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Synthesis and application of RGD polypeptide coupled SiPc (silicon phthalocyanine) photosensitizer

A technology of silicon photosensitizer and silicon phthalocyanine, which is applied in the field of new photosensitizers for photodynamic therapy of tumors, can solve problems such as failure to meet performance requirements and weak photoactivity of zinc phthalocyanine

Active Publication Date: 2017-10-03
KANGHONG YAOYUAN TECH CO LTD TIANJIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, most of the research at home and abroad is focused on the combination of zinc phthalocyanine and polypeptide. Although this type of compound has certain water solubility and tumor targeting, due to the weak photoactivity of zinc phthalocyanine, EC 50 The value is only between 1-10 μM, which cannot meet the performance requirements for the application of photosensitizers in photodynamic therapy of cancer in vivo

Method used

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  • Synthesis and application of RGD polypeptide coupled SiPc (silicon phthalocyanine) photosensitizer
  • Synthesis and application of RGD polypeptide coupled SiPc (silicon phthalocyanine) photosensitizer
  • Synthesis and application of RGD polypeptide coupled SiPc (silicon phthalocyanine) photosensitizer

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Experimental program
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Embodiment 1

[0030] Synthesis of embodiment 1 RGD polypeptide (attached figure 1 )

[0031] We first synthesized RGD polypeptide compounds by solid-phase method. The resin was swollen with dichloromethane 1 h before the synthesis, and we used a triphenyl chloride resin with a loading of 0.5 mmol / g. Dissolve Fmoc-Asp(OAll)-OH (1.0 g, 1.0 mmol) and N,N-diisopropylethylamine (DIEA) (680 μL, 4.0 mmol) in 10 mL N,N-dimethylformamide (DMF ) into the solid-phase synthesizer, and reacted at room temperature for 5h. Then configure the blocking solution (dichloromethane CH 2 Cl 2 : Methanol MeOH: DIEA=17:1:2), added to the solid-phase synthesizer to block unreacted chlorine. The Fmoc protecting group was removed with 20% piperidine in DMF for 30 min. The coupling reaction of four amino acids (Fmoc-Gly-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Lys(Dde)-OH and Fmoc-D-Phe-OH) was protected by 1.5eq. of Fmoc in each step In-situ addition of condensing agent O-benzotriazole-tetramethyluronium hexafluorophosphate...

Embodiment 2

[0033] Embodiment 2 RGD-Linker, RGD-(Linker) 2 and RGD-(Linker) 2 -Synthesis of Glu (attached figure 2 )

[0034] 1. Synthesis of the compound called RGD-Linker for short

[0035] Deprotected resin-RGD (1.0g, 0.5mmol) and diglycolic anhydride (116.1mg, 1.0mmol) were dissolved in 5mL DMF and shaken for 5h to obtain the product resin-COOH. Then, resin-COOH was activated with N,N'-carbonyldiimidazole (0.5M CDI) and reacted for 1h. Activated resin-COOH, 0.5M 1-hydroxybenzotriazole (HOBt), bis(3-aminopropyl)diethylene glycol (1.1g, 5mmol) were mixed and shaken for 5h, and then mixed with DMF and dichloromethane After washing, vacuum-dry to obtain the product resin-RGD-Linker. Add 500 μL of eluent (TFA / triisopropylsilane Tris / water=95:2.5:2.5) for elution at room temperature for 1 h. Anhydrous ether (1.5 mL) was added to the eluate for precipitation, washed three times and dried at room temperature to obtain the product RGD-Linker (0.18 g, yield 39%). (HRMS-ESI: m / z calculat...

Embodiment 3

[0040] Embodiment 3 is abbreviated as RGD-SiPc, RGD-Linker-SiPc, RGD-(Linker) 2 -SiPc and RGD-(Linker) 2 -Synthesis of Glu-SiPc (attached image 3 )

[0041] 1. Synthesis of a compound called SiPc-PQ for short

[0042] 1-(2-Hydroxyethyl)piperazine (20.8mg, 0.016mmol) and SiPcCl 2 (10.0mg, 0.016mmol) was added to a mixed solution of toluene and pyridine (1mL, v / v=5:1) and refluxed for 10h, the solvent was removed under reduced pressure, and dichloromethane (CH 2 Cl 2 ) diluted, washed three times with saturated brine, combined the organic phases, added anhydrous sodium sulfate (Na 2 SO 4 ) was dried, the solvent was removed, and the silica gel column was purified, and the eluent was methanol (MeOH), dichloromethane (CH 2 Cl 2 ), and a small amount of triethylamine (TEA) was added to obtain the product SiPc-PQ (5.0 mg, yield 42%). (HRMS(ESI):m / z calculated for C 44 h 42 N 12 o 2 Si[M+H] + 799.3396, found 799.3392)

[0043] 2. Synthesis of the compound referred to ...

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Abstract

The invention relates to a SiPc (silicon phthalocyanine) photosensitizer using RGD polypeptide as a targeted group, a preparation method of the SiPc photosensitizer and application of the SiPc photosensitizer to an aspect of tumor photodynamics therapy. The SiPc is used as a photosensitive part to be connected with an RGD polypeptide ligand; PEG (polyethylene glycol) and fragments containing carboxy groups are introduced into the structure; a series of novel photosensitizers with the tumor targeting performance can be prepared. One coupling compound RGD-(Linker)2-Glue-SiPc has good optical physic and photodynamic performance; the EC50 value on the receptor positive tumor cells is 10 to 20nm; under the condition of once medication, the spongioblastoma on the mouse body can be cured; after the continuous observation for 35 days, recurrence does not occur; good application prospects are shown in the field of tumor photodynamics therapy.

Description

[0001] The invention belongs to the field of novel photosensitizers for photodynamic therapy of tumors, and relates to a silicon phthalocyanine photosensitizer with RGD polypeptide as a targeting group, a preparation method thereof and an application in photodynamic therapy of tumors. Background technique [0002] As a typical representative of the second-generation photosensitizers for photodynamic therapy (PDT), phthalocyanine photosensitizers have strong light absorption (extinction) in the infrared to near-infrared region (>650nm) due to their superior photophysical properties. Coefficient ε>1×10 5 liter / mole cm) and higher singlet oxygen quantum yield, etc., has been a research hotspot in the field of photosensitizers, but the structure of this type of photosensitizer contains a highly hydrophobic phthalocyanine ring, and its solubility in water is very low. Small and easily aggregated to cause optical quenching, it is difficult for most phthalocyanine photosensitiz...

Claims

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Application Information

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IPC IPC(8): C07K5/113C07K1/113A61K41/00A61P35/00
CPCA61K41/0071C07K5/1021C07K19/00Y02P20/55
Inventor 洪章勇黄伟强
Owner KANGHONG YAOYUAN TECH CO LTD TIANJIN
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