Photodynamic therapy effect enhancement-targeted fluorinated nano-composite and preparation and application thereof

A nano-composite, photodynamic therapy technology, applied in the field of biomedicine, can solve the problems of poor water solubility and obvious side effects, so as to improve the hypoxia state, reduce the toxic and side effects, and enhance the anti-tumor effect.

Inactive Publication Date: 2021-04-20
FUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to overcome the deficiencies of the prior art, the present invention prepares a novel APFHG targeting nanocomposite that enhances the effect of tumor photodynamic therapy, which not only overcomes the defects of poor water solubility and obvious side effects of Gef and Hp, but also utilizes the surface-modified PAMAM The fluorocarbon chain carries a certain amount of oxygen to improve the hypoxic state of the tumor microenvironment, enhance the therapeutic effect of PDT and improve the resistance of lung cancer cells to EGFR-TKIs, and through the dual targeting of EGFR mutant tumor cells by Apt and Gef , improve the bioavailability of the drug, and give full play to the synergistic effect of molecular targeted therapy and photodynamic therapy

Method used

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  • Photodynamic therapy effect enhancement-targeted fluorinated nano-composite and preparation and application thereof
  • Photodynamic therapy effect enhancement-targeted fluorinated nano-composite and preparation and application thereof
  • Photodynamic therapy effect enhancement-targeted fluorinated nano-composite and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Weigh G5 PAMAM (10 mg) and dissolve it in 0.5 mL of anhydrous methanol, add HFBA according to different feeding ratios (molar ratios) (PAMAM:HFBA=1:32, 1:128, 1:512), and then add 10 times molar TEA equivalent to anhydride. Stir at room temperature for 48 h. The reaction solution was placed in a dialysis bag with a molecular weight cut-off of 8000-14000 Da, dialyzed for 72 h and then freeze-dried to obtain fluffy white crystal PF 32 、PF 128 、PF 512 . With TFEA as the internal standard, TFEA and HFBA (mass ratio 1:0.5), TFEA and PF (mass ratio 100:1) were dissolved in deuterated dimethyl sulfoxide solution to determine the concentration of the sample. 19 F NMR spectrum, figure 1 middle, PF 128 and HFBA's 19 The peak positions of the F NMR spectra are roughly the same, indicating that the fluorocarbon chains have been successfully coupled to the surface of PAMAM.

Embodiment 2

[0048] Weigh G5 PAMAM (10 mg) and dissolve it in 0.5 mL of anhydrous methanol, add HFBA according to different feeding ratios (molar ratios) (PAMAM:HFBA=1:32, 1:128, 1:512), and then add 10 times molar TEA equivalent to anhydride. Stir at room temperature for 48 h. The reaction solution was placed in a dialysis bag with a molecular weight cut-off of 8000-14000 Da, dialyzed for 72 h and then freeze-dried to obtain fluffy white crystal PF 32 、PF 128 、PF 512 . Take 1 mg / mL of PAMAM and PF respectively 32 、PF 128 、PF 512 1 mL of aqueous solution of PAMAM and PF 32 、PF 128 、PF 512 The oxygen contained in it is used to react with excess Na2SO3. Then, the unreacted Na in the solution 2 SO 3 Further with KMnO 4 react. Finally, according to KMnO 4 The UV-Vis absorption value at 544 nm draws a standard curve to indirectly determine PAMAM and PF 32 、PF 128 、PF 512 oxygen content, such as figure 2 As shown, it can be seen that the oxygen content is: PF 512 >PF 128 ...

Embodiment 3

[0050] Weigh 2 mg of EDC and 1 mg of NHS dissolved in ddH 2 O was placed in a round bottom flask, and 10 μL of Apt (10 μM, 5’-COOH-TGA ATG TTG TTT TTT CTC TTT TCT ATA GTA-3’) was added to it, stirred at room temperature for 3 h at low speed to activate the carboxyl group. Then, 2 mg of PF or PAMAM prepared in Examples 1 and 2 were added, and stirred overnight at a low speed. Finally, in order to remove unlinked Apt, the reaction mixture was dialyzed (MWCO 14 kDa) for 48 h, and then freeze-dried to obtain the nano drug carrier APF or AP. like image 3 As shown, through polyacrylamide gel electrophoresis experiments, it was found that after the aptamer reacted with PAMAM, the band disappeared, indicating that the aptamer was successfully coupled to PAMAM. After the aptamer coupled with fluorescent molecules was fed into the reaction, it was found that APF and AP detected fluorescent signals, which again proved that the aptamer was successfully coupled to PAMAM.

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Abstract

The invention discloses a preparation method of an oxygen-carrying and fluorocarbon chain-modified drug and photosensitizer targeted co-delivery nano-composite and application of the nano-composite to preparation of anti-epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) drug-resistant lung cancer drugs. The preparation method of the nano-composite comprises the steps of performing fluorocarbon chain and EGFR-targeted aptamer (Apt) modification on polyamidoamine (PAMAM) to form a nano-drug delivery carrier APF with oxygen carrying capacity and tumor targeting property, and then co-entrapping photosensitizer hematoporphyrin and molecular targeting drug gefitinib to construct the targeting nano-composite APFHG for enhancing the photodynamic therapy effect. The nano-composite overcomes the defect that photodynamic therapy is limited by a tumor anoxic microenvironment and improves the sensitivity of drug-resistant lung cancer cells to EGFR-TKIs, thereby promoting the combined treatment effect of molecular targeted therapy and photodynamic therapy.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and relates to a method for preparing an oxygen-carrying fluorocarbon chain-modified drug and a photosensitizer co-transporting targeting nanocomposite and its effect in preparing anti-EGFR-TKIs drug-resistant lung cancer. Background technique [0002] Lung cancer is a complex disease with high aggressiveness and molecular heterogeneity, mainly divided into two categories: small cell carcinoma (SCLC, 13% of cases) and non-small cell carcinoma (NSCLC, 83% of cases). In patients with NSCLC, 40% of them have epidermal growth factor receptor (EGFR) mutations, and they have a high response rate (55%-78%) to EGFR-TKIs treatment, and significantly higher progression-free survival (PFS) , making EGFR-TKIs the standard treatment for patients with these mutations. Currently, EGFR inhibitors represented by Gef and Erlotinib are used as first-line treatment for lung cancer with activating EGFR mutations...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K41/00A61K31/5377A61K33/00A61K9/51A61K47/34A61K47/26A61K47/14A61P35/00
Inventor 高瑜朱芳银徐靓陈海军
Owner FUZHOU UNIV
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