Biological evaluation of complexes of cyclopentadienyl M(CO)3+ (M = Re, 99mTc) with high blood-brain barrier penetration potential as brain cancer agents.

To address the major medical need for effective chemotherapeutics/diagnostics for brain cancer, in this work three cyclopentadienyl M(CO)3+ (M = Re, 99mTc) complexes, which cross the blood-brain barrier (BBB) in high % and are designed to mimic the anticancer agent 2-phenylbenzothiazole, are in vitro and in vivo evaluated for anticancer action. The study includes cytotoxicity and uptake studies in cancer and healthy neuronal cell lines, mechanistic investigation of potential anticancer pathways, and biodistribution studies in mice bearing glioblastoma xenografts. The stable Re complexes exhibit selective uptake and significant antiproliferative effect, particularly against U-251 MG glioblastoma cells, with no significant toxicity in healthy neurons, demonstrating the suitability of this type of complexes to serve as selective therapeutic/imaging agents for brain cancer. Furthermore, they result in the generation of elevated Reactive Oxygen Species (ROS) levels, and lead to significant G2/M arrest followed by apoptosis. Biodistribution studies in U-251 MG xenograft bearing mice with the radioactive 99mTc complex that exhibits the highest BBB penetration, show retention at the tumor-site offering a diagnostic prospect and, in addition, indicating the capability of the Re analogue to accumulate at the tumor site for therapeutic action. Overall, the complexes demonstrate significant anticancer properties that, combined with their high BBB penetration potential, render them strong candidates for further evaluation as brain cancer agents.

Curcumin derivatives as photosensitizers in photodynamic therapy: photophysical properties and in vitro studies with prostate cancer cells.

Photodynamic therapy (PDT) is a minimally invasive approach to treat various forms of cancer, based on the ability of certain non-toxic molecules (photosensitizers) to generate reactive oxygen species (ROS) after excitation by light of a certain wavelength and eventually induce strong phototoxic reactions against malignant cells and other pathogens. Curcumin is one of the most extensively investigated phytochemicals with a wide range of therapeutic properties and has been shown to induce strong photocytotoxic effects in micromolar concentrations against a variety of cancer cell lines. Curcumin (1) is comparatively evaluated with the naturally occurring bisdemethoxy Curcumin (2), which lacks the two methoxy groups, as well as two newly synthesized curcuminoids, the cinnamaldehyde derivative (3) and the dimethylamino one (4), designed to increase the absorption maximum and hence the tissue penetration. The synthetic curcuminoids were successfully synthesized in sufficient amounts and their photophysical properties such as absorption, fluorescence, photobleaching and free radical generation were investigated. Compound 4 exhibited a significant increase in peak absorption (497 nm) and strong fluorescent emission signals were recorded for all curcuminoids. Photobleaching of 4 was comparable to 1 whereas 2 and 3 showed more extended photobleaching but much higher ROS production in very short irradiation times. Compounds 2 and 4 exhibited specific intracellular localization. After dark and light cytotoxicity experiments against LNCaP prostate cancer cell line for all curcuminoids, concentration of 3 µM and irradiance of 6 mW cm-2 were selected for the PDT application which resulted in remarkable results with very short LD50. Curcuminoids 2 and 4 exhibited a significant dose-dependent PDT effect. The biphasic dose-response photodynamic effect observed for 1 and 3 may provide a strategy against prolonged and sustained photosensitivity.