized, and then t...

Embodiment 2

[0049] Example 2: Transmission electron microscopy (TEM) examination of Dox-Suc-KIGLFRWR self-assembly

[0050] Dox-Suc-KIGLFRWR solution with a concentration of 100 μM was prepared. After 0, 1, 6, and 12 hours of assembly, the solution was dropped onto a copper mesh coated with a support film for 60 s, and the excess solution was absorbed with filter paper. After negative staining with uranyl acetate stain for 90 s, use filter paper to absorb excess dye solution, dry naturally, and place it under a transmission electron microscope for observation, see figure 2 , from left to right are the electron microscope images of assembly 0h, 1h, 3h, and 6h, respectively. It can be seen from the figure that the peptide-drug conjugate self-assembles to form spherical micelles with a size of 40-50 nm at 0 h. After 1 h, the micelles further aggregate to form primary fibers. After 6 h, the fibers are intertwined and aggregated, indicating that the synthesized polypeptide-drug The conjugate...

Embodiment 3

[0051] Example 3: Preparation of FB-Dox-Suc-KIGLFRWR-NPs

[0052] 1. Materials

[0053] 2,3-Dimethylmaleic anhydride (DMMA, 99%), ε-polylysine (ε-PL, Mw: 3000-5000), triethylamine, N-hydroxysuccinimide (NHS, 99 %), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 99%); ordinary dialysis bag (molecular weight 2000D), pure water, glacial acetic acid.

[0054] 2. Preparation method

[0055] (1) Synthesis of β-carboxyamide polylysine (FB):

[0056] Add 180 mg of DMMA to 15 mL of ε-polylysine aqueous solution dissolved in 160 mg, add triethylamine to adjust the pH to be alkaline, add 190 mg of NHS after stirring and dissolving, add 240 mg of EDCI after dissolving, and stir and add triethylamine , keep the pH value of the reaction system at 8.5-9, and react overnight. The reaction solution was transferred into the activated dialysis bag (molecular weight 2000D), pure water was used as the dialysis medium, the volume ratio was 1:1000, and the dialysis medium was...

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Abstract

The invention discloses a nanoparticle compound with tumor microenvironment responsive deformation. The nanoparticle compound is formed by combining an amphiphilic oligo-polypeptide drug conjugate andbeta-carboxylic acid amide polylysine through electrostatic interaction. The amphiphilic oligo-polypeptide drug conjugate is a product obtained by condensation of an anti-cancer drug adriamycin and an oligo-polypeptide KIGLFRWR through a chemical bond. The nanoparticle compound can be passively gathered at a tumor site in a targeted manner; under the acidic pH condition of a tumor region, a beta-carboxylic acid amide group connected to polylysine is broken, charge of the polylysine is changed into positive charge from negative charge, and the polylysine repels the amphiphilic oligo-polypeptide drug conjugate with positive charge, so that the nanoparticle compound is dissociated; and then the amphiphilic oligo-polypeptide drug conjugate can be further assembled into a long fiber, so that long-time retention is achieved at the tumor site, the drug adriamycin is slowly released, and the efficient anti-cancer effect is achieved.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to a nanoparticle complex that deforms in response to tumor microenvironment, which is formed by electrostatically combining an amphiphilic oligomeric polypeptide drug conjugate and β-carboxylic acid amide polylysine. Background technique [0002] Cancer is the second leading cause of death in the world. In 2015, the number of new cancer cases in my country reached 4.29 million, accounting for 20% of the 21.45 million new cases in the world that year. In the same year, there were 8.8 million cancer deaths worldwide, including 2.81 million cancer deaths in my country. The rate is the highest in the world. Although humans have made good progress in anti-tumor therapy in the past few decades, cytotoxic chemotherapeutic drugs (such as doxorubicin, etc.) commonly used in clinical tumor treatment still suffer from poor targeting and difficulty in accumulating at tumor sites. Pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K31/704A61K47/64A61P35/00
CPCA61K31/704A61K47/6935A61K47/645A61P35/00
Inventor 陈志鹏王晶晶徐柳李伟东吴丽李亚荣
Owner NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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