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Polyethylene glycol modified tumor angiogenesis inhibitor HM-1 and application thereof

An angiogenesis-inhibiting, polyethylene glycol technology, applied in non-active ingredients medical preparations, active ingredients-containing medical preparations, anti-inflammatory agents, etc. short and so on

Inactive Publication Date: 2016-06-08
NANJING ANJI BIOLOGICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In view of the shortcomings of the existing angiogenesis inhibitor polypeptide HM-1, such as short half-life, high plasma clearance rate, and frequent administration, the present invention provides a polyethylene glycol-modified angiogenesis inhibitor HM-1 and its application. HM-1 has undergone PEG modification, but during the PEG modification process, the reaction conditions will affect the yield of the modified product, the type of product and the stability of PEG

Method used

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  • Polyethylene glycol modified tumor angiogenesis inhibitor HM-1 and application thereof
  • Polyethylene glycol modified tumor angiogenesis inhibitor HM-1 and application thereof
  • Polyethylene glycol modified tumor angiogenesis inhibitor HM-1 and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Preparation and Test of Angiogenesis Inhibitor Polypeptide HM-1

[0084] Polypeptide HM-1 was synthesized by solid-phase synthesis, separated and purified by preparative HPLC, and its purity was determined by analytical RP-HPLC.

[0085] Polypeptide HM-1 solid-phase synthesis method uses Fmoc-wang-resin or Fmoc-CTC-resin as the starting material, and then connects dipeptide to thirteen peptides in sequence with protected amino acids. After the peptide connection is completed, it is fully washed, and then the peptide is cut. , post-treatment to obtain crude angiogenesis inhibitors. The crude product was dissolved, purified twice by preparative high-performance liquid phase, concentrated and freeze-dried to obtain the pure product, and finally purified for the third time to obtain the refined peptide product. The method can not only ensure the synthesis efficiency, but also improve the product purity.

[0086] 1. The steps of receiving peptide are as follows:

[0087] ...

Embodiment 2

[0110] Steps for modifying HM-1 with polyethylene glycol

[0111] 1. Steps of modifying HM-1 with mPEG-SC

[0112] 1. mPEG-SC 5k Reaction with HM-1

[0113] Weigh 0.25gmPEG-SC respectively 5k and 40 mg of HM-1 (molar ratio: 1.5:1) were placed in 40 mL-100 mL of PBS buffer solution prepared at pH 8.0-8.5, and reacted overnight at 4°C.

[0114] 2. mPEG-SC 10k Reaction with HM-1

[0115] Weigh 0.5gmPEG-SC respectively 10kand 40 mg of HM-1 (molar ratio: 1.5:1) were placed in 40 mL-100 mL of PBS buffer solution prepared at pH 8.0-8.5, and reacted overnight at 4°C.

[0116] 3. mPEG-SC 20k Reaction with HM-1

[0117] Weigh 1gmPEG-SC respectively 20k and 40 mg of HM-1 (molar ratio: 1.5:1) were placed in 40 mL-100 mL of PBS buffer solution prepared at pH 8.0-8.5, and reacted overnight at 4°C.

[0118] 4. mPEG-SC 40k Reaction with HM-1

[0119] Weigh 2gmPEG-SC respectively 40k and 40 mg of HM-1 (molar ratio: 1.5:1) were placed in 40 mL-100 mL of PBS buffer solution prepared...

Embodiment 3

[0148] Separation and purification steps of polyethylene glycol modified HM-1

[0149] 1. Separation

[0150] The reacted sample was purified by semi-preparative high-performance liquid phase (HPLC, Beijing Innovation Tongheng), and the purification conditions were:

[0151] Semi-preparative chromatographic column: YMC, 250mm×20mm (5μm filler);

[0152] Mobile phase: Phase A is acetonitrile, phase B is water;

[0153] Loading volume: 5mL;

[0154] Flow rate: 15mL / min;

[0155] Detection wavelength: 220nm;

[0156] Elution gradient: mPEG-SC 5k -HM-1, mPEG 2 -NHS 5k -HM-1, mPEG-ALD 5k -HM-1 and mPEG-bALD 5k - See elution gradient 1 (Table 10) for the elution gradient of HM-1; mPEG-SC 10k -HM-1, mPEG 2 -NHS 10k -HM-1, mPEG-ALD 10k -HM-1 and mPEG-bALD 10k - See elution gradient 2 (Table 11) for the elution gradient of HM-1; mPEG-SC 20k -HM-1, mPEG 2 -NHS 20k -HM-1, mPEG-ALD 20k -HM-1 and mPEG-bALD 20k - See elution gradient 3 (Table 12) for the elution gradient ...

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Abstract

The invention discloses a polyethylene glycol modified tumor angiogenesis inhibitor HM-1 and application thereof, and belongs to the field of polypeptide drugs. The peptide sequence adopted in the polyethylene glycol modified tumor angiogenesis inhibitor HM-1 is mPEG-Arg-Gly-Ala-Asp-Arg-Ala-Gly-Gly-Gly-Gly-Arg-Gly-Asp, wherein mPEG is mPEG-SC, mPEG2-NHS, mPEG-ALD or mPEG-bALD, and the molecular weight range is 500 to 40000. The polypeptide modified by polyethylene glycol has the capacity of restraining endothelial cell migration and integrin affinity and binding, and can be applied to prevention and treatment of tumours, various phlegmonosis and neovascular eye diseases. The polyethylene glycol modified tumor angiogenesis inhibitor is prepared through an artificial synthesis method.

Description

technical field [0001] The invention belongs to the field of polypeptide medicine, and more specifically relates to a polyethylene glycol-modified angiogenesis inhibitor HM-1 and its application. Background technique [0002] Angiogenesis refers to the proliferation and migration of vascular endothelial cells on the basis of existing capillaries and (or) venules, and the generation of new capillaries in the form of sprouting or non-sprouting from pre-existing vessels. Angiogenesis plays a very important role in the process of placenta formation, embryonic development and wound healing. But in many diseases, angiogenesis plays a crucial role, such as: tumors, various inflammations and eye diseases (such as AMD). [0003] Malignant tumors are the primary killer of human health. In recent years, the incidence and mortality of tumors in my country have been increasing. Unlimited growth, invasion, and metastasis are hallmarks of tumor malignancy and major causes of treatment fa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08A61K38/10A61K47/48A61P35/00A61P29/00A61P27/02A61P19/02A61P19/08
CPCC07K7/08A61K38/00A61K38/10A61K47/60A61P27/02A61P19/02A61P29/00A61P35/00A61K9/0019
Inventor 康志安王贝
Owner NANJING ANJI BIOLOGICAL TECH CO LTD
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