Developing stealth nanomaterials for intravenous administration to overcome complement-mediated hypersensitivity reactions
Loading...
Links to Files
Permanent Link
Author/Creator
Author/Creator ORCID
Date
2020-01-01
Type of Work
Department
Chemical, Biochemical & Environmental Engineering
Program
Engineering, Chemical and Biochemical
Citation of Original Publication
Rights
Distribution Rights granted to UMBC by the author.
This item may be protected under Title 17 of the U.S. Copyright Law. It is made available by UMBC for non-commercial research and education. For permission to publish or reproduce, please see http://aok.lib.umbc.edu/specoll/repro.php or contact Special Collections at speccoll(at)umbc.edu
This item may be protected under Title 17 of the U.S. Copyright Law. It is made available by UMBC for non-commercial research and education. For permission to publish or reproduce, please see http://aok.lib.umbc.edu/specoll/repro.php or contact Special Collections at speccoll(at)umbc.edu
Abstract
A significant hurdle in clinical translation of intravenously infused nanoparticles is that it may lead to complement-mediated infusion reactions. The complement pathway is a part of the innate immune system, always active in eliminating threats to the immune system. However, complement activation can lead to the unwanted clearance of therapeutic nanomaterials. This can result in complement-mediated hypersensitivity reactions and cause anaphylaxis, which can even be fatal. Moreover, the bioavailability of the therapeutic is impacted as well. As 7-10% of the human population are prone to complement activation, this is a significant safety challenge while designing nanomaterials meant to be delivered intravenously. Materials properties and surface architecture of nanoparticles are significant contributors to the complement response. These dictate the interaction with plasma and complement proteins when the nanoparticles are in the bloodstream. We hypothesized that tuning materials properties would generate stealth nanoparticles that do not activate the complement pathways. To test our hypothesis, we also required a sensitive screening tool, as current methods of quantifying complement are qualitative or semiquantitative and often overlook the interference introduced due to the presence of nanomaterials. Hence, our research objectives were:1. Developing a sensitive screening tool for tracking changes in complement proteins in vitro for nanomaterials
2. Utilizing the developed assay to understand what are the surface and material properties that leads to complement activation in vitro
3. Developing stealth nanomaterials by applying the gathered input and evaluate its impact in complement activation
To achieve our research objective, we first determined the optimum assay conditions to assess the complement-mediated response in vitro, mimicking the in vivo response. Using the developed screening tool, we tracked how surface properties like zeta-potential and PEGylation impact the complement pathways by tracking the complement protein C5a. Based on the outcomes from screening a wide range of nanomaterials, we worked on developing stealth polyurethane-based nanomaterials that did not lead to complement activation and assessed its role as a hemostatic nanomaterial intended for intravenous infusion. Overall, the knowledge gathered from this dissertations will be critical in designing stealth nanomaterials that would not lead to complement-mediated infusion reactions.