Nanomolar concentrations of the photodynamic compound TLD-1433 effectively inactivate numerous human pathogenic viruses.

The anti-viral properties of a small (≈1 kDa), novel Ru(II) photo dynamic compound (PDC), referred to as TLD-1433 (Ruvidar™), are presented. TLD-1433 had previously been demonstrated to exert strong anti-bacterial and anti-cancer properties. We evaluated the capacity of TLD-1433 to inactivate several human pathogenic viruses. TLD-1433 that was not photo-activated was capable of effectively inactivating 50 % of influenza H1N1 virus (ID50) at a concentration of 117 nM. After photo-activation, the ID50 was reduced to <10 nM. The dose of photo-activated TLD-1433 needed to reduce H1N1 infectivity >99 % (ID99) was approximately 170 nM. Similarly, the ID99 of photo-activated TLD-1433 was determined to range from about 20 to 120 nM for other tested enveloped viruses; specifically, a human coronavirus, herpes simplex virus, the poxvirus Vaccinia virus, and Zika virus. TLD-1433 also inactivated two tested non-enveloped viruses; specifically, adenovirus type 5 and mammalian orthoreovirus, but at considerably higher concentrations. Analyses of TLD-1433-treated membranes suggested that lipid peroxidation was a major contributor to enveloped virus inactivation. TLD-1433-mediated virus inactivation was temperature-dependent, with approximately 10-fold more efficient virucidal activity when viruses were treated at 37 °C than when treated at room temperature (∼22 °C). The presence of fetal bovine serum and virus solution turbidity reduced TLD-1433-mediated virucidal efficiency. Immunoblots of TLD-1433-treated human coronavirus indicated the treated spike protein remained particle-associated.

Efficacy of ruthenium coordination complex-based Rutherrin in a preclinical rat glioblastoma model.

BACKGROUND: Glioblastoma is an aggressive brain cancer in adults with a grave prognosis, aggressive radio and chemotherapy provide only a 15 months median survival. METHODS: We evaluated the tolerability and efficacy of the Ruthenium-based photosensitizer TLD-1433 with apo-Transferrin (Rutherrin) in the rat glioma 2 (RG-2) model. The specific tumor uptake ratio and photodynamic therapy (PDT) threshold of the rat glioblastoma and normal brain were determined, survival and CD8+T-cell infiltration post-therapy were analyzed. Results were compared with those obtained for 5-aminolevulinic acid (ALA)-induced Protoporphyrin IX (PpIX)-mediated photodynamic therapy in the same animal model. As both photosensitizers have different photophysical properties, the number of absorbed photons required to achieve an equal cell kill was determined for in vitro and in vivo studies. RESULTS: A significantly lower absorbed energy was sufficient to achieve LD50 with Rutherrin versus PpIX-mediated PDT. Rutherrin provides a higher specific uptake ratio (SUR) >20 in tumors versus normal brain, whereas the SUR for ALA-induced PpIX was 10.6. To evaluate the short-term tissue response in vivo, enhanced T2-weighted magnetic resonance imaging (MRI) provided the spatial extent of edema, post PpIX-PDT at twice the cross-section versus Rutherrin-PDT suggesting reduced nonspecific damage, typically associated with a secondary wave of neuronal damage. Following a single therapy, a significant survival increase was observed in rats bearing glioma for PDT mediated by Rutherrin versus PpIX for the selected treatment conditions. Rutherrin-PDT also demonstrated an increased CD8+T-cell infiltration in the tumors. CONCLUSION: Rutherrin-PDT was well tolerated providing a safe and effective treatment of RG-2 glioma.

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.