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Hypoxic tumor targeted short chain polypeptide micromolecule self-assembly nanometer material and preparation method and application thereof

A nanomaterial and self-assembly technology, which is applied in the preparation method of peptides, antineoplastic drugs, chemical instruments and methods, etc., can solve the problems of lack of hypoxia and cancer treatment, and achieve inhibition of angiogenesis, promotion of intracellular uptake, strong inhibition of The effect of potency

Active Publication Date: 2019-12-20
THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, until now, self-assembled molecular nanomaterials based on short peptides are lacking in the application of hypoxic cancer therapy.

Method used

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  • Hypoxic tumor targeted short chain polypeptide micromolecule self-assembly nanometer material and preparation method and application thereof
  • Hypoxic tumor targeted short chain polypeptide micromolecule self-assembly nanometer material and preparation method and application thereof
  • Hypoxic tumor targeted short chain polypeptide micromolecule self-assembly nanometer material and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] This example is used to illustrate the synthesis of isothiocyanate-benzenesulfonamide.

[0107] 4-(2-Aminoethyl)benzenesulfonamide (0.5 mmol) was dissolved in 1 mL of DMF, and triethylamine (3 mmol) was added to the above solution. 1,1'-thiocarbonyldiimidazole (1 mmol) was dissolved in 1.5 mL of DMF at 50°C, and added dropwise to the above solution. The solution was stirred continuously at room temperature for 30 min, then washed with dd H 2 O quenching. The product was first extracted with ethyl acetate and then purified by silica gel chromatography (ethyl acetate-hexane). NMR information is as follows: 1 H NMR (400MHz, DMSO-d 6 ) δ7.79(d, J=7.8Hz, 2H), 7.49(d, J=7.8Hz, 2H), 7.35(s, 2H), 3.96(t, 2H), 3.04(t, 2H).

Embodiment 2

[0109] This example is used to illustrate the synthesis of 2-naphthaleneacetic acid-(D)-Phe-(D)-Phe-(D)-Lys-OH.

[0110] Short peptide hydrogels were prepared by standard solid-phase peptide synthesis (SPPS), that is, 2-chlorotrityl chloride resin (1.10mmol / g) and with side chain amino groups protected by tert-butoxycarbonyl, and Fmoc protected It is prepared by reacting various D-type amino acids of the main chain amino group. The resin was swollen by bubbling nitrogen gas in anhydrous dichloromethane (DCM) for 30 minutes, then washed three times with 5 mL of dry N,N-dimethylformamide (DMF). A mixed solution (1 mL DMF) of the first Fmoc-protected amino acid (2eqv. Fmoc-D-Lys-Boc-OH) and N,N-diisopropylethylamine (DIPEA) was then added and passed through the solution by bubbling Soak the resin to react with the amino acid C-terminus for 40 minutes. The resin was then washed three times with 5 mL of DMF. Blocking solution (16:3:1 DCM / MeOH / DIPEA) was then added to the resin t...

Embodiment 3

[0113] This example is used to illustrate the synthesis of 2-naphthaleneacetic acid-(D)-Phe-(D)-Phe-(D)-Lys-(benzenesulfonamide)-OH.

[0114] Add 0.3 mmol of the short peptide small molecule prepared in the above-mentioned Example 2 to methanol (6 mL) and dd H 2 O (1 mL), then 1M NaOH was added to adjust the pH to 8, the activated isothiocyanate-benzenesulfonamide (0.33 mmol) was dissolved in methanol (1 mL) and added to the in the mixed solution. The mixture was stirred overnight at room temperature. The obtained crude product was purified by high performance liquid chromatography HPLC.

[0115] NMR information is as follows: 1 H NMR (400MHz, DMSO-d 6 )δ8.25(d, J=8.1Hz, 1H), 8.13(d, J=8.3Hz, 1H), 7.85(d, J=7.4Hz, 1H), 7.80–7.76(m, 1H), 7.75( d,J=2.9Hz,2H),7.73(d,J=3.5Hz,2H),7.58(s,1H),7.50–7.44(m,2H),7.43(d,2H),7.30–7.12(m ,10H),4.61–4.55(m,2H),4.54–4.46(m,1H),4.20(dd,1H),),3.59(s,2H),3.53(dd,J=35.9,14.0Hz,2H ),3.08–3.03(m, 2H),2.95–2.79(m,2H),2.69(dd,J=13.4,10.3Hz,1H)...

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Abstract

The invention provides a preparation method and application of a hypoxic tumor region targeted short chain polypeptide micromolecule self-assembly nanometer material. The nanometer material is a shortchain polypeptide modified micromolecule carbonic anhydrase inhibitor, wherein an N end of short chain polypeptide is combined with a substituted or unsubstituted aromatic group. Through targeting carbonic anhydrase expressing film height of hypoxic tumor cells, tumor microenvironment in situ responsive self-assembly is realized, and specific internalization of the hypoxic tumor cells is induced,so that the hypoxic tumor cells are adjusted, controlled, killed and damaged. The material is simple in preparation technology, has higher biological safety biological safety, can effectively kill and damage the hypoxic tumor cells, can significantly improve conventional clinical chemotherapy treatment effects, can retard tumor metastasis process and can provide more thinking and means for clinical tumor treatment.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a short peptide small molecule self-assembled nanomaterial targeting hypoxic tumors, a preparation method and application thereof. Background technique [0002] As a common feature in various solid tumors, the tumor hypoxic microenvironment has far-reaching clinical significance in tumor multidrug resistance and cancer cell metastasis. At the same time, the tumor hypoxic microenvironment also suppresses the immune response and recruits tumor-associated macrophages, providing protection for the survival of tumor stem cells. During conventional tumor radiation therapy or chemotherapy treatment, the tumor microenvironment can significantly promote cancer cell survival. α-Carbonic anhydrase is a large family with 16 different phenotypes, among which carbonic anhydrase IX (CA IX) is highly dependent on the tumor hypoxic microenvironment and requires transcriptional acti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/54A61K31/145A61K45/00A61P35/00C07K5/087C07K1/16C07K1/107
CPCA61K47/542A61K31/145A61K45/00C07K5/0812A61P35/00
Inventor 陈春英李佳阳泽纳布·法哈蒂·沙贝特史可鉴
Owner THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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