Drug nanocrystals (NCs) are colloidal dispersions composed almost entirely of drug. As such, there is substantial interest in targeting them to diseased tissues, where they can locally deliver high doses of the therapeutic. However, because of their uncontrolled dissolution characteristics in vivo and uptake by the monomolecular phagocyte system, achieving tumor accumulation is challenging. To address these issues, a layer-by-layer approach is adopted to coat paclitaxel NCs with alternating layers of oppositely charged polyelectrolytes, using a PEGylated copolymer as the top layer. The coating successfully slows down dissolution in comparison to the noncoated NCs and to Abraxane (an approved paclitaxel nanoformulation), provides colloidal stability in physiologically relevant media, and has no intrinsic effect on cell viability at the concentrations tested. Nevertheless, their pharmacokinetic and biodistribution profile indicates that the NCs are rapidly cleared from the bloodstream followed by accumulation in the mononuclear phagocyte system organs (i.e., liver and spleen). This is hypothesized to be a consequence of the shedding of the PEGylated polyelectrolyte from the NCs' surface. While therapeutic efficacy was not investigated (due to poor tumor accumulation), overall, this work questions whether approaches that rely solely on electrostatic interactions for retaining coatings on the surfaces of NCs are appropriate for use in vivo.
Many potent drugs are difficult to administer intravenously due to poor aqueous solubility. A common approach for addressing this issue is to process them into colloidal dispersions known as "nanocrystals" (NCs). However, NCs possess high-energy surfaces that must be stabilized with surfactants to prevent aggregation. An optimal surfactant should have high affinity for the nanocrystal's surface to stabilize it, but may also include a trigger mechanism that could offer the possibility of altering size distribution and uptake of the NC. This study presents a modular and systematic strategy for optimizing the affinity of polymeric stabilizers for drug nanocrystals both before and after oxidation (i.e., the selected trigger), thus allowing for the optimal responsiveness for a given application to be identified. A library of 10 redox-responsive polymer stabilizers was prepared by postpolymerization modification, using the thiol-yne reaction, of two parent block copolymers. The stabilizing potential of these polymers for paclitaxel NCs is presented as well as the influence of oxidation on size and dissolution following exposure to reactive oxygen species (ROS), which are strongly associated with chronic inflammation and cancer. Owing to the versatility of postpolymerization modification, this contribution provides general tools for preparing triggered-sheddable stabilizing coatings for nanoparticles.
The monitoring of lymphatic drainage is of great importance, particularly in the context of the early detection and diagnosis of several diseases. Existing methods of imaging and monitoring lymphatic drainage can be costly and require trained personnel, posing problems for at-home or point-of-care monitoring. Recently, an alternative approach has been proposed, consisting of using microneedles to deliver a near-infrared (NIR) fluorescent tattoo to the skin, which can be monitored with traditional laboratory-based fluorescence detectors. In this work, we present further development of this approach, using a specifically designed NIR-fluorescent probe and rational optimization of microneedle properties and the spatial location of the NIR dye within the microneedles. Moreover, we demonstrate that this method is compatible with a custom-made portable fluorescence measurement device and able to discriminate between drainage and lack of drainage in vivo in rats.
The interleukin 7 receptor alpha chain (IL-7Rα) is predominately expressed by lymphocytes, and activation by its ligand IL-7 supports the development and maintenance of T cells and boosts T-cell mediated immunity. We recently reported that lymphatic endothelial cells (LECs) in dermal lymphatics also express IL-7 and its receptor chains (IL-7Rα and CD132) and that IL-7 supports lymphatic drainage. This suggested that activation of IL-7Rα signaling in lymphatics could exert inflammation-resolving activity, by promoting the clearance of excess tissue fluid. Here we investigated how the potentially opposing effects of IL-7Rα signaling in immune cells and in the lymphatic vasculature would affect the development and progression of psoriasis-like skin inflammation. We found that during acute and chronic skin inflammation mice with an endothelial-specific deletion of IL-7Rα (IL-7Rα
ΔEC
mice) developed more edema compared to control mice, as a consequence of impaired lymphatic drainage. However, systemic treatment of wild-type mice with IL-7 exacerbated edema and immune cell infiltration in spite of increasing lymphatic drainage, whereas treatment with IL-7Rα blocking antibody ameliorated inflammatory symptoms. These data identify IL-7Rα signaling as a new pathway in psoriasis-like skin inflammation and show that its pro-inflammatory effects on the immune compartment override its anti-inflammatory, drainage-enhancing effects on the endothelium.
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