The Design Of BODIPY Dyes And Thire Applications For Tumor Photodynamic/Photothermal Therapy

Phototherapy has advantages of minimally invasive,high space-time precision,controllability,repeatable local treatment and no drug resistance.It is a new method of tumor therapy besides surgery,chemotherapy and radiotherapy.According to different principles,phototherapy can be divided into photodynamic therapy and photothermal therapy.In clinical optical therapy,photosensitizers（PSs）generally have the disadvantages of low near-infrared molar extinction coefficient,low photothermal conversion efficiency,much higher than maximum permissible exposure,low singlet oxygen quantum yield,low tumor targeting,short tumor retention time,etc.,the application of phototherapy in clinic is severely limited.Therefore,how to synthesize high-performance photosensitizers by molecular design has been an important topic.Traditional photothermal therapy requires high-intensity laser excitation for cancer treatments due to the low photothermal conversion efficiency（PCE）of photothermal agents（PTAs）.PTAs with ultra-high PCEs can decrease the required excited light intensity,which allows safe and efficient therapy in deep tissues.In this work,we synthesize a PTA with high PCE of 88.3%based on a BODIPY scaffold,by introducing a-CF₃“barrier-free”rotor on the meso-position（tfm-BDP）.In both the ground and excited state,the-CF₃ moiety in tfm-BDP has no energy barrier to rotation allowing it to efficiently dissipate absorbed（NIR）photons as heat.Importantly,the barrier-free rotation of-CF₃ can be maintained after encapsulating tfm-BDP into polymeric nanoparticles（NPs）.Thus,laser irradiation with safe intensity（300m W/cm²,808 nm）can lead to complete tumor ablation in tumor-bearing mice after intravenous injection of tfm-BDP NPs.This strategy of“barrier-free rotation”provides a new platform for future design of PTT agents for clinical cancer treatment.Conventional photosensitizers（PSs）often show poor tumor retention and are rapidly cleared from the bloodstream,which is one of the key hindrances to guarantee precise and efficient photodynamic therapy（PDT）in vivo.In this work,we present a photosensitizer assembly nanosystem that sharply enhances tumor retention up to～10 days.The PSs are synthesized by meso-substituting anthracene onto the BODIPY scaffold（AN-BDP）,which then self-assemble into stable nanoparticles（AN-BDP NPs）with amphiphilic block copolymers due to the strong intermolecularπ-πinteraction of anthracene.Additionally,the incorporated anthracene excites the PSs,producing singlet oxygen under red light irradiation.Although AN-BDP NPs could completely suppress regular test size tumor（～100 mm³）by one-time radiation,only 12%tumour growth inhibition rate was observed in the case of large size tumor（～350mm³）under the same conditions.Due to the long time tumor retention,AN-BDP NPs allows single-dose injection and three-time light treatments,resulting in an over 90%inhibition rate,much more efficient than single-time radiation of conventional clinically used PSs including chlorin（Ce6）and porphyrin with poor tumor retention.The results reveal the importance of long tumor retention time of PSs for efficient PDT,which can accelerate the clinical development of nanophotosensitizers.In order to solve the problem that heavy atom substituted photosensitizers lead to high dark toxicity and short triplet lifetime,in this paper,an asymmetric or sterically hindered heavy-atom-free BODIPY photosensitizers were constructed,the spin-orbit coupling（SOC）of singlet and triplet states will be increased when the orbital angular momentum of the molecule is perpendicular to the plane axis.In addition,because the C-C bond of the parallel ring is fixed,the rotation of the C-C bond is limited,and the nonradiative transition caused by the rotation is reduced,so the fluorescence and ISC are improved.BDP-3 NPs can effectively accumulate and retain in the tumor.It not only can inhibit the normal subcutaneous tumor,but also has a good therapeutic effect on in situ liver cancer in mice.