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Amphipathic compound using somatostatin analogue as target radical and pharmaceutics application thereof

A technology of amphiphilic compounds and somatostatin, which is applied in somatostatin, drug combinations, medical preparations of non-active ingredients, etc., can solve the problem of affecting drug efficacy, drug loss of targeting, and limiting the range of drug selection, etc. question

Inactive Publication Date: 2011-04-06
CHINA PHARM UNIV
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AI Technical Summary

Problems solved by technology

[0006] At present, there are few foreign reports on the application of SSA as a "targeting warhead" for tumors, mainly in the following two aspects: (1) combining SSA with antineoplastic drugs such as doxorubicin (Nagy A, Schally AV, Halmos G, et al. al.Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin[J].Proc Natl AcadSci USA, 1998,95(4):1794-1799.), paclitaxel (Sun ML, Wei JM, Wang X W, et al.Paclitaxel-octreotide conjugates inhibit growth of human non-small cell lung cancer cells in vitro[J].Exp Oncol, 2007,29(3):186-191.) and camptothecin (Moody TW, Fuselier J, Coy DH, et al. Camptothecin-somatostatin conjugates inhibit the growth of small cell lung cancer cells [J]. Peptides, 2005, 26 (9): 1560-1566.) are coupled by chemical bonds, although It has been proved to have better tumor tissue targeting and cytotoxicity, but there are the following problems: there must be reactive groups in the chemical structure of the drug, which greatly limits the range of drug selection; targeting molecules and drugs are generally 1: 1 or 1:2 coupling, that is, one target molecule can only target 1 to 2 drug molecules to tumor cells, and cannot achieve efficient targeted delivery of drugs; the firmness of chemical bonds directly affects its targeting effect in vivo
If it is easy to dissociate, the drug will lose its targeting; if it is too stable to reach the target cells, it will not be able to dissociate and release the active drug well, which will affect the efficacy of the drug.
Somatostatin analogs, polyethylene glycol and long-chain fatty acids / amines have not yet been coupled to make amphiphilic compounds with tumor targeting and long-circulation functions, and used as modifiers for anti-tumor drugs Literature and patent coverage of delivery systems

Method used

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  • Amphipathic compound using somatostatin analogue as target radical and pharmaceutics application thereof
  • Amphipathic compound using somatostatin analogue as target radical and pharmaceutics application thereof
  • Amphipathic compound using somatostatin analogue as target radical and pharmaceutics application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0058] Preparation of octreotide-polyethylene glycol-stearic acid (OCT-PEG-R, R is an alkyl chain) conjugate:

[0059] 1. Preparation of octreotide-polyethylene glycol (OCT-PEG) conjugate

[0060] (Boc)HN-PEG-COO-NHS(PEG 5000 ) was dissolved in acetonitrile (MeCN), octreotide was dissolved in N,N-dimethylformamide (DMF), then the PEG solution was added dropwise to the octreotide solution, and triethylamine (TEA ), stirred at 4°C for 12 h. The reaction solution was poured into cold diethyl ether, the precipitate was filtered and the filter cake was washed with a small amount of diethyl ether, and the product was obtained by vacuum drying. The reaction solution can also be purified by HPLC, then diluted with water and freeze-dried to obtain (Boc)HN-PEG-OCT.

[0061] 2. Preparation of Octreotide-Polyethylene Glycol-Stearic Acid (OCT-PEG-R)

[0062] (Boc)HN-PEG-OCT was dissolved in trifluoroacetic acid (TFA) in acetonitrile (MeCN) solution, stirred at room temperature for 4 ho...

Embodiment 2

[0064] Octreotide succinate-polyethylene glycol-stearylamine ((S-OCT)-PEG-R, R is an alkyl chain) coupling preparation:

[0065] 1. Preparation of stearylamine-polyethylene glycol (R-PEG)

[0066] (Boc)HN-PEG-COO-NHS(PEG 5000 ) was dissolved in MeCN, stearylamine was dissolved in DMF, and then the PEG solution was added dropwise to the stearylamine solution, and TEA was added to the above mixed solution, and stirred at 4°C for 12h. The reaction solution was poured into cold diethyl ether, the precipitate was filtered and the filter cake was washed with a small amount of diethyl ether, and the product was obtained by vacuum drying. The reaction solution can also be purified by HPLC and then diluted with water and freeze-dried to obtain (Boc)HN-PEG-R.

[0067] 2. Preparation of octreotide succinate-polyethylene glycol-stearylamine ((S-OCT)-PEG-R)

[0068] (Boc)HN-PEG-R was dissolved in the MeCN solution of TFA, stirred at room temperature for 4h, the reaction solution was dil...

Embodiment 3

[0070] Octreotide-polyethylene glycol-stearic acid (OCT-PEG-R) modified N-deoxycholic acid-N, O-hydroxyethyl chitosan polymer micelles loaded with doxorubicin

[0071] 1. Preparation of N-deoxycholic acid-N, O-hydroxyethyl chitosan micelles loaded with doxorubicin (ADR)

[0072] Take the carrier N-deoxycholic acid-N, O-hydroxyethyl chitosan 17mg, accurately weighed, add 3mL of water, swell at 50°C for 1h, add the ADR solution neutralized by TEA drop by drop, stir at room temperature, and sonicate in an ice bath After 30 minutes, filter to obtain the drug-loaded micellar solution.

[0073] 2. Preparation of drug-loaded micelles modified by OCT-PEG-R

[0074] Take 1 mg of R-PEG-OCT, dissolve it in water, add it dropwise to the above micellar solution, stir at room temperature for 30 minutes, and sonicate in an ice bath for 10 minutes. The obtained micellar solution was dialyzed against water for 6 hours to obtain a drug-loaded solution with tumor targeting and long-circulation f...

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Abstract

The invention belongs to the field of pharmaceutics, and particularly relates to a novel Amphipathic compound with tumour target and long-circulation functions. The compound is formed by coupling three parts of a target radical somatostatin analogue, hydrophile long-chain polyethylene glocyl and lyophobic alkyl chain fatty acid or fatty amine. The invention relates to a preparation method of the compound. The invention also relates to a drug delivering system which has the tumour target and long-circulation functions and is applied to micelle, liposome, nanometer particles, nanometer suspensions and micro emulsion as the modifier. The invention has the characteristics that (1) the tumour target function of the modified carrier can be improved through the endocytosis deviated by the somatostatin receptor, and (2) the hydrophilic long chain can improve the hydrophilia on the surface of the modified carrier and has long-circulation characteristic in the body.

Description

technical field [0001] The invention relates to a novel amphiphilic compound with tumor targeting and long circulation functions. The compound is formed by coupling three parts: a targeting group somatostatin analogue, a hydrophilic long-chain polyethylene glycol, and a hydrophobic alkyl chain fatty acid or fatty amine. The present invention relates to the preparation method of the compound, and the present invention also relates to its application as a modifier in micelles, liposomes, nanoparticles, nanosuspensions, and microemulsion preparations to obtain tumor-targeting functions and long-circulation properties drug delivery system. Background technique [0002] For a long time, for the clinical treatment of cancer patients, most of them use chemotherapy combined with surgery and radiotherapy. However, the antitumor drugs used in chemotherapy face the problems of high toxicity and side effects on normal tissues, rapid elimination from the blood, and low effectiveness du...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K14/655A61K47/18A61K47/22A61K45/00A61K9/00A61K9/127A61K9/14A61K9/10A61K9/107A61P35/00
Inventor 周建平霍美蓉姚成丽邹爱峰朱钦女
Owner CHINA PHARM UNIV
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