Synthesis Of Near-infrared Sulfone Rhodamine Dye And Its Application In Tumor Photothermal Therap

Photothermal therapy（PTT）is an innovative approach to cancer treatment that offers non-invasive benefits.In contrast to conventional methods,PTT can effectively eliminate cancer cells even in environments with low oxygen levels,without relying on the availability of oxygen.This characteristic makes photothermal therapy highly promising for clinical applications.The success of PTT is contingent upon the selection of an appropriate photothermal agent（PTA）.The ideal PTA should possess strong near-infrared absorption,exhibit high photothermal conversion efficiency,demonstrate good photostability,and exhibit biocompatibility.Hence,the focus of this study was to design and synthesize nine variations of rhodamine dyes substituted with 10-site-sulfone groups.The investigation aimed to analyze the impact of these substituents on the compounds’stability and thoroughly explore their photothermal properties.Additionally,a tumor model using mice with tumors was established to further validate the applicability of these compounds in photoacoustic imaging-assisted photothermal therapy.The main objectives of this research encompassed the following:（1）Study on synthesis and stability of near infrared sulfoxide Rhodamine dyesNine sulfone rhodamine compounds were successfully synthesized and their structures were determined using techniques such as ¹H NMR,¹³C NMR,and HRMS.The UV absorption spectra results demonstrated that these compounds exhibited strong near-infrared（NIR）absorption around 700 nm and emitted light at approximately 730 nm.For example,theФ_f of SO₂R2 was determined to be 0.703 in CH₂Cl₂ and 0.09 in H₂O.In order to investigate the effects of different substituents on the stability of the compound,the stability of the compound under different solvents,p H and light was tested.The results showed that the ortho-substituents could effectively protect the C-9 site from the attack of the nucleophile.By screening different substituents,it was found that SO2R2with CF₃ group and with 2,6-substituted SO2R2 showed high stability,while para-substituted and meso-substituted compounds showed poor stability.We speculated that the reason for the instability of the compound was that C-9 site was vulnerable to nucleophilic attack,which destroyed the conjugate structure of the compound,making the color of the solution of the compound change from green to colorless,and this process was reversible.After adding trifluoroacetic acid,the solution gradually returned to the initial green.（2）Study on the photothermal effect of near infrared sulfoxide rhodamine dye and the photothermal treatment of tumorWe used the compound SO2R2 with high stability for the study of photothermal treatment,and the photothermal conversion efficiency was calculated to be 53.06%.Cytotoxicity test showed that it had low toxicity and good biocompatibility.The IC₅₀ of SO₂R2 was 65.82μM.The results of cell life/death staining showed that the compound had high efficiency photothermal treatment.The strong photoacoustic signal and good biocompatibility of SO2R2 indicate its potential in non-invasive monitoring of deep histopathological processes.In order to evaluate the tumor inhibition effect of the compound,4T1 tumor model of tumor-bearing mice was established,which can significantly inhibit tumor growth.In conclusion,the photothermal agent has excellent photothermal therapeutic ability.We further investigated reversible photothermal therapy with the moderately stable compound SO2R6.The spectral test results showed that SO2R6 showed a p H reversible discoloration response.With the increase of p H value（p H>6）,the color of the solution changed from green to colorless.In acidic solution（p H<6）,the color of the solution returned to green,and the p K_a was about 6.The compound SO2R6 also has a certain photothermal effect,the calculated photothermal conversion efficiency is 72.36%,and has good photothermal stability in acidic aqueous solution（p H<6）.Therefore,these compounds can achieve p H-regulated photothermal therapy.Cytotoxicity and cell life/death tests showed that the compound had good biocompatibility.The IC₅₀ of SO2R6was 72.52μM by calculation.The photoacoustic imaging results show that SO₂R6produces good photoacoustic signal.The tumor model of 4T1 tumor bearing mice was established,and the results showed that the photothermal agent could successfully inhibit the growth of tumor.In conclusion,SO2R2 and SO2R6 have excellent photothermal therapeutic ability and can be used for photoacoustic imaging guided photothermal treatment of tumors.