Triphenylphosphonium-functionalized dimeric BODIPY-based nanoparticles for mitochondria-targeting photodynamic therapy.

The dimerization of boron dipyrromethene (BODIPY) moieties is an appealing molecular design approach for developing heavy-atom-free triplet photosensitizers (PSs). However, BODIPY dimer-based PSs generally lack target specificity, which limits their clinical use for photodynamic therapy. This study reports the synthesis of two mitochondria-targeting triphenylphosphonium (TPP)-functionalized meso-ß directly linked BODIPY dimers (BTPP and BeTPP). Both BODIPY dimers exhibited solvent-polarity-dependent singlet oxygen (1O2) quantum yields, with maximum values of 0.84 and 0.55 for BTPP and BeTPP, respectively, in tetrahydrofuran. The compact orthogonal geometry of the BODIPY dimers facilitated the generation of triplet excited states via photoinduced charge separation (CS) and subsequent spin-orbit charge-transfer intersystem crossing (SOCT-ISC) processes and their rates were dependent on the energetic configuration between the frontier molecular orbitals of the two BODIPY subunits. The as-synthesized compounds were amphiphilic and hence formed stable nanoparticles (∼36 nm in diameter) in aqueous solutions, with a zeta potential of ∼33 mV beneficial for mitochondrial targeting. In vitro experiments with MCF-7 and HeLa cancer cells indicated the effective localization of BTPP and BeTPP within cancer-cell mitochondria. Under light irradiation, BTPP and BeTPP exhibited robust photo-induced therapeutic effects in both cell lines, with half-maximal inhibitory concentration (IC50) values of ∼30 and ∼55 nM, respectively.

Red fluorescent BODIPY-based nanoparticles for targeted cancer imaging-guided photodynamic therapy.

Imaging-guided diagnosis and treatment of cancer hold potential to significantly improve therapeutic accuracies and efficacies. Central to this theragnostic approach has been the use of multicomponent-based multimodal nanoparticles (NPs). Apart from this conventional approach, here we propose a design strategy for the simple and straightforward formulation of NPs based on boron dipyrromethene (BODIPY) derivatives, LaB-X (X = H, Et, and Br). Specifically, the conjugation of lactose to the inherently hydrophobic BODIPY promoted the formation of LaB-X NPs in water. Furthermore, the BODIPY backbone was subjected to distyrylation, dibromination, and diethylation to tailor the optical window and the balance between fluorescence and singlet oxygen generation capabilities. We demonstrate that while the photoinduced anticancer activities of LaB-H and LaB-Et NPs were trivial, LaB-Br NPs effectively induced the apoptotic death of hepatocellular carcinoma cells under red light irradiation while allowing fluorescence cell imaging in the phototherapeutic window. This dual fluorescence photosensitizing activity of LaB-Br NPs could be switched off and on, so that both fluorescence and singlet oxygen generation were paused during NP formation in an aqueous solution, while both processes resumed after cellular uptake, likely due to NP disassembly.

BODIPY nanoparticles functionalized with lactose for cancer-targeted and fluorescence imaging-guided photodynamic therapy.

A series of four lactose-modified BODIPY photosensitizers (PSs) with different substituents (-I, -H, -OCH3, and -NO2) in the para-phenyl moiety attached to the meso-position of the BODIPY core were synthesized; the photophysical properties and photodynamic anticancer activities of these sensitizers were investigated, focusing on the electronic properties of the different substituent groups. Compared to parent BODIPY H, iodine substitution (BODIPY I) enhanced the intersystem crossing (ISC) to produce singlet oxygen (1O2) due to the heavy atom effect, and maintained a high fluorescence quantum yield (ΦF) of 0.45. Substitution with the electron-donating methoxy group (BODIPY OMe) results in a significant perturbation of occupied frontier molecular orbitals and consequently achieves higher 1O2 generation capability with a high ΦF of 0.49, while substitution with the electron-withdrawing nitro group (BODIPY NO2) led a perturbation of unoccupied frontier molecular orbitals and induces a forbidden dark S1 state, which is negative for both fluorescence and 1O2 generation efficiencies. The BODIPY PSs formed water-soluble nanoparticles (NPs) functionalized with lactose as liver cancer-targeting ligands. BODIPY I and OMe NPs showed good fluorescence imaging and PDT activity against various tumor cells (HeLa and Huh-7 cells). Collectively, the BODIPY NPs demonstrated high 1O2 generation capability and ΦF may create a new opportunity to develop useful imaging-guided PDT agents for tumor cells.

Mitochondrion-targeting PEGylated BODIPY dyes for near-infrared cell imaging and photodynamic therapy.

A series of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-based photosensitizers (AmBXI, X = H, M, Br) featuring a cationic mitochondrion-targeting group and near-infrared (NIR) absorption was synthesized. After extending the photosensitizers' π conjugation via Knoevenagel reaction, both the absorbance and emission maxima of AmBXI shifted to the phototherapeutic wavelength range (650-900 nm). Theoretical computations indicate that the introduction of bromine atoms promotes spin-orbit coupling, so that for each additional bromine atom in AmBXI an increase in singlet oxygen quantum yield would be expected (0.3%, 2.2%, and 4.1%, for AmBHI, AmBMI, and AmBBrI, respectively). Moreover, AmBXI photosensitizers exhibited low cytotoxicity in the dark and high phototoxicity, with the half maximal inhibitory concentrations of AmBBrI found to be 46.93 nM and 22.84 nM, while those of AmBMI were 129.7 nM and 58.34 nM in HeLa and MCF-7 cancer cells, respectively. Notably, introduction of a single bromine atom was enough to produce a cytotoxic effect. Furthermore, the presence of a quaternary ammonium group in AmBXI enabled the dyes to localize and stain the negatively charged mitochondria. The results presented herein indicate the straightforward and facile synthesis of NIR-light triggered mitochondrion-targeting photosensitizers.

Effect of Substituents on the Photophysical Properties and Bioimaging Application of BODIPY Derivatives with Triphenylamine Substituents.

We investigated the intramolecular charge transfer characteristics in the S1 state of boron-dipyrromethene (BODIPY) derivatives with triphenylamine (TPA) substituents, depending on the substituted position and the number of substituents. Based on the spectroscopic and theoretical results, the ß-substitution of TPA on BODIPY hybridizes locally excited and intramolecular charge transfer characteristics in the S1 state because of strong coupling between the highest occupied molecular orbitals of BODIPY and TPA moieties, and consequently, the BODIPY derivatives with ß-substituted TPAs exhibit strong red-color fluorescence around 640 nm in nonpolar and moderately polar solvents. The TPA substituent with propeller-like nonplanar geometry could prevent H-type aggregation between neighboring BODIPY derivative units and induce aggregation-induced emission enhancement (AIEE) characteristics of the BODIPY derivatives with TPA substituents, which are helpful to maintain their emission efficiencies under highly concentrated and condensed conditions. Since the red-color emission and AIEE property of the BODIPY derivatives with ß-substituted TPAs are promising characteristics for a bioimaging application, we applied these derivatives to L-929 fibroblast cells for cellular imaging. The BODIPY derivative with a single ß-substituted TPA (compound 2) was effectively loaded into porous silica nanoparticles (SNPs). Consequently, we achieved good cellular uptake of 2-SNPs and good cellular imaging, which further confirmed the bioimaging ability of 2-SNPs.