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CN-122010990-A - Preparation method and application of red light activated hydrogen sulfide donor heavy atom-free photosensitizer based on fluoroboric dipyrrole dye

CN122010990ACN 122010990 ACN122010990 ACN 122010990ACN-122010990-A

Abstract

The invention relates to a preparation method of a heavy atom-free photosensitizer based on a fluoroborodipyrrole dye, which comprises a thiocarbamate photo-cage, can generate singlet oxygen ( 1 O 2 ) under red light irradiation, can release carbonyl sulfide (COS), and can generate hydrogen sulfide (H 2 S) under physiological conditions through catalysis of carbonic anhydrase. By reasonably adjusting the molecular structure, the singlet oxygen quantum yield and the hydrogen sulfide release efficiency of the photosensitizer are obviously improved. This is the first example reported so far that the organic light functional small molecules releasing H 2 S and 1 O 2 can be activated simultaneously by a single beam of red light. The strategy effectively solves the problem of oxygen dependence in type II photodynamic therapy (PDT), and further effectively improves the effect of PDT hypoxic tumor. In vitro and in vivo experiments, the hydrogen sulfide gas and the photodynamic therapy are used for cooperatively treating, triggering cell apoptosis, promoting maturation of dendritic cells and stimulating anti-tumor immune response. Therefore, the invention provides a cooperative treatment strategy combining gas, photodynamic and immunotherapy, which has remarkable effect on the aspect of treating the hypoxic tumor. The photosensitizer material disclosed by the invention is simple to prepare and low in cost, has a wide application prospect, and particularly provides a potential solution for cancer treatment in the biomedical field.

Inventors

  • SU MEIHUI
  • LI DONGJIE
  • GAO HUI
  • ZHANG LUYI

Assignees

  • 天津工业大学

Dates

Publication Date
20260512
Application Date
20241112

Claims (10)

  1. 1. A preparation method of red light activated hydrogen sulfide donor heavy atom-free photosensitizer based on a fluoroboric dipyrrole dye is characterized by comprising the following steps of.
  2. 2. A method for preparing a red light activated hydrogen sulfide donor heavy atom free photosensitizer based on a fluoroborodipyrrole dye according to claim 1, comprising the steps of: step 1b (1.69 g,5.5 mmol) was added to a solution of 1a (2 g,10 mmol) in dry dichloromethane (50 mL) and stirred under nitrogen for 12h. The reaction was cooled to room temperature, triethylamine (1.75 mL,12.5 mmol) was added, and then boron trifluoride diethyl ether (1.58 mL,12.5 mmol) was added dropwise. Stirring for another 0.5h, evaporating the solvent under reduced pressure, purifying the mixture by column chromatography (1:2, petroleum ether/dichloromethane) to give B1 (0.8 g,1.15mmol, 23%); Step 2B 1 (300 mg,0.4 mmol) was dissolved in 10mL of anhydrous dichloromethane and methyl magnesium bromide (2.07 mL,17.9 mmol) was added dropwise. The reaction was stirred at 0℃for 10min and followed by thin layer chromatography (1:1, petroleum ether/dichloromethane). After completion of the reaction, the reaction was quenched by addition of 50mL of saturated ammonium chloride and the organic phase was collected using a separation funnel. The organic phase was washed with saturated brine solution and then filtered over solid sodium sulfate. The reaction was concentrated on a rotary evaporator and purified by column chromatography (1:1, petroleum ether/dichloromethane) to give B2 (60 mg,0.42mmol, 20%); Step 3B 2 (60 mg,0.087 mmol) was dissolved in 50mL of anhydrous dichloromethane, DDQ (39 mg,0.17 mmol) was added thereto, and the mixture was stirred for 10min. After completion of the reaction, work up was as in step 2, and pure product B3 (50 mg,0.07mmol, 83%) was obtained as a black solid by column chromatography (1:1, petroleum ether/dichloromethane).
  3. 3. The method for preparing the red light activated hydrogen sulfide donor heavy atom-free photosensitizer based on the fluoroboric dipyrromethene dye according to claim 2, wherein in the step 1, the ratio of the amounts of the substances 1a and 1b is 1:0.6-08.
  4. 4. The method for preparing red light activated hydrogen sulfide donor heavy atom-free photosensitizer based on fluoroboric dipyrrole dye according to claim 2, wherein the ratio of the amount of B1 to the amount of methyl magnesium bromide in step 2 is 1:30.
  5. 5. The method for preparing the red light activated hydrogen sulfide donor heavy atom-free photosensitizer based on the fluoroboric dipyrrole dye according to claim 2, wherein in the step 3, the mass ratio of the B2 to the 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) is 1:2-4.
  6. 6. The preparation of red light activated hydrogen sulfide donor heavy atom-free photosensitizer nanoparticles based on fluoroboric dipyrromethene dye according to claim 2, characterized by the following preparation method: Weighing a certain mass of fluorine boron dipyrrole dye molecules, dissolving the fluorine boron dipyrrole dye molecules in DMSO (1 mg/mL), weighing a certain mass of F127 polymer, dissolving the F127 polymer in ultrapure water (1 mg/mL), placing the F127 polymer solution under an ultrasonic condition, slowly dropwise adding the fluorine boron dipyrrole dye molecule solution into the F127 polymer solution, dialyzing the F127 polymer solution with ultrapure water, and passing the solution through a 0.22 mu m water-based filter membrane to obtain the fluorine boron dipyrrole dye nanoparticle solution.
  7. 7. The red light activated hydrogen sulfide donor heavy atom free photosensitizer nanoparticle preparation method based on the fluoroboric dipyrromethene dye according to claims 1-6, wherein the resulting nanoparticle has 78% hydrogen sulfide release efficiency within one hour of illumination, and singlet oxygen quantum yield of 0.21.
  8. 8. Red light activated hydrogen sulfide donor heavy atom-free photosensitizer nanoparticles based on fluoroborodipyrrole dye obtained according to the preparation method of claims 1-6 have a killing efficiency of up to 90% on 4T1 cells under light (LED, 660nm,0.5w/cm 2 ) for 15 minutes at a concentration of 10 μm.
  9. 9. The red light activated type photosensitizer nanoparticle without heavy atoms obtained by the preparation method according to the claims 1-6 can effectively induce 4T1 cells to undergo scorching.
  10. 10. Red-activated hydrogen sulfide donor heavy atom-free photosensitizer nanoparticles based on fluoroborodipyrrole dye exhibit excellent anti-tumor effects in 4T1 subcutaneous tumor model. After 100 mu M nano particles are injected by tail vein, most of tumor cells die under the effect of irradiation for 30 minutes, and meanwhile, dendritic cell maturation is obviously promoted, immune effect is activated, and tumor inhibition rate reaches 99%.

Description

Preparation method and application of red light activated hydrogen sulfide donor heavy atom-free photosensitizer based on fluoroboric dipyrrole dye Technical Field The invention belongs to the technical field of nano-medicament for treating cancer, and particularly relates to a preparation method and application of red light activated hydrogen sulfide donor heavy atom-free photosensitizer of a BODIPY dye (BODIPY). Background Common treatment modes of cancers include phototherapy, chemotherapy, radiotherapy, microwave hyperthermia and the like, wherein photodynamic therapy (PDT) has the advantages of space-time controllability, low toxicity, remarkable immune activation effect, no wound and the like, and has become a very promising cancer treatment method. PDT works primarily through two photochemical mechanisms, type I and type II reactions. In type I reactions, photosensitizers generate free radicals and hydrogen peroxide by electron transfer, while in type II reactions photosensitizers interact with molecular oxygen through triplet-triplet mechanisms to form singlet oxygen (1O2), which can cause killing effects on cancer cells. However, a major disadvantage of type II PDT is its high dependence on oxygen, which is particularly pronounced in hypoxic tumor microenvironments, greatly limiting its efficacy. To overcome this problem, researchers are developing new therapeutic strategies. For example, type I photosensitizers are designed to generate free radicals that kill cancer cells, and although free radical generation can solve the oxygen dependence problem to some extent, this strategy has certain limitations in treatment due to the extremely short half-life of free radicals and the susceptibility to reduction by intracellular reducing agents such as Glutathione (GSH). In addition, some studies have attempted to deliver oxygen directly to the tumor site to alleviate the hypoxia problem, however this approach may simultaneously promote tumor cell growth with side effects. Another approach is to enhance the ability of photosensitizers to kill cancer cells by introducing heavy atoms into the organic functional molecule, and utilizing the heavy atom effect to increase their singlet oxygen quantum yield. However, heavy atom-containing photosensitizers may trigger significant cytotoxicity, limiting their clinical application prospects. Therefore, how to avoid oxygen dependence and reduce potential toxicity while improving PDT efficacy remains an important direction of current research. In cancer treatment, the effect of monotherapy is often limited, so combining multiple therapeutic strategies is often critical to improving efficacy. Hydrogen sulfide (H 2 S) as an important bioactive gas exhibits significant anti-tumor potential in modulating Tumor Microenvironment (TME) and immune response. H 2 S can inhibit mitochondrial respiration, relieve the hypoxia state of tumors, inhibit proliferation of myelogenous suppressor cells (MDSCs), enhance maturation of Dendritic Cells (DC) in the immune system and promote generation of immune effect by improving permeability of tumor blood vessels, so that inhibition of tumor growth is realized. In view of the multiple role of H 2 S in regulating tumor microenvironment and immune activation, it is considered an "auxiliary gas" for photodynamic therapy (PDT) to enhance the anticancer effect of PDT. By combining H 2 S with PDT, the therapeutic effect can be further improved on the basis of PDT, for example, the sensitivity of the tumor to drugs is improved, the activation of the immune system is promoted, the dependence of PDT on oxygen is reduced, and thus a more effective anti-tumor strategy is formed. This synergy provides a promising research direction for future cancer treatments. The variety of hydrogen sulfide (H 2 S) donors currently developed is wide ranging, with the photoactivated H 2 S donor receiving a great deal of attention due to its unique advantages. The light activated H 2 S donor can realize the accurate release of H2S through external illumination control under the condition of not interfering with the normal biochemical process. The control mode can effectively reduce off-target effect, and realize accurate space-time regulation, thereby avoiding damage to healthy tissues to the maximum extent. However, most current photo-activated H 2 S donors require ultraviolet or short wavelength visible light to trigger, which places a limit on the depth of tissue penetration. Ultraviolet and short wavelength light have weaker penetrability and can cause phototoxicity or damage to normal tissues at larger doses, especially when treating deep tumors. Therefore, the development of H 2 S donors that can be activated at long wavelength light (e.g., red or near infrared light) is an important point of current research. The long-wavelength light has stronger tissue penetrating power, and can realize accurate treatment of deep tumors under the condition of not damaging norm