Spermidine/Spermine N1-Acetyltransferase 1 (SAT1)—A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA

Spermidine/spermine N1-acetyltransferase 1 (SAT1) responsible for cell polyamine catabolism is overexpressed in glioblastoma multiforme (GB). Its role in tumor survival and promoting resistance towards radiation therapy has made it an interesting target for therapy. In this study, we prepared a lipid nanoparticle-based siRNA delivery system (LNP-siSAT1) to selectively knockdown (KD) SAT1 enzyme in a human glioblastoma cell line. The LNP-siSAT1 containing ionizable DODAP lipid was prepared following a microfluidics mixing method and the resulting nanoparticles had a hydrodynamic size of around 80 nm and a neutral surface charge. The LNP-siSAT1 effectively knocked down the SAT1 expression in U251, LN229, and 42MGBA GB cells, and other brain-relevant endothelial (hCMEC/D3), astrocyte (HA) and macrophage (ANA-1) cells at the mRNA and protein levels. SAT1 KD in U251 cells resulted in a 40% loss in cell viability. Furthermore, SAT1 KD in U251, LN229 and 42MGBA cells sensitized them towards radiation and chemotherapy treatments. In contrast, despite similar SAT1 KD in other brain-relevant cells no significant effect on cytotoxic response, either alone or in combination, was observed. A major roadblock for brain therapeutics is their ability to cross the highly restrictive blood–brain barrier (BBB) presented by the brain microcapillary endothelial cells. Here, we used the BBB circumventing approach to enhance the delivery of LNP-siSAT1 across a BBB cell culture model. A cadherin binding peptide (ADTC5) was used to transiently open the BBB tight junctions to promote paracellular diffusion of LNP-siSAT1. These results suggest LNP-siSAT1 may provide a safe and effective method for reducing SAT1 and sensitizing GB cells to radiation and chemotherapeutic agents

Sex as an Independent Prognostic Factor in a Population-Based, Non-Small Cell Lung Cancer Cohort

BACKGROUND: Males with non-small cell lung cancer (NSCLC) tend to experience worse outcomes, as do those with nonadenocarcinoma histology; however, the independent effects of these factors remain unclear

Geographical Variation and Factors Associated with Non-Small Cell Lung Cancer in Manitoba

Background. Screening decreases non-small cell lung cancer (NSCLC) deaths and is recommended by the Canadian Task Force on Preventive Health Care. We investigated risk factor prevalence and NSCLC incidence at a small region level to inform resource allocation for lung cancer screening. Methods. NSCLC diagnoses were obtained from the Canadian Cancer Registry, then geocoded to 283 small geographic areas (SGAs) in Manitoba. Sociodemographic characteristics of SGAs were obtained from the 2006 Canadian Census and Canadian Community Health Survey. Geographical variation was modelled using a Bayesian spatial Poisson model. Results. NSCLC incidence in SGAs ranged from 1 to 343 cases per 100,000 population per year. The highest incidence rates were in the Southeastern, Southwestern, and Central regions of Manitoba, while most of Northern Manitoba had lower rates. Poisson regression suggested areas with higher proportions of Aboriginal people and higher average income, and immigrants had lower NSCLC incidence whereas areas with higher proportions of smokers had higher incidence. Conclusion. On an SGA level, smoking rates remain the most significant factor driving NSCLC incidence. Socioeconomic status and proportions of immigrants or Aboriginal peoples independently impact NSCLC rates. We have identified SGAs in Manitoba to target in policy and infrastructure planning for lung cancer screening