Reduction-sensitive-type water-soluble molecularly-targeted photosensitizer and preparation method and application thereof

A molecularly targeted, water-soluble technology, applied in the fields of biology and medicine, can solve the problem of poor photodynamic tumor inhibitory activity, achieve the effects of ensuring photodynamic activity, improving bioavailability, and reducing phagocytosis

Inactive Publication Date: 2016-02-24
THE THIRD AFFILIATED HOSPITAL OF THIRD MILITARY MEDICAL UNIV OF PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when investigating its photodynamic activity, the inventors found that although its tumor targeting and water-lipid solubility have been significantly improved, its photodynamic anti-tumor activity is not as good as that of the precursor compound mTHPC

Method used

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  • Reduction-sensitive-type water-soluble molecularly-targeted photosensitizer and preparation method and application thereof
  • Reduction-sensitive-type water-soluble molecularly-targeted photosensitizer and preparation method and application thereof
  • Reduction-sensitive-type water-soluble molecularly-targeted photosensitizer and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] The reduction-sensitive water-soluble molecular targeting photosensitizer described in the present invention is composed of a porphine structural unit with a hydroxyl group on the middle benzene ring through a carbonate bond, a disulfide bond, and a PEG amine and a folic acid structural unit combined by an amide bond. of conjugates.

[0055] The preparation method of the reduction-sensitive water-soluble molecular targeting photosensitizer of the present invention is carried out according to the following steps:

[0056] (1) First mTHPC, 2-(n-hydroxyalkyl) dithiopyridine and equimolar triphosgene condensation reaction in the dark, control the temperature and time of the reaction, purify, and obtain the porphine intermediate containing carbonate and disulfide bond Body; The general structural formula of porphine intermediate is shown in formula I:

[0057]

[0058] Among them, n=1-5.

[0059] (2) polyethylene glycol diamine (NH 2 PEGNH 2 ) and folic acid are conde...

Embodiment 2

[0070] The synthesis of embodiment 22-(2-hydroxyethyl)-dithiopyridine

[0071] Under the protection of argon, 250ml of sulfuryl chloride was added to 250ml of dry dichloromethane containing 25g of 2-mercaptopyridine, reacted at room temperature for 4h, and evaporated to dryness under reduced pressure. Newly add 200ml of dichloromethane to dissolve, add 50ml of dichloromethane (containing 17ml of 2-mercaptoethanol) dropwise to the above solution, react at 0°C for 30min, leave at room temperature overnight, evaporate to dryness under reduced pressure, add 2 times of 4-dimethylaminopyridine , stir. Column chromatography (SiO 2, dichloromethane: acetone = 40:1), to obtain 23.1g of product, yield: 54.87%. 1 HNMR (500MHz, CD 3 OD)δ9.97(s, 1H), 9.39(dd, J=20.7, 7.4Hz, 2H), 8.79(s, 1H), 5.34(t, J=4.8Hz, 2H), 4.50(t, J= 4.8Hz, 2H); MS (ESI): 188.0162 (M+1). The structural formula is as follows:

[0072]

Embodiment 3

[0073] Example 3 Porphine intermediate (5-{3-[(2-pyridinedithio)ethyl]oxycarbonyloxy}phenyl-10,15,20-three-(3-hydroxyphenyl)porphine) synthesis

[0074] Under the protection of argon, dissolve 1.36g of 2-dithioethyl alcohol pyridine, 1ml of triethylamine, and 0.72g of triphosgene in 200ml of dichloromethane. After reacting at room temperature for 20min, add dropwise to 15ml of acetonitrile (containing 4.5gm-THPC, 1ml of triethylamine), reacted at room temperature for 10 h, evaporated the solvent under reduced pressure, and separated by reverse-phase silica gel column chromatography (ODS-AQ, methanol) to obtain 906.5 mg, yield: 15.36%. UV-Vis (CH 3 OH,nm):414,514,540,594,648; 1 HNMR (500MHz, DMSO-d 6 )δ9.81,8.72~8.21(m,6H,CH,Pyrrole),8.21~7.06(m,20H),4.48(s,2H,CH 2, OCH 2 ),4.17(s,4H,CH 2 ,Pyrrole),3.23(s,2H,CH 2 ,CH 2 S), 1.23 (s, 2H, NH); MS (ESI): 894.1722 (M+H); HPLC: 96.6%. Its structural formula is as follows:

[0075]

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Abstract

The invention provides a reduction-sensitive-type water-soluble molecularly-targeted photosensitizer. The photosensitizer is a conjugate which is formed by sequentially connecting meso-tetrahydroxy phenyl chlorine (mTHPC) with a folic acid group through a carbonic ester bond, a disulfide bond and a PEG chain. The invention further provides a chlorine intermediate and a folic acid PEG cysteine amide intermediate which are used for preparing the photosensitizer and a preparation method of the targeted photosensitizer. According to the photosensitizer which has the good tumor targeting performance, the photodynamic activity and water solubility, by introducing the disulfide bond and the carbonic ester bond into the molecular structure, the targeted photosensitizer can generate an exchange reaction of a sulfydryl and the disulfide bond and a nucleophilic substitution reaction in molecules in a strong reducing environment of a tumor cell after entering the cell, therefore, the mTHPC is completely released, and it is guaranteed that the photodynamic activity of the mTHPC cannot be reduced due to the structural change.

Description

technical field [0001] The invention relates to the fields of biology and medicine, in particular, the invention relates to a molecularly targeted photosensitizer and a preparation method thereof, in particular to a photosensitizer mediated by folic acid receptors for tumor-targeted photodynamic therapy and its preparation method. Background technique [0002] Tumor photodynamic therapy (Photodynamic Therapy, PDT) is an emerging minimally invasive or non-invasive treatment method for tumors. It kills tumor cells by first administering a photosensitizer that has a selective aggregation effect on tumor tissue, and then irradiating the lesion with a light source of a specific wavelength to trigger photodynamic oxidative damage in the lesion. It has attracted people's attention because of its targeting, reproducibility and synergy. In the past two decades, PDT has been formally approved by the governments of various countries to enter the clinic, and has become a routine treat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K41/00A61K47/48A61P35/00
Inventor 李东红李鹏熙
Owner THE THIRD AFFILIATED HOSPITAL OF THIRD MILITARY MEDICAL UNIV OF PLA
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