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Diagnostic nano-drug which utilizes photothermal effect to assist penetration

A nano-medicine and photothermal technology, which is applied in the field of diagnostic and therapeutic nano-medicines and instant diagnostic and therapeutic nano-medicines, can solve the problems that the release kinetics cannot be completely consistent, it takes half an hour to several hours, and the space distance is different, so as to improve the curative effect, Increased blood flow and reduced systemic toxicity

Active Publication Date: 2019-07-09
FUDAN UNIV
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0006] However, there are obvious problems in the above design: once the trigger bond such as disulfide bond breaks, the drug in the "half-masked" state is structurally separated from the probe, but the probe is still in a quenched state, and the complete self-sacrificing cyclization The process takes half an hour to several hours; when the fluorescence performance of the probe is restored, there is a huge difference in the spatial distance between the drug molecule and the probe due to the free diffusion of molecules or complex physiological processes in the cell, such as endocytosis and exocytosis. , Therefore, it is difficult to confirm that the probe can reflect the information of drug release in situ; another factor that cannot be ignored is that under this design, the recovery of the probe and the drug, the reaction rate depends to a large extent on the drug or The structure of the probe is likely to lead to the result that the release kinetics of the two cannot be completely consistent

Method used

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  • Diagnostic nano-drug which utilizes photothermal effect to assist penetration
  • Diagnostic nano-drug which utilizes photothermal effect to assist penetration
  • Diagnostic nano-drug which utilizes photothermal effect to assist penetration

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079]

[0080] 4-Chlororesorcinol (140 mg, 0.95 mmol) and triethylamine (0.35 mL, 2.4 mmol) were dissolved in anhydrous DMF (1.5 mL) at room temperature under argon atmosphere and stirred for 30 minutes. IR-780 iodide (250 mg, 0.375 mmol) was dissolved in anhydrous DMF (1 mL) and slowly added to the above solution in the dark. The temperature was raised to 50°C and kept for 4 hours, then cooled to room temperature, pure water (10 mL) was added, and extracted with dichloromethane (20 mL×3). The organic phases were combined, dichloromethane was distilled off under reduced pressure, and the crude product was purified by preparative column chromatography (dichloromethane:ethanol=30:1, v:v) to obtain a pure product in the form of blue-green crystals (71 mg, 63%).

[0081] Rf=0.5 (dichloromethane:methanol=30:1, v:v); 1 H NMR (400MHz, CDCl 3 , δ, ppm): 8.13 (d, J=13.2Hz, 1H, H-4), 7.42 (s, 1H, H-3), 7.32-7.28 (m, 3H, H-1, 2and 27), 7.08 (t, J=7.6Hz, 1H, H-28), 6.86(d, J=4.0Hz,...

Embodiment 2

[0083]

[0084] At room temperature under nitrogen atmosphere, 2-aminoethanethiol (1.0g, 13mmol, 1eq) and 2,2'-dipyridyl disulfide (5.7g, 26mmol, 2eq) were dissolved in ethanol: acetic acid (20:1, v: v, 30 mL) in the mixed solvent and stirred overnight. The solvent was evaporated under reduced pressure, and the crude product was purified by preparative column chromatography (ethyl acetate:petroleum ether=1:1, v:v) to obtain a pure product in the form of a white wax (0.71 g, 29.4%).

[0085] Rf=0.3 (ethyl acetate: petroleum ether=1: 1, v: v); 1 H NMR (400MHz, CDCl 3 , δ, ppm): 8.42(dd, J1=4.4Hz, J2=1.6Hz, 1H, H-1), 7.63-7.54(m, 2H, H-2, 3), 7.08-7.03(m, 1H, H-4), 2.98-2.93(m, 2H, H-5, 6), 2.76(dt, J1=43.2Hz, J2=5.6Hz, 2H, H-7, 8), 1.88(s, w, 1H , H-9, 10); MS-ESI Calc.for C 7 h 11 N 2 S 2 [M+H] + 187.3, Found, 187.0.

Embodiment 3

[0087]

[0088] Imidazole (1.7g, 25mmol) and tert-butyldimethylsilyl chloride (TBSCl, 3.8g, 25mmol) were dissolved in dry DMF (10mL), 2-hydroxy-5-methyl-m-xylylenedimethanol (6g, 35.7mmol ) was dissolved in dry DMF (10 mL) and added to the above solution and stirred at room temperature for 2 hours, then diluted into diethyl ether (100 mL) and washed with pure water (100 mL×3). The organic phases were combined, diethyl ether was distilled off under reduced pressure, and the crude product was purified by preparative column chromatography (ethyl acetate:petroleum ether=5:95, v:v) to obtain a pure product in the form of a colorless oil (3.8g, 80% ).

[0089] Rf=0.8 (ethyl acetate: petroleum ether=1: 10, v: v); 1 H NMR (400MHz, CDCl 3 , δ, ppm): 8.02 (s, 1H, H-6), 6.90 (s, 2H, H-3), 4.82 (s, 4H, H-5), 2.26 (s, 3H, H-4), 0.96-0.89(m, 18H, H-1), 0.18-0.08(m, 12H, H-2); HRMS Calc.for C 21 h 40 NaO 3 Si 2 [M+Na] + 419.2408, Found, 419.2413.

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Abstract

The invention belongs to the technical field of biology, in particular to a diagnostic nano-drug which utilizes a photothermal effect to assist deep penetration of tumors. A drug-probe coupling body is synthesized by a one-pot method, and a probe is in a quenched state in the coupled state; targeted biodegradable polylactic acid-glycolic acid copolymer (PEG-PLGA) micelles can be used for targeteddelivery to a tumor site. However, under the stimulation of high-concentration glutathione in tumor microenvironment, drugs and probe molecules can be released simultaneously, in the same place and inthe same amount, quenching probe molecules can emit near-infrared fluorescence when activated to achieve the purpose of real-time reporting of drug release, the in-situ released probes can generate aphotothermal effect under near-infrared illumination to increase the temperature of a tumor region, increase blood flow and blood flow volume, and meanwhile, molecular diffusion is increased to achieve the purpose of deep penetration into the tumor region, and finally, triple purposes of tracing, targeting and photothermal penetration are achieved.

Description

[0001] Technical field: [0002] The invention belongs to the field of biotechnology, and relates to a diagnostic and therapeutic nano-medicine for photothermal assisted penetration, in particular to an instant diagnostic and therapeutic nano-medicine that uses photothermal effect to assist deep tumor penetration. [0003] Background technique: [0004] According to data, small molecule drugs are still the main weapon for humans to fight diseases. Research has disclosed that prodrugs, also known as prodrugs, refer to compounds that are inactive or less active in vitro after chemical structure modification, and release active drugs through enzymatic or non-enzymatic conversion in vivo to exert drug effects. Prodrugs can improve the pharmacokinetics of the parent drug by modifying the drug, prolong the action time, mask the unsuitable pharmaceutical properties, improve the solubility or enhance the membrane penetration ability, and finally achieve the purpose of reducing toxic si...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K41/00A61K31/4745A61P35/00
CPCA61K9/0004A61K9/1075A61K31/4745A61K41/0038A61K47/34
Inventor 孙涛蒋晨
Owner FUDAN UNIV
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