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Amphiphilic oligopeptide drug conjugate

A technology of oligomeric polypeptides and conjugates, which can be used in drug combination, drug delivery, pharmaceutical formulations, etc., can solve the problem of insufficient anti-tumor preparations, and achieve the effects of rich varieties, high yield and stable structure

Active Publication Date: 2016-02-03
NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is to solve the problem of insufficient anti-tumor preparations of existing drugs, and provide an amphiphilic oligomeric polypeptide drug conjugate with high drug loading, good biocompatibility, and long residence time in lesion sites. The hydrophilic oligomeric polypeptide-drug conjugates can spontaneously form highly ordered nanostructures in solution under the guidance of hydrophobic interactions, hydrogen bonds and electrostatic interactions, and can further form gels as the environment changes

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0029] Embodiment 1: Amphiphilic oligomeric polypeptide drug conjugate (Dox- Fmoc-KGFRWR: doxorubicin-fluorenylmethoxycarbonyl protected lysine-glycine-phenylalanine-arginine-tryptophan-arginine)

[0030] 1. Materials

[0031] Lysine (K) protected with fluorenylmethoxycarbonyl (Fmoc) and 4-methyl-trityl (Mtt), glycine (G) protected with tert-butoxycarbonyl (Boc), phenylpropanoid protected with Boc amino acid, Boc-protected arginine and tryptophan, N,N'-diisopropylcarbodiimide (DIC, 99%), 1-hydroxybenzotriazole (HOBt, 99%), 2- (1H-Benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 99%), N,N-dimethylaminopyridine (DMAP, 99%), 9-fluorenylmethoxycarbonyl (Fmoc, 99%), N,N-diisopropylethylamine (DIEA, 99%), triisopropylsilane (TIS), (3H-1,2,3-triazole [4,5-b]pyridine-3-oxyl)tris-1-pyrrolidinyl hexafluorophosphate (PyAOP), N,N-dimethylformamide (DMF, 99%), pyridine, piperidine , acetic anhydride, ninhydrin, king resin, acetonitrile, trifluoroacetic acid (TFA),...

Embodiment 2

[0039] Embodiment 2: the establishment of the standard curve of Dox-Fmoc-KGFRWR

[0040] Get the Dox-Fmoc-KGFRWR prepared in Example 1 and be formulated with 1mg / ml mother liquor, serially diluted to 5, 10, 50, 100, 250, 500ug / ml, enter high-performance liquid phase (HPLC), record peak area, draw standard curve , see Figure 4 .

Embodiment 3

[0041] Example 3: Transmission Electron Microscopy (TEM) Inspection of Dox-Fmoc-KGFRWR Self-Assembly at Different pH Values

[0042] (1) Hydrochloric acid and sodium hydroxide solution adjust the pH value of the aqueous solution to 3 and 7 respectively, and set aside. Weigh an appropriate amount of Dox-Fmoc-KGFRWR from Example 1 and add it into prepared solutions with different pH values ​​to make a 500uM solution, and let it stand for several days.

[0043] (2) First, drop the prepared sample to be tested on the 400-mesh copper grid, use it for a while, take out the copper grid with tweezers, absorb the excess liquid with filter paper, put the copper grid on the phosphotungstic acid stain for about 90 seconds, and use After taking out the copper mesh with tweezers, suck off the excess liquid with filter paper, place it to dry, prepare for the experiment, and observe its imaging situation with a transmission electron microscope, see Figure 5 , left to right are electron micr...

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Abstract

The invention discloses an amphiphilic oligopeptide drug conjugate. Hydroxyl or an amino group of the chemical structure of a drug and a carboxyl group at the end C of oligopeptide directly undergo a condensation reaction to produce an ester bond or an amido bond, or a carboxyl group of the chemical structure of a drug and an amino group at the end N of oligopeptide undergo a condensation reaction to produce an amido bond, or a certain bonding molecule of a drug and oligopeptide are bonded. Oligopeptide prepared from high-safety amino acids is used as a main construction material and is coupled with an anticancer drug so that the amphiphilic oligopeptide drug conjugate is prepared. Compared with the traditional preparation, the amphiphilic oligopeptide drug conjugate has good safety and a high drug loading capacity because of direct bonding of the drug and a carrier material, and can produce drug effects for a long time after entering into the human body.

Description

technical field [0001] The invention belongs to the field of polypeptide self-assembly, and particularly relates to an oligomeric polypeptide prepared from amino acid with high safety, which is used as a main construction material, coupled with an antitumor drug, and prepared as an oligomeric polypeptide drug conjugate (Amphiphilicpeptidedrugconjugate: APD). Background technique [0002] In my country, the annual incidence of liver cancer ranks third among all kinds of tumors, reaching 25.7 / 100,000, and the death toll due to liver cancer is 23.7 / 100,000. It is one of the major diseases that endanger the health of our people. Because patients with liver cancer are often complicated by liver fibrosis, it is difficult to perform surgical resection, so radiotherapy and chemotherapy are often used for treatment. Arterial embolization is a commonly used chemotherapy method for liver cancer in clinical practice, which can achieve local accumulation of chemotherapy drugs while block...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K9/00A61K9/06A61K31/704A61P35/00A61K31/337
Inventor 陈志鹏李伟东吴丽范亲
Owner NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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