Photochemotherapy of Infrared Active BODIPY-Appended Iron(III) Catecholates for in Vivo Tumor Growth Inhibition

Abstract

Iron(III) catecholates of BODIPY (boron-dipyrromethene)-conjugated dipicolylamine ligands, viz. [Fe(L 1 )(cat)Cl] ( 1 ) and [Fe(L 2 )(cat)Cl] ( 2 ) (H 2 cat = catechol), with a ligand-to-metal charge transfer band at ∼800 nm were studied for their in vivo activity in dark and infrared light in luciferase-expressing human breast adenocarcinoma (BT474luc) cells. Complex 2 displayed in vitro photocytotoxicity in BT474luc cells (IC 50 : 6 μM) in infrared light of 600–720 nm with moderate dark toxicity (IC 50 : 18 μM) as evidenced from the MTT and Annexin-V FITC/PI staining assays. The mitochondria-localizing complexes showed apoptotic cell death involving reactive oxygen species whose generation was evidenced from 2,7-dichlorofluorescein diacetate assay. In vivo studies showed tumor growth inhibition in mice with an optimized complex 2 dose of 5 mg per kg body weight on exposure to infrared light of 685 nm (dose of 20 mW/cm 2 ). The in vivo results exemplify complex 2 as a unique iron-based infrared-active photochemotherapeutic agent.

Versatile Nanoplatform Loaded with Doxorubicin and Graphene Quantum Dots/Methylene Blue for Drug Delivery and Chemophotothermal/Photodynamic Synergetic Cancer Therapy

“…AO/EB staining was utilized to assess the mechanism of cell death induced by the nanoparticles. − As shown in Figure a, HeLa cells appeared in lightful green without nanoparticles and laser irradiation, revealing that the cells were living with a normal structure. However, when the cells were cultured under different conditions for 24 h, a very obvious phenomenon was observed: the number of cells presenting green fluorescence were decreased, and the number of apoptotic cells were increased, revealing that the synergetically treated cells were late apoptotic cells or nonapoptotic necrotic cells.…”

Maloplatin-B, a Cisplatin-Based BODIPY-Tagged Mito-Specific “Chemo-PDT” Agent Active in Red Light

“…A combination of PDT- and CP-based chemotherapy can be achieved by designing a new generation of cisplatin-derived platinum­(II) complexes having a dissociable ligand tagged with a photosensitizer as a “chemo-PDT” agent that can generate singlet oxygen on irradiation using near-IR red light. − The light within the PDT spectral window has the advantage of the highest penetration to reach the cancer cells in deep tissues for better efficacy, and red-light-absorbing tissue chromophores are generally absent in the human body. Although Photofrin is the FDA-approved PDT drug, it suffers from selectivity, post-treatment skin sensitivity, and hepatotoxicity. − Reports from our group have shown that boron-dipyrromethene-appended transition-metal complexes can be used as photosensitizers for generating singlet oxygen in high yield on light activation. − BODIPY dyes have good photostability, and their core is amenable for tuning the absorption and emission properties within a broad spectral window ranging from the visible to the near-IR region. , In addition, BODIPY dyes can be tuned to localize into different cellular organelles, thus specifically enhancing their therapeutic potential. − We have recently reported a diplatinum­(II) catecholate, [{Pt­(dach)} 2 (μ-Dcrb)] (DP), where dach is 1,2-diaminocyclohexane and Dcrb is a tetraanionic morpholine-conjugated BODIPY-linked dicatecholate base, as a lysosome-targeting PDT agent in red light . This complex acts more as an organelle-targeting PDT agent localizing in lysosomes than as a chemotherapeutic agent with IC 50 values of 0.6 μM in HeLa cells in red light (600–720 nm) and 105 μM in the dark with a remarkable PI (phototoxic index) value.…”

Iron(III) Complex-Functionalized Gold Nanocomposite as a Strategic Tool for Targeted Photochemotherapy in Red Light

“…The complexation of iron­(III) with the π-donor ligands in an octahedral geometry typically results in a reduced energy gap between t 2g and e g * molecular orbitals − that lead to low-energy metal-centered or ligand-to-metal charge-transfer (LMCT) transition with the typical wavelength of absorption in the range of 450–600 nm. − When such complexes are activated with light at the LMCT band, there is typical homolytic fission of the metal–ligand bond, which consequently leads to the oxidation of the ligand (carboxylate-O or phenolate-O) and reduction of the iron­(III) center to iron­(II). − Such a light-induced intramolecular redox reaction is typically responsible for the generation of extremely cytotoxic ROS, such as superoxide anions (O 2 •– ) and hydroxyl radicals. − Therefore, the ability of the phenolate or carboxylate-based complexes of iron­(III) to yield ROS with low-energy or longer-wavelength light activation has shown potential as a promising strategic tool for photochemotherapeutic utility. Recently, our group, along with Chakravarty et al, has reported visible-light-induced hydroxyl radical-mediated photocytotoxicity with iron­(III)-phenolate/carboxylate-based complexes in different cancer cells. − However, the complexes did not satisfy the criteria for being ideal photochemotherapeutic agents as the majority of the iron­(III) complexes lacked target-specificity and showed photocytotoxicity only in the visible light (<600 nm).…”