Macrophages represent an important therapeutic target, because their activity has been implicated in the progression of debilitating diseases such as cancer and atherosclerosis. In this work, we designed and characterized pH-responsive polymeric micelles that were mannosylated using ‘click’ chemistry in order to achieve CD206 (mannose receptor)-targeted siRNA delivery. CD206 is primarily expressed on macrophages and dendritic cells, and upregulated in tumor-associated macrophages, a potentially useful target for cancer therapy. The mannosylated nanoparticles improved siRNA delivery into primary macrophages by 4-fold relative to a non-targeted version of the same carrier (p < 0.01). Further, 24h of treatment with the mannose-targeted siRNA carriers achieved 87±10% knockdown of a model gene in primary macrophages, cell type that is typically difficult to transfect. Finally, these nanoparticles were also avidly recognized and internalized by human macrophages and facilitated the delivery of 13-fold more siRNA into these cells relative to model breast cancer cell lines. We anticipate that these mannose receptor-targeted, endosomolytic siRNA delivery nanoparticles will become an enabling technology to target macrophage activity in various diseases, especially those where CD206 is up-regulated in macrophages present within the pathologic site. This work also establishes a generalizable platform that could be applied for click functionalization with other targeting ligands to direct siRNA delivery.
Recently, two-dimensional paper networks have been developed to enable multistep assays to be performed in a lateral flow format. These devices have been used to perform simple enzyme linked immunoassays on paper. However, these devices have yet to incorporate more complex immunoassays, including the use of streptavidin-biotin detection strategies. Here we present a modified two-dimensional paper network capable of consecutively delivering six reagents. The device requires only a single user step and delivers (i) the sample, (ii) the biotinylated detection antibody, (iii) streptavidin horse-radish peroxidase (iv) a wash buffer (v) a colorimetric substrate and (vi) a final wash buffer. To demonstrate the utility of this approach we designed an assay to detect the malaria protein Pf HRP2. Using this platform, we were able to achieve a limit-of-detection equivalent to that of a traditional 96-well plate sandwich ELISA. In addition to improvements in the limit-of-detection, the inclusion of streptavidin-biotin simplifies the development of similar tests for other targets.
Each day, approximately 830 women and 7,400 newborns die from complications during pregnancy and childbirth. Improving maternal and neonatal health will require bringing rapid diagnosis and treatment to the point of care in low-resource settings. However, to date there are few diagnostic tools available that can be used at the point of care to detect the leading causes of maternal and neonatal mortality in low-resource settings. Here we review both commercially available diagnostics and technologies that are currently in development to detect the leading causes of maternal and neonatal mortality, highlighting key gaps in development where innovative design could increase access to technology and enable rapid diagnosis at the bedside.
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