Design And Synthesis Of BODIPY-Based Phototheranostics And Their Application In The Cancer Therapy

Phototheranostics integrates photodiagnosis and phototherapy,which displays outstanding advantages in cancer thherapy.Its principle is that phototheranostic agents generate fluorescence or photoacoustic signals under light irradiation for imaging diagnosis,simultaneously generating reactive oxygen species（ROS）or heat for photodynamic therapy（PDT）or photothermal therapy（PTT）.To overcome the disadvantages of clinic phototheranostic agents,such as short excitation wavelength,low ROS yields and photothermal conversion efficiency（PCE）,and poor water-solubility,Boron dipyrrolidone（BODIPY）with high molar extinction coefficient,good structural stability,and easy molecular modification was selected as the parent molecule in this paper.By expanding the conjugated system,introducing strong push-pull electron groups,introducing steric groups and other strategies,a series of near infrared（NIR）phototheranostic agents can produce NIR fluorescence,ROS and heat,and BODIPY type phototherapeutics under NIR light irradiation were designed and synthesized.The relationship between the molecular structure of phototheranostic agents and their photophysical and photochemical properties was explored and clarified.BODIPY nanoparticles（NPs）with good water-solubility were prepared by molecular assembly or nano-coprecipitation strategy.The effects of intermolecular aggregation mode on absorption,fluorescence,ROS and PCE of BODIPY NPs were studied.Moreover,the phototheranostic effects of BODIPY NPs were systematically evaluated through in vitro cell and in vivo animal model systems.The research results of this paper provide a new approach for designing high-efficiency phototheranostic agents with NIR absorption for multimodal imaging guided combination therapy.（1）Four BODIPY derivatives（B-H,B-OCH₃,B-NO₂,and B-2NO₂）were designed and synthesized by modifying with-H,-OCH₃,and-NO₂group at meso position of BODIPY,two-NO₂ group at ortho position of BODIPY,respectively.The electron donating group-OCH₃ can improve the singlet oxygen quantum yield（¹O₂ QY）and fluorescence quantum yield（FLQY）of BODIPY,while the electron withdrawing group-NO₂ can partially quench its fluorescence and reduce the ¹O₂ QY,improving its photothermal conversion ability.NPs with good were prepared by encapsulating BODIPY derivatives with DSPE-PEG-2000.Among them,B-OMe-NPs exhibited the highest ¹O₂ production ability,excellent PCE（66.5%）,and strong NIR fluorescence emission(λ_Em=809 nm).The experimental results of in vitro cell and in vivo mice bearing tumor model indicated that B-OMe NPs can be used for NIR fluorescence imaging（FLI）and photoacoustic imaging（PAI）guided synergistic PDT and PTT.（2）Three BODIPY derivatives（B-1F,B-3F,and B-5F）were designed and synthesized by modifying with phenyl groups with 1,3,and5 F atom substitutions at meso position of BODIPY.The substitution of F enhances the intramolecular charge transfer effect of BODIPY,red-shifting its absorption and fluorescence emission wavelengths to 752 nm and 806 nm,respectively;Theπ-conjugated structure and intermolecular halogen bonds of B-5F trigger and control intermolecular"interlaced"π-πstacking to form J type-aggregates,further red-shifting their absorption and fluorescence spectra.B-5F NPs were prepared using Pluronic F-127encapsulated J type-aggregates of B-5F,and their absorption and fluorescence emission wavelengths red-shifted to 792 nm and 942 nm,respectively.B-5F NPs can generate ¹O₂（¹O₂ QY=0.7%）and heat（PCE=67.4%）under 808 nm laser irradiation.The experimental results of in vitro cell indicated that B-5F NPs mainly provide PTT to kill tumor cells.The experimental results of mice bearing tumor model indicated that B-5F NP can be used for NIR FLI guided PTT.（3）The parent structure of BODIPY is a strong electron-withdrawing group.B-2TPA with the structure of electron donor-π-electron acceptor（D-π-A）was designed and synthesized by introducing strong electron donating groups（triphenylamine and N,N-diethylaniline）at theαandβpposition of BODIPY.The absorption and fluorescence emission wavelengths of B-2TPA were 729 nm and 778 nm,respectively.The ¹O₂QY and PCE of B-2TPA is only 2.3%and 39.8%.Moreover,B-2TPA exhibits obvious TICT effect.B-2TPA NPs with good water-dispersibility were prepared by encapsulating B-2TPA with DSPE-PEG-2000.The intermolecular aggregation reduces the energy gap between the excited singlet state and the excited triplet state,improving the intersystem crossing efficiency to increase the ¹O₂ QY of B-2TPA NPs to 6.7%.In addition,B-2TPA NPs have good photostability,with a PCE of 60.1%.Therefore,B-2TPA NPs can provide NIR FLI and PAI guided synergistic PDT and PTT.（4）Three BODIPY compounds with D-π-A structure（B-B,B-C,and B-C-Pt）were designed and synthesized by introducing multiple C=C and platinum pyridine quaternary ammonium into the BODIPY.The introduction of C=C bond expands theπ-conjugated structures of B-C and B-C-Pt,improving their photothermal conversion ability;The strong electron-withdrawing effect of platinum pyridine quaternary ammonium salt enhanced the intramolecular charge transfer of B-C-Pt,red-shifting its absorption and fluorescence emission wavelengths to 748 nm and 947 nm,respectively.The presence of cisplatin not only enhances the ¹O₂generation ability of B-C-Pt by heavy atom effect,but also endows it with chemotherapy efficacy.Because DSPE-PEG-2000 can inhibit the H aggregation of B-C-Pt in water,the absorption and fluorescence emission wavelengths of B-C-Pt NPs red-shifted to 762 nm and 985 nm,respectively.The B-C-Pt NPs ¹O₂ QY and PCE are 4.0%and 40.6%,respectively.B-C-Pt NPs can be used for NIR Ⅱ FLI and PAI guided synergistic PDT,PTT,and chemotherapy.102 images,4 tables,and 150 references...