Ruthenium(II)-Arene Curcuminoid Complexes as Photosensitizer Agents for Antineoplastic and Antimicrobial Photodynamic Therapy: In Vitro and In Vivo Insights.

Photodynamic therapy (PDT) is an anticancer/antibacterial strategy in which photosensitizers (PSs), light, and molecular oxygen generate reactive oxygen species and induce cell death. PDT presents greater selectivity towards tumor cells than conventional chemotherapy; however, PSs have limitations that have prompted the search for new molecules featuring more favorable chemical-physical characteristics. Curcumin and its derivatives have been used in PDT. However, low water solubility, rapid metabolism, interference with other drugs, and low stability limit curcumin use. Chemical modifications have been proposed to improve curcumin activity, and metal-based PSs, especially ruthenium(II) complexes, have attracted considerable attention. This study aimed to characterize six Ru(II)-arene curcuminoids for anticancer and/or antibacterial PDT. The hydrophilicity, photodegradation rates, and singlet oxygen generation of the compounds were evaluated. The photodynamic effects on human colorectal cancer cell lines were also assessed, along with the ability of the compounds to induce ROS production, apoptotic, necrotic, and/or autophagic cell death. Overall, our encouraging results indicate that the Ru(II)-arene curcuminoid derivatives are worthy of further investigation and could represent an interesting option for cancer PDT. Additionally, the lack of significant in vivo toxicity on the larvae of Galleria mellonella is an important finding. Finally, the photoantimicrobial activity of HCurc I against Gram-positive bacteria is indeed promising.

Phototoxicity of two positive-charged diaryl porphyrins in multicellular tumor spheroids.

Photodynamic therapy (PDT) is a clinically approved cancer treatment in which reactive oxygen species are formed only when three harmless components, a photosensitizer (PS), light and molecular oxygen, are present at the same time, leading to cell death. Most of the PSs were tested on monolayer cells, but differences between 2D cells and solid tumors significantly limit the value of in vitro PDT studies, whereas the use of 3D spheroid might be more suitable for drug development and preclinical drug testing for PDT. In a previous work we have shown that two positive-charged diaryl porphyrins (2 and 4) were more potent than the corresponding neutral molecules (1 and 3) on a panel of 2D-cultured cancer cell lines. In the present study the photodynamic effects of these molecules have been evaluated on HCT116 and MCF7 spheroids. Induction of apoptotic and necrotic cell death, and generation of reactive oxygen species (ROS) have been also evaluated, along with accumulation and localization of PSs into spheroids. Our findings indicate that 2 and 4 retained their phototoxic effects also in 3D spheroids; furthermore, they were more potent than 1 and 3 and as potent as Foscan (m-THPC), the most successful PS approved for clinical PDT of cancer, used as reference. Although further aspects of their mechanisms of action need to be addressed, our results strongly suggest a potential in vivo photodynamic application of 2 and 4, considering that spheroids represent a more realistic indicator of in vivo therapeutic efficacy than 2D cell lines.

Hybrid giant lipid vesicles incorporating a PMMA-based copolymer.

BACKGROUND: In recent years, there has been a growing interest in the formation of copolymer-lipid hybrid self-assemblies, which allow combining and improving the main features of pure lipid-based and copolymer-based systems known for their potential applications in the biomedical field. As the most common method used to obtain giant vesicles is electroformation, most systems so far used low Tg polymers for their flexibility at room temperature. METHODS: Copolymers used in the hybrid vesicles have been synthesized by a modified version of the ATRP, namely the Activators ReGenerated by Electron Transfer ATRP and characterized by NMR and DSC. Giant hybrid vesicles have been obtained using electroformation and droplet transfer method. Confocal fluorescence microscopy was used to image the vesicles. RESULTS: Electroformation enabled to obtain hybrid vesicles in a narrow range of compositions (15 mol% was the maximum copolymer content). This range could be extended by the use of a droplet transfer method, which enabled obtaining hybrid vesicles incorporating a methacrylate-based polymer in a wide range of compositions. Proof of the hybrid composition was obtained by fluorescence microscopy using labeled lipids and copolymers. CONCLUSIONS: This work describes for the first time, to the best of our knowledge, the formation of giant hybrid polymer/lipid vesicles formed with such a content of a polymethylmethacrylate copolymer, the glass temperature of which is above room temperature. GENERAL SIGNIFICANCE: This work shows that polymer structures, more complex than the ones mostly employed, can be possibly included in giant hybrid vesicles by using the droplet transfer method. This will give easier access to functionalized and stimuli-responsive giant vesicles and to systems exhibiting a tunable permeability, these systems being relevant for biological and technological applications.

New BODIPYs for photodynamic therapy (PDT): Synthesis and activity on human cancer cell lines.

A new class of compounds based on the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene core, known as BODIPYs, has attracted significant attention as photosensitizers suitable for application in photodynamic therapy (PDT), which is a minimally invasive procedure to treat cancer. In PDT the combination of a photosensitizer (PS), light, and oxygen leads to a series of photochemical reactions generating reactive oxygen species (ROS) exerting cytotoxic action on tumor cells. Here we present the synthesis and the study of the in vitro photodynamic effects of two BODIPYs which differ in the structure of the substituent placed on the meso (or 8) position of the dipyrrolylmethenic nucleus. The two compounds were tested on three human cancer cell lines of different origin and degree of malignancy. Our results indicate that the BODIPYs are very effective in reducing the growth/viability of HCT116, SKOV3 and MCF7 cells when irradiated with a green LED source, whereas they are practically devoid of activity in the dark. Phototoxicity occurs mainly through apoptotic cell death, however necrotic cell death also seems to play a role. Furthermore, singlet oxygen generation and induction of the increase of reactive oxygen species also appear to be involved in the photodynamic effect of the BODIPYs. Finally, it is worth noting that the two BODIPYs are also able to exert anti-migratory activity.