Anticancer Photodynamic Therapy Using Ruthenium(II) and Os(II)-Based Complexes as Photosensitizers

Photodynamic therapy (PDT) is an approved procedure using a photosensitizer (PS) activated by light to selectively destroy malignant/premalignant cells. Transition metal complexes, such as Ru(II)- and Os(II)-based PSs (Theralase Technologies Inc., Ontario. Canada), are activated in a wide range of wavelengths, are resistant to photobleaching and have a high singlet oxygen quantum yield and ability to produce cytotoxic reactive oxygen species (ROS). Their design allows fine-tuning of the photophysical and photochemical properties. They demonstrate Type I and II photoreactions, and some are activated in hypoxia. High PDT potency and activation under NIR light and even X-ray may provide an advantage over the approved PSs. Their ability to associate with transferrin (Tf) as an endogenous delivery system increases photobleaching resistance, ROS production, selective cellular uptake, and PDT efficacy in combination with a decreased systemic toxicity. This makes these PSs attractive for systemic therapy of recurrent/progressive cancers. Their PDT efficacy has been demonstrated in various in vitro and in vivo clinically relevant models. The unique properties of the mentioned PSs allow bypassing such limitations of PDT as low specific uptake ratio, insufficiently broad absorption band, and low efficacy in hypoxia. One of these PSs (TLD-1433) was successful against non-muscle invasive urinary bladder cancer unresponsive to contemporary anticancer therapies

Self-renewing resident arterial macrophages arise from embryonic CX3CR1+ precursors and circulating monocytes immediately after birth

Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene-expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1+ precursors and postnatally from bone marrow–derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche

Reverse Transendothelial Migration of Intimal CD11c+ Dendritic Cells: Role in Intracellular Pathogen Removal and Effect on Atherosclerotic Lesions.

Dendritic cells are antigen presenting cells that play a key role in the initiation of the adaptive immune response and in chronic inflammatory diseases such as atherosclerosis. Resident intimal CD11c+ cells are abundant in the normal arterial intima of mice, in regions predisposed to atherosclerosis. Upon induction of hypercholesterolemia, these cells engulf lipids and become the first foam cells in nascent lesions. However, their function in the normal aorta remains poorly understood. The purpose of this study is to show that their function is to protect the arterial intima against Chlamydia (C.) muridarum infection, and potentially against other intracellular and extracellular bacteria. This protection is achieved when intimal CD11c+ cells undergo reverse transendothelial migration (RTM) through the endothelium into the arterial circulation to remove the pathogen from the vessel wall. Systemic pathogens and stimulation of pattern recognition receptors trigger two waves of RTM of intimal CD11c+ cells, each was followed by recovery through proliferation of the remaining cells. Both waves of RTM were dependent on up-regulated expression of CCR7 and its ligand CCL19 by intimal CD11c+ cells. C. muridarum enters the arterial intima when infected circulating monocytes are recruited. The second wave of RTM removes the pathogen from the vessel wall. Inhibition of RTM (e.g. in Ccr7-/- mice) results in accumulation of C. muridarum in the vessel wall, which induces a local inflammatory response, that could be harmful to the arteria intima. Hypercholesterolemia and lipid loading of intimal CD11c+ cells by feeding Ldlr--/- mice high fat diet for one week results in inhibition of RTM of CD11c+ foam cells. Lipid loading did not affect CCR7 or CCL19 induction in intimal cells and incubation with CCL19 did not rescue RTM in atherosclerotic lesions. Studies in Asc-/- and Casp1-/- mice that are deficient in the production of cleaved IL-1ď ˘, as well as antibody blockade and rescue experiments revealed that RTM is dependent on IL-1ď ˘ production from the arterial endothelial cells. In addition, experiments with Il-1r1-/- mice suggest that RTM is dependent on receptor expression by the endothelial cells. Future studies will continue to investigate other factors and mechanisms that might play a role in RTM of intimal CD11c+ cells, and explore how they can be used to induce RTM in atherosclerotic lesions as a potential preventative therapy to reduce atherosclerotic plaque burden.Ph.D

Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs.

peer reviewedThe blood contains high concentrations of circulating extracellular vesicles (EVs), and their levels and contents are altered in several disease states, including cardiovascular disease. However, the function of circulating EVs, especially the microRNAs (miRNAs) that they contain, are poorly understood. We sought to determine the effect of secreted vesicles produced by quiescent endothelial cells (ECs) on monocyte inflammatory responses and to assess whether transfer of microRNAs occurs between these cells. We observed that monocytic cells cocultured (but not in contact) with ECs were refractory to inflammatory activation. Further characterization revealed that endothelium-derived EVs (EC-EVs) suppressed monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses. EVs isolated from mouse plasma also suppressed monocyte activation. Importantly, injection of EC-EVs in vivo repressed monocyte/macrophage activation, confirming our in vitro findings. We found that several antiinflammatory microRNAs were elevated in EC-EV-treated monocytes. In particular, miR-10a was transferred to monocytic cells from EC-EVs and could repress inflammatory signaling through the targeting of several components of the NF-kappaB pathway, including IRAK4. Our findings reveal that ECs secrete EVs that can modulate monocyte activation and suggest that altered EV secretion and/or microRNA content may affect vascular inflammation in the setting of cardiovascular disease