CN-122010994-A - BODIPY fluorescent dye, preparation method and application thereof, FRET-ACQ double-effect near infrared probe

Abstract

The invention relates to a BODIPY fluorescent dye, a preparation method and application thereof, and a FRET-ACQ double-effect near infrared probe, wherein the embodiment of the invention provides the BODIPY fluorescent dye which has a structural formula shown in a formula 1, wherein R is alkyl with 1-5 carbons. The BODIPY fluorescent dye (BDP 1) has the advantages that the BODIPY fluorescent dye (BDP 1) is a probe with bright fluorescence in an NIR-I region and excellent ACQ property, and can be independently used as an ACQ probe, and simultaneously, the BDP1 absorption and emission wavelength is matched with the ACQ probe P1, so that the combination of the two probes is possible. The method can improve the accuracy of the drug carrier tracing in organisms, is beneficial to elucidating the in vivo action mechanism of the nano-drug, and has great clinical transformation significance.

Inventors

• WU WEI
• LIU CHANG
• LU YI
• ZHANG RUNTONG

Assignees

• 复旦大学

Dates

Publication Date

20260512

Application Date

20251230

Claims (10)

1. 1. A BODIPY fluorescent dye, characterized by having a structural formula shown in formula 1: ; Wherein R is alkyl of 1-5 carbons.
2. 2. A process for the preparation of a BODIPY fluorescent dye as claimed in claim 1, comprising the steps of: S1, dropwise adding phosphorus oxychloride into N, N-dimethylformamide with the same molar weight in an ice water bath, stirring for 10-15min, and then, turning to room temperature and continuously stirring for 15-20min to prepare a first reaction solution; S2, dropwise adding a1, 2-dichloroethane solution of 7-alkoxy-4, 5-dihydro-1H-benzo [ g ] indole-3-phenyl into the first reaction solution, performing Vilsmeier reaction, and synthesizing and separating a product 7-alkoxy-4, 5-dihydro-1H-benzo [ g ] indole-3-phenyl-2-formaldehyde; S3, dissolving 7-alkoxy-4, 5-dihydro-1H-benzo [ g ] indole-3-phenyl-2-formaldehyde and an equal molar amount of 7-alkoxy-4, 5-dihydro-1H-benzo [ g ] indole-3-phenyl in the re-evaporated and dried 1, 2-dichloroethane under the condition of inert gas atmosphere and room temperature, dropwise adding phosphorus oxychloride, stirring and reacting for 12-14H, adding triethylamine and boron trifluoride diethyl ether, stirring for 4-5H at room temperature, and preparing a second reaction solution, wherein the alkoxy is an alkoxy with 1-5 carbons; s4, concentrating the second reaction solution, and performing column chromatography to separate a solid with green metal luster, wherein the solid is BODIPY fluorescent dye shown in the formula 1.
3. 3. Use of the BODIPY fluorescent dye of claim 1 for fluorescent tracing of nanocarriers in vivo.
4. 4. The method according to claim 3, wherein the BODIPY fluorescent dye is used as a donor ACQ probe, the P1 is used as an acceptor ACQ probe, the BODIPY fluorescent dye and the P1 form a FRET-ACQ double-effect near infrared probe, the FRET-ACQ double-effect near infrared probe is used for fluorescent tracing of the nano-carrier in the organism, and the structural formula of the P1 is shown as formula 2: 。
5. 5. The use according to claim 4, wherein the BODIPY fluorescent dye is used at a concentration of 10 to 40. Mu.M and the P1 is used at a concentration of 5 to 15. Mu.M when the FRET-ACQ dual-effect near infrared probe is supported on the nano-carrier.
6. 6. The use according to claim 4, wherein the FRET-ACQ dual effect near infrared probe is entrapped inside a nanocarrier; The nano-carrier has a hydrophobic matrix structure or a hydrophobic core-hydrophilic shell structure; the FRET-ACQ double-effect near infrared probe is coated in a hydrophobic matrix or a hydrophobic inner core of the nano-carrier.
7. 7. The use according to claim 6, wherein the hydrophobic matrix structure is at least one of polymer nanoparticles/microspheres, solid lipid microparticles/nanoparticles, microemulsions, nanoemulsions and nanocrystals; The hydrophobic core-hydrophilic shell structure is a polymer nano micelle.
8. 8. The use according to any one of claims 4 to 7, wherein the nanocarrier is at least one of a nano-polymer micelle, a polymer nanoparticle, a solid lipid nanoparticle, a nano-microemulsion, an inorganic nanoparticle, a nano-emulsion, and a nanocrystal.
9. 9. The use according to claim 8, wherein the nanocarrier is a nanoscale material for drug delivery or gene delivery.
10. 10. The FRET-ACQ double-effect near infrared probe is characterized by comprising a donor ACQ probe and an acceptor ACQ probe, wherein the acceptor ACQ probe is BODIPY fluorescent dye with a structure shown in a formula 1, and the acceptor ACQ probe is a compound with a structure shown in a formula 2; wherein, formula 1 and formula 2 are as follows: , 。

Description

BODIPY fluorescent dye, preparation method and application thereof, FRET-ACQ double-effect near infrared probe Technical Field The invention relates to the technical field of organic fluorescent dyes, in particular to a BODIPY fluorescent dye, a preparation method and application thereof, and a FRET-ACQ double-effect near infrared probe. Background The nano-drug can accurately deliver the active drug to the focus part through a specific nano-carrier, so that the synergistic toxicity reduction is realized, and the nano-drug has excellent application prospect in the treatment of various diseases such as cancers, infectious diseases, nervous system diseases and the like. However, since little is known about the in vivo behavior of nanomedicines, the clinical conversion of nanomedicines is very low. The nano-drug comprises three major elements in vivo, namely drug-carrying particles, active drugs and carrier materials. The relationship between these elements and between them and the body is always in dynamic change. When the in-vivo fate of the drug-loaded particles (namely nano-carriers) is monitored, the important information of biological distribution, interaction with organisms, in-vivo drug release, biodegradation, metabolism, elimination and the like of the nano-carriers can be obtained, so that the in-vivo action mechanism of the nano-drugs is clarified, the nano-drugs are optimized in a vector manner, and the method has great clinical transformation significance. Due to the small size of the nanocarriers and the constant dynamic degradation process, real-time, in-vivo monitoring of nanocarriers is very difficult. In order to effectively distinguish between nanocarriers and free probes, avoiding interference of free probes, environmental response type fluorescent probes, such as a series of probes based on aggregation-induced emission (AIE), fluorescence Resonance Energy Transfer (FRET), and aggregation-induced quenching (ACQ) mechanisms, have been developed, which are able to distinguish between signals of nanocarriers and free probes to some extent. However, AIE probes are prone to reaggregation to emit light after release from the nanocarrier, and the wavelength is typically short, limiting their use in vivo imaging. FRET probes refer to the phenomenon of energy transfer from a donor to an acceptor when the donor emission spectrum and the acceptor absorption spectrum overlap highly and the distance between the donor and the acceptor is less than 10 nm. When the nanocarrier is labeled with a FRET probe, FRET effect is generated due to a small distance between the donor and the acceptor, resulting in a decrease in fluorescence of the donor, while the acceptor emits bright fluorescence (FRET signal). After the nano-carrier is degraded or depolymerized, the donor and the acceptor are separated, the distance is increased, the FRET effect disappears, the fluorescence of the donor is recovered, the fluorescence of the acceptor disappears, and the FRET signal or the ratio of the FRET signal to the donor signal is monitored, so that the whole recognition of the nano-carrier can be realized. Although FRET probes have been used for in vivo monitoring of various nano-drug carriers, free FRET probes dispersed in single molecule form are often susceptible to re-enrichment in cell membranes or organs, producing reproducible signals and even causing difficult interpretation results. The applicant has developed a new approach to develop several environmentally-responsive BODIPY (BODIPY) near infrared first-region (NIR-I/II) fluorescent probes (P1, P2, FD-B21, FD-C7 and ACQ 1) based on the ACQ effect. These probes are dispersed in the form of single molecules in the lipophilic parent nucleus of the nanocarrier, and emit intense near infrared fluorescence (ON). And after the nano-carrier is degraded or depolymerized, the probe is released into the surrounding water environment, immediately gathers based on pi-pi action, and fluorescence is rapidly and completely quenched (OFF), so that the interference of the free probe on the nano-carrier can be effectively overcome, and the accurate real-time tracing in the nano-carrier is realized. However, the aggregated and quenched free ACQ probe can redisperse in the lipophilic environment of the biomacromolecule or phospholipid, generating fluorescent recurrence and causing some degree of interference, thereby reducing the accuracy of in vivo monitoring and analysis Disclosure of Invention First, the technical problem to be solved In view of the above-mentioned shortcomings and disadvantages of the prior art, the invention provides BODIPY fluorescent dye, a preparation method and application thereof, and a FRET-ACQ double-effect near infrared probe, which solves the technical problem that the in-vivo monitoring accuracy of the existing drug-loaded particles (nano-carriers) needs to be further improved. (II) technical scheme In order to achieve the above purpose, the main technic