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Construction of Photosensitizer-Chemotherapeutic "Photochemical Integrated" Small Molecule Prodrug and Its Self-Assembled Nanoparticles

A technology of self-assembled nanoparticles and photochemical integration, which is applied in the direction of drug combination, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc. It can solve the problem of crystallization of chemotherapeutic drugs and photosensitizers, and photosensitizer aggregation quenching , poor stability and other issues, to avoid aggregation quenching effect, easy surface modification, good stability

Active Publication Date: 2020-11-13
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, most chemotherapeutic drugs and photosensitizers are co-loaded on nanocarriers by physical embedding. This non-covalent co-loading strategy has the disadvantages of low drug loading, poor stability, and easy Problems such as crystallization or premature leakage in the carrier
In addition, encapsulating photosensitizers on nanocarriers can easily lead to the aggregation quenching effect of photosensitizers

Method used

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  • Construction of Photosensitizer-Chemotherapeutic "Photochemical Integrated" Small Molecule Prodrug and Its Self-Assembled Nanoparticles
  • Construction of Photosensitizer-Chemotherapeutic "Photochemical Integrated" Small Molecule Prodrug and Its Self-Assembled Nanoparticles
  • Construction of Photosensitizer-Chemotherapeutic "Photochemical Integrated" Small Molecule Prodrug and Its Self-Assembled Nanoparticles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Synthesis of pyropheophytin α-paclitaxel prodrug (PPa-S-PTX) linked by ROS sensitive bond

[0045] PPa, DMAP, HOBt and EDCI were dissolved in dichloromethane. The reaction solution was stirred at 0°C for 2 hours, then ethylene glycol was added and the reaction was continued for 48 hours at 37°C under nitrogen protection. The progress of the reaction was monitored by TLC. The target product was purified by preparative liquid chromatography to obtain PPa-EG. PTX, thiodiacetic anhydride and DMAP were dissolved in dichloromethane. The reaction solution was stirred at 25° C. for 12 hours under nitrogen protection. The progress of the reaction was monitored by TLC. Purified using preparative liquid chromatography. The product was dissolved in dichloromethane with DMAP, HOBt and EDCI. The reaction solution was stirred at 0°C for 2 hours, then PPa-EG was added and the reaction was continued for 48 hours at 37°C under nitrogen protection. The target product was...

Embodiment 2

[0047] Embodiment 2: the synthesis of the porphyrin-paclitaxel prodrug (PPa-C-PTX) of non-ROS sensitive bond

[0048] PPa, DMAP, HOBt and EDCI were dissolved in dichloromethane. The reaction solution was stirred at 0°C for 2 hours, then ethylene glycol was added and the reaction was continued for 48 hours at 37°C under nitrogen protection. The progress of the reaction was monitored by TLC. The target product was purified by preparative liquid chromatography to obtain PPa-EG. PTX, glutaric anhydride and DMAP were dissolved in dichloromethane. The reaction solution was stirred at 25° C. for 12 hours under nitrogen protection. The progress of the reaction was monitored by TLC. Purified using preparative liquid chromatography. The product was dissolved in dichloromethane with DMAP, HOBt and EDCI. The reaction solution was stirred at 0°C for 2 hours, then PPa-EG was added and the reaction was continued for 48 hours at 37°C under nitrogen protection. The target product was pu...

Embodiment 3

[0050] Embodiment 3: porphyrin-paclitaxel prodrug ultraviolet and fluorescence spectroscopic analysis

[0051] Dissolve PPa, PPa-EG, PPa-S-PTX and PPa-C-PTX in DMSO with the same concentration of PPa (2μM), and then use a multifunctional microplate reader to obtain their UV spectra and excitation wavelength at 415nm emission fluorescence spectrum. The result is as image 3 and Figure 4 As shown, no obvious changes were found in the peak positions and intensities of the ultraviolet spectrum and the fluorescence spectrum, indicating that the chemical modification has little effect on the optical properties of PPa.

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Abstract

The invention belongs to the technical field of medicines, relates to a photosensitizer-chemotherapeutic drug 'photosensitizer-chemotherapeutic integration' micromolecule prodrug, and aims to connecta chemotherapeutic drug with a photosensitizer through ester bonds or mono-thioether bonds to achieve efficient co-carrying and synchronous delivery of the chemotherapeutic drug and the photosensitizer. The photosensitizer-chemotherapeutic drug is prepared from paclitaxel as a chemotherapeutic drug and coked phaeophytin a as a photosensitizer, a self-assembled nano medicine delivery system is alsoprepared, and synergetic medicine release, in-vivo pharmacokinetics and anti-tumor effects of the drug are evaluated. The predrug is simple in preparation process, small and uniform in nanoparticle size, beneficial to enrichment of nanoparticles at tumor parts through an EPR (Enhanced Permeability and Retention) effect, super large in drug loading capacity and easy in surface modification, and reticuloendothelial system uptaking can be effectively avoided, in addition, uptaking of tumor cells upon the nanoparticles can be effectively improved; while photodynamic treatment is carried out, selective release of medicines can be synergistically triggered in tumor cells; by adopting the 'photosensitizer-chemotherapeutic integration' micromolecule prodrug self-assembled nano drug delivery system designed by the invention, the synergetic anti-tumor effects of the photosensitizer and the chemotherapeutic drug can be remarkably improved.

Description

technical field [0001] The invention belongs to the field of new excipients and new dosage forms of pharmaceutical preparations, and relates to photosensitizer-chemotherapy "photochemically integrated" prodrug and its synthesis method, and also relates to the construction of said "photochemically integrated" prodrug self-assembled nanoparticles, and Its use in drug delivery systems. Background technique [0002] Cancer is still a major disease that threatens human health. According to the World Health Organization, more than 8 million people die of cancer every year worldwide. Chemotherapy is an important means of cancer treatment, but most chemotherapeutic drugs are cytotoxic drugs with a narrow therapeutic window, and traditional chemotherapeutic drug solutions have poor tumor targeting after intravenous administration, resulting in poor curative effect and toxic side effects serious. In recent years, the wide application of nanotechnology in the field of drug delivery ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K41/00A61K31/337A61K9/16A61K47/54A61K47/60A61P35/00
CPCA61K9/1617A61K9/1641A61K31/337A61K41/0071A61P35/00A61K2300/00
Inventor 孙进罗聪何仲贵孙丙军于涵
Owner SHENYANG PHARMA UNIVERSITY
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