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Synthesis and application of folic acid-targeted pyro photosensitizers

A targeted and photosensitive technology, applied in the direction of medical preparations containing active ingredients, drug combinations, organic active ingredients, etc., can solve problems such as difficulties

Active Publication Date: 2019-11-22
康宏药源(河南)科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, for most porphyrin-based photosensitizers, it is difficult to directly modify the core structure to improve the hydrophilic / hydrophobic properties due to the limitation of self-fixed structures.

Method used

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  • Synthesis and application of folic acid-targeted pyro photosensitizers
  • Synthesis and application of folic acid-targeted pyro photosensitizers
  • Synthesis and application of folic acid-targeted pyro photosensitizers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1 is referred to as the synthesis of the targeted photosensitizing compound of FA-PEG-Pyro for short (attachment figure 1 )

[0029] 1. Synthesis of a compound called FA-Cys-SH for short

[0030] FA-Cys-SH is synthesized by Fmoc-based solid phase synthesis. Weigh 1 g of triphenyl chloride resin (1 g, 0.5 mmol, 1.0 eq) into a solid phase synthesizer, add 3 ml of dichloromethane (DCM) to swell for 5 hours. Fmoc-Cys(Trt)-OH (1.05g, 1.8mmol, 3.6eq) was dissolved in 2ml of dichloromethane and added to a solid-phase synthesizer for overnight reaction at room temperature. Configure a blocking solution (methanol: water = 17:2), add the resin blocking solution to the solid-phase synthesizer, and block at room temperature for 30 minutes. The resin was washed 5 times with N,N-dimethylformamide (DMF), and the Fmoc group was removed with 5% piperidine in DMF for 2 hours. Wash the resin 5 times with DMF, dissolve folic acid (FA, 780mg, 1.8mmol, 3.6eq) and O-benzotriazo...

Embodiment 2

[0035] figure 1 Middle FA-PEG1K-Pyro, FA-PEG3.5K-Pyro, FA-PEG5K-Pyro and FA-PEG10K-Pyro correspond to FA-PEG-Pyro compounds with molecular weights of 1K, 3.5K, 5K and 10K in the middle PEG chain, respectively . Evaluation of the drug activity of embodiment 2FA-PEG-Pyro on the cellular level (attachment figure 2 )

[0036] The frozen KB and 4T1 cell lines were taken out from liquid nitrogen, placed in a 37°C water bath to thaw quickly, and then centrifuged at 1000rpm / min for 5min. Replace the supernatant, add preheated complete medium, and place in a 5% CO2, 37°C incubator to culture overnight. The medium was changed the next day. Continue to culture until the cells cover the bottom of the dish. Subculture 2-3 times. KB cells or 4T1 cells in 1×10 4 The cell density per well was spread in a 96-well plate, placed in a 5% carbon dioxide incubator at 37°C and cultured overnight. After the supernatant was removed, FA-PEG-Pyro (the molecular weights of the polyethylene glyco...

Embodiment 3

[0040] Example 3 The selective killing ability and dark toxicity analysis of the FA-PEG1K-Pyro drug activity of 1kDa polyethylene glycol linking chain (attached image 3 , 4)

[0041] KB oral squamous cell carcinoma cells with high expression of folate receptor and A549 lung cancer cells with low expression of folate receptor in the logarithmic phase were taken respectively, with 8×10 3 Add 100 μL of cell suspension to a 96-well plate at a cell density of 1 cell / well, and incubate for 24 hours in a 37°C incubator. Replace with FA-PEG1K-Pyro containing different concentrations of polyethylene glycol linking chain of 1kDa, continue to culture for 12h, give different light doses (0min, 5min, 10min, 20min), continue to culture for 4h, replace with 0.5mg / The fresh medium of mL MTT continued to incubate for 4h. The absorbance of each well was measured at 490nm by an enzyme-linked immunosorbent assay.

[0042] Experimental results and conclusions:

[0043] We used FA-PEG1K-Pyro ...

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Abstract

Long chain polyethylene glycol (Polyethylene Glycol, PEG) is connected with Pyro and small molecule folic acid to develop a novel photodynamic therapy drug. The Pyro is a potential photosensitive compound, and has high singlet oxygen production capacity and high extinction coefficient. Folic acid molecules have strong affinity to tumor cells. The novel long chain polyethylene glycol-modified folic acid targeting Pyro photosensitizer can significantly increase the accumulation ability of the photosensitizer in tumor tissues, and significantly improves the photodynamic therapy effect of the photosensitizer, and the polyethylene glycol with different chain lengths have different influence on enrichment of the photosensitizer in a tumor site and the photodynamic therapy effect of the photosensitizer.

Description

[0001] The invention relates to the synthesis of long-chain polyethylene glycol-coupled folic acid targeting Pyro photosensitizer (referred to as FA-PEG-Pyro) and its application in tumor photodynamic therapy and tumor imaging diagnosis. Background technique [0002] At present, the clinical methods for treating cancer mainly include radiotherapy, chemotherapy and surgery. However, these traditional treatment methods not only kill tumor tissues, but also damage normal tissues of the body, resulting in systemic toxicity. Photodynamic therapy (Photodynamic Therapy, PDT), as a minimally invasive treatment strategy for clinical application, has attracted more and more attention. When the photosensitizer is excited by light of a specific wavelength, PDT utilizes the O in the tissue 2 Singlet oxygen is generated, thereby generating a series of photochemical and photobiological processes that lead to irreversible photosensitive damage to tumor tissue (Dolmans et al., 2003; Dougherty ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D519/00A61K31/525A61K41/00A61K49/00A61P35/00
CPCA61K41/0071A61K49/0036C07D519/00
Inventor 洪章勇黄伟强
Owner 康宏药源(河南)科技有限公司
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