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Near-infrared dyes, their targeted imaging agents, nanocarriers and anticancer drugs and their applications

A compound, CH2 technology, applied in the field of targeted diagnosis and treatment, biomedicine, can solve the problems of increasing difficulty in diagnosis, difficulty in imaging positioning, etc.

Active Publication Date: 2020-07-03
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the super proliferation and migration ability of tumor cells, it is difficult to accurately locate them in imaging.
Moreover, most of the current fluorescent probes have a broad spectrum, not only for imaging tumor cells, but also responding to normal cells will make diagnosis more difficult

Method used

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  • Near-infrared dyes, their targeted imaging agents, nanocarriers and anticancer drugs and their applications
  • Near-infrared dyes, their targeted imaging agents, nanocarriers and anticancer drugs and their applications
  • Near-infrared dyes, their targeted imaging agents, nanocarriers and anticancer drugs and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] preparation.

[0112] d is an integer ranging from 1 to 7, and compounds corresponding to different d values ​​are prepared by selecting different raw materials according to the method of this embodiment. Take d=4 as an example:

[0113]

[0114] Preparation of intermediate 1: Boc-Arg(Pbf)-OH 11.3g (0.02mol, 2.5eq) and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate ( HBTU) 9.76g (0.024mol, 3eq) were dissolved in 20mL N,N-dimethylformamide (DMF), after mixing in a 250mL round bottom flask, N,N-diisopropylethylamine (DIEA ) 3.33g (0.024mol, 3eq) reacted. 2 g (0.008 mol, 1 eq) of L-lysine methyl ester hydrochloride was dissolved in 20 mL of DMF, and added dropwise to the above reaction solution. N 2 The reaction was carried out at 30° C. for 48 h under protection, and the reaction process was monitored by TLC. After the reaction, the DMF was distilled off under reduced pressure with a rotary evaporator, and 200 mL of dichloromethane was added to r...

Embodiment 2

[0118] Preparation of Linker Molecules Containing Reduction Sensitive Bonds:

[0119] Disulfide Linked Molecules:

[0120]

[0121] p and q are independently 1

[0122] Preparation of Compound 3: In a 1L round bottom flask, 8g (0.035mol, 1eq) of cystamine dihydrochloride was dissolved in 300mL of methanol, and then 7.07g (0.070mol, 2eq) of triethylamine was added. Dissolve 6.7g (0.031mol, 0.88eq) of di-tert-butyl dicarbonate in 200mL of methanol, under stirring, in an ice-water bath, slowly drop the methanol solution of di-tert-butyl dicarbonate into the methanol solution of cystamine dihydrochloride . React overnight at 30°C, then use a rotary evaporator to distill off methanol under reduced pressure, and add 100 mL of dichloromethane to redissolve. The organic phase was washed twice with 50 mL of saturated NaCl solution, dried over anhydrous sodium sulfate, filtered with suction, and spin-dried. 7.2 g of crude product was obtained by weighing, and the crude yield was ...

Embodiment 3

[0124] Preparation of near-infrared fluorescent dyes:

[0125]

[0126]

[0127] Among them, R 1 for C 2-18 Alkyl, R 2 for -C(O)R 5 , R 3 for H, R 4 for H, R 5 for NR 6 R 7 , R6 and R7 are -(CH 2 ) p -S-S-(CH 2 ) q -NR 8 R 9 , where p is 1, q is 1, R 8 and R 9 for-C(O)-CHR 10 R 11 , R 10 and R 11 is an independent Q, Q is selected from the following groups:

[0128]

[0129]

[0130] r is an integer of 1-4; k is an amino acid repeating unit, preferably the amino acid is lysine or arginine.

[0131] Compounds with different substituents are prepared by selecting the raw materials corresponding to the substituents as follows.

[0132] For example:

[0133] 3.1 Preparation of Intermediate 4:

[0134]

[0135] Mix 10g (0.082mol, 1eq) of salicylaldehyde with 4.92g (0.164mol, 2eq) of formaldehyde, and then add 100mL of concentrated hydrochloric acid dropwise to the mixture in an ice-water bath. After reacting at room temperature for 5 h, it was...

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Abstract

The invention discloses a class of near infrared fluorescent dyes, a targeted imaging agent thereof, a nanocarrier, an anticancer drug and an application. The near-infrared fluorescent dyes and hydrophilic dendrimers are linked by environmentally sensitive bonds to form amphiphilic dendrimers with self-assembly capability. The hydrophilic dendrimers have good tumor targeting performance and transmembrane performance when lysine and arginine are used as backbone structures. The amphiphilic dendrimers also have nitroreductase responsiveness and can be self-assembled into nanoliposomes or micelles or vesicles for gene and / or drug carriers that are disassembled in the tumor microenvironment to release genes and / or drugs for therapeutic purposes. The amphiphilic dendrimers can also produce reactive oxygen in near infrared light and can be used in photodynamic therapy. The dendrimers are fluorescence quenched before and after self-assembly and after disassembly, and can generate fluorescenceenhancement only under the action of nitroreductase of tumor cells. The penetrating capability is higher, and the penetrating is more precise.

Description

technical field [0001] The invention belongs to the field of biomedicine, especially the field of targeted diagnosis and treatment, and specifically relates to a near-infrared dye, a targeting imaging agent constructed from the near-infrared dye, nanocarriers and anticancer drugs, and their applications. Background technique [0002] So far, human health is still seriously threatened by some diseases, such as: cardiovascular and cerebrovascular diseases, malignant tumors and diabetes. For cancer treatment, commonly used treatment methods are: surgery, radiation therapy and chemotherapy. As a new type of treatment, gene therapy has attracted more and more attention. Gene therapy is the most promising way to completely cure tumors, and the key to the success of gene therapy lies in the selection of gene carriers. As we all know, gene vectors mainly include viral vectors and non-viral vectors. Viral vectors are the earliest developed type of vectors with the best gene transf...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/08C07D405/12A61K31/404A61K9/107A61K9/127A61K41/00A61K45/00A61K48/00A61K49/00A61P35/00B82Y5/00B82Y40/00A61K47/22
CPCA61K9/1075A61K9/1271A61K41/0057A61K45/00A61K48/0041A61K49/0034A61K49/0084A61P35/00B82Y5/00C07D209/08C07D405/12
Inventor 聂宇梁鸿柯博文陈晓冰金蓉蓉胡傲毕群杰
Owner SICHUAN UNIV
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