Pyriplatin-Boron-Dipyrromethene Conjugates for Imaging and Mitochondria-Targeted Photodynamic Therapy

Abstract

Monofunctional pyriplatin analogues cis-[Pt-(NH 3 ) 2 (L)Cl](NO 3 ) (1−3) having boron-dipyrromethene (BODIPY) pendants (L) with 1,3,5,7-tetramethyl-8-(4-pyridyl)-4,4′-difluoroboradiazaindacene moieties were designed and synthesized, and their photocytotoxic properties were studied. The Pt-BODIPY conjugates displayed an absorption band within 505−550 nm and a green emissive band near 535 nm in 1% DMSO/DMEM (Dulbecco's modified Eagle's medium) buffer. Complex cis-[Pt(NH 3 ) 2 (4-Me-py)Cl](NO 3 ) (4) was used as a control for determining the structural aspects by X-ray crystallography. The mono-and diiodinated BODIPY complexes 2 and 3 showed generation of singlet oxygen on light activation as evidenced from the 1,3-diphenylisobenzofuran (DPBF) titration experiments. The cytotoxicity of the BODIPY complexes was tested against A549 (human lung cancer), MCF-7 (human breast cancer), and HaCaT (human skin keratinocyte) cells in dark and visible light (400−700 nm, 10 J cm −2 ). While complexes 2 and 3 showed excellent photocytotoxicity (IC 50 ≈ 0.05 μM), they remained essentially nontoxic in the dark (IC 50 > 100 μM). The emissive bands of 1 and 2 were used for cellular imaging by confocal microscopy study, which showed their mitochondrial localization. This was further supported by platinum estimation from isolated mitochondria and mitochondrial depolarization through a JC-1 assay. The photomediated apoptotic cell death was evidenced from flow cytometric assays, annexin-V/FITC-PI (fluorescein isothiocyanate-propidium iodide) and cell cycle arrest in sub-G1 and G2/M phases. The complexes bind to 9-ethylguanine as a model nucleobase to form monoadducts. A mechanistic study on DNA photocleavage activity using pUC19 DNA showed singlet oxygen as the reactive oxygen species (ROS). The combination of photodynamic therapy with DNA cross-linking property enhanced the anticancer potential of the monofunctional BODIPY-conjugates of pyriplatins.

Optimization and characterization of poly(lactic-co-glycolic acid) nanoparticles loaded with astaxanthin and evaluation of anti-photodamage effect in vitro

“…Red fluorescence stands for the mitochondrial aggregated form of JC-1 because of a high Δ Ψ m, while green fluorescence represents the monomeric form of JC-1 owing to low Δ Ψ m [47]. Variation in Δ Ψ m leads to mitochondrial dysfunction and maybe the generation of ROS [48]. The relative Δ Ψ m value was analysed by flow cytometry and the results are shown in figure 7 a,b .…”

Unprecedented isolation of a dinuclear tin (II) complex stabilized by pyridine‐2,6‐dimethanol: structure, DFT and in vitro screening of cytotoxic properties

“…Lastly, furthering our interest, we have assessed the anticancer properties of the present tin (II) complex against the cervical cancer cell line (HeLa) and human lung cancer cell line (A549) employing MTT assay. The 24 and 48 hr assays indicate excellent anticancer activity with IC 50 values ~10.47 ± 0.9–17.77 ± 1.3 for HeLa and A549 (Figure , Table ).…”

Photodynamic Therapy Directed by Three‐Photon Active Rigid Plane Organic Photosensitizer

“…We used several methods to quantitatively evaluate the in vitro ROS production efficiency and dark/light cytotoxicity of these compounds. Methylene blue (MB), a ROS inducer with known ROS conversion efficiency (0.52) [ 18 ] and 1,3‐Diphenylisobenzofuran (DPBF) as a common ROS quencher [ 19 ] were used to detect the ROS conversion efficiency of U‐TsO, U‐OAc and U‐OH ( Figure a,b). Under 365 nm (0.2 mW cm −2 ) laser irradiation at 10 s intervals, all compounds (U‐TsO, U‐OAc, and U‐OH) caused DPBF absorption to decrease, indicating that DPBF is oxidized by the ROS generated by the three probes, of which U‐TsO led to the greatest DPBF absorption decrease.…”