Amphiphilic NIR BODIPY Nanoparticles For Dual-mode Imaging And Photothermal Therapy In Thyroid Cancer

As one of the most common endocrine malignancies,the incidence of thyroid cancer is increased year by year.In the past 30 years,the incidence of thyroid cancer has tripled.According to the report of global cancer statistics 2018,the incidence of thyroid cancer ranked eleventh in all kinds of malignancies and ranked fourth in women.In China,the incidence increases more rapidly and has ranked seventh.The traditional treatments include surgery,thyrotropin inhibition therapy,131 I internal radiation therapy.Besides those normal treatments,scientists are enthusiastic about developing more promising treatments.Comparing to the traditional treatments,photothermal therapy(PTT)is noninvasive and has minimal side effects.PTT could convert light energy into thermal energy via photosensitizer and be applied to kill cancer cells.Boron-dipyrrome-thenes(BODIPY)is one kind of photo-sensitive dyes with high photoluminescence quantum yields and stability in physiological environment.It is widely used in PTT,imaging and theranostics which means integrating tumor treatment and diagnosis concurrently.Theranostics could elicit multiple functions such as combining tumor imaging with photothermal therapy.Combining tumor imaging with treatment is an efficient way to monitor the pharmacokinetics and measure the treatment effect,meanwhile,the location,shape,size and type of tumor could be detected.Nanoparticles have been widely applied in drug delivery.They could not only package the drugs to reduce the biodegradation,but also help to overcome the waterinsolubility of many hydrophobic drugs such as BODIPY.PEGylation helps to modify hydrophobic drugs and imaging agents,and the obtained amphiphilic compounds could form into stable nanoparticles in water.It is reported that the concentration of GSH in tumor is much higher than that in normal tissues,so that we can design GSH-sensitive(redox-sensitive)nanoparticles.Many redox-sensitive structures such as disulfide bonds and diselenide bond are sensitive to GSH and could be used to form redoxsensitive nanoparticles.The structure could be broken by intracellular GSH and induced the dissociation of nanoparticles and the release of drugs.Therefore,we designed and synthesized an amphiphilic NIR BODIPY,andt then the BODIPY self-assembled into nanoparticles and was utilized in tumor theranostics.Meanwhile,disulfide bond could accelerate the dissociation of nanoparticles to turn on the NIRF fluorescence via GSH.In our work,the physicochemical properties and photothermal property of PEG-SS-BDP NPs were investigated in detail,the photothermal therapy effect and biocompatibility were verified via in vitro and in vivo experiments.The main contents are listed as followed:(1)We designed and synthesized an amphiphilic BODIPY(PEG-SS-BDP)containing disulphide which was modified by PEG.PEG-SS-BDP was purified and confirmed by proton nuclear magnetic resonance,matrix-assisted laser desorption/ ionization time-of-light mass spectrometry and size-exclusion chromatography.PEGSS-BDP could self-assemble into nanoparticles.The image of transmission electron(TEM)microscopy and the results of dynamic light scattering(DLS)verified the uniform sphere shape of nanoparticles.According to the DLS data,PEG-SS-BDP NPs showed good stability in water and mimic physiological environment,otherwise,the addition of glutathione broke the stability of nanoparticles.(2)The physicochemical properties and photothermal property of PEG-SS-BDP NPs were demonstrated in detail.According to the UV-vis absorption spectrum,the maximum absorption peak of PEG-SS-BDP NPs was in NIR region.In photoluminescence spectrum,PEG-SS-BDP in DCM showed its fluorescence peak at around 750 nm.PEG-SS-BDP NPs possessed high photothermal conversion efficiency and photothermal repeatability.The heating rate was accelerated,with the increase of concentration of PEG-SS-BDP NPs.(3)The cellular uptake and photothermal therapy effect of PEG-SS-BDP NPs were detected.The image of confocal laser scanning microscopy(CLSM)demonstrated that PEG-SS-BDP NPs possessed capability of time-dependent cellular uptake and glutathione could accelerate the breakdown of disulphide,dissociation of nanoparticles and turning on of fluorescence.The thiazolyl blue tetrazolium bromide(MTT)assays stated that with the increase of the concentration,the photothermal therapy effect under irradiation enhanced.At the meantime,PEG-SS-BDP NPs showed no photothermal effect without irradiation.(4)Tumor imaging,photothermal therapy effect and biocompatibility were confirmed in vivo.Photoacoustic imaging and near-infrared fluorescence imaging could describe the shape and size of tumors.The sizes of tumors and weights of mice bearing human thyroid cancer were measured,which demonstrated PEG-SS-BDP NPs possessed favorable photothermal therapy effect.Via observing the histological analysis image of main organs(including heart,liver,spleen,lung and kidney),no obvious damage could be found,confirming the biocompatibility of PEG-SS-BDP NPs.In summary,PEG-SS-BDP NPs designed in our work showed many excellent physicochemical properties,such as good stability in water,suitable UV-vis absorption in near-infrared region,strong fluorescence and high photothermal conversion efficiency.PEG-SS-BDP NPs were potential theranostical nanoparticles with wonderful photoacoustic imaging,near-infrared imaging and photothermal therapy effect,which could be polished for further clinical application.