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PDFOpen Access (License Unspecified), Open Access
Dissertation
Engineering out the side effects of lipid nanoparticles: evasion of neutrophil uptake and clotting
Doctor of Philosophy (Ph.D.), Drexel University
May 2024
DOI:
https://doi.org/10.17918/00010786
Abstract
The field of nanomedicine aims to achieve targeted delivery of therapeutic agents to specific organs and cell types. However, achieving this goal has been challenging for most targets. In this work we discuss two methods to achieve targeting of lipid nanoparticles (LNPs) to the lung. The first of these methods is antibody-mediated targeting to the pulmonary endothelium. Lung targeting using this method directs binding utilizing antibodies against endothelial surface markers like platelet endothelial cell adhesion molecule (PECAM), intercellular cell adhesion molecule (ICAM), or plasmalemma vesicle associated protein (PLVAP). The second method is physicochemical targeting which utilizes intrinsic physical properties (size, shape, charge) or chemical features (binding to specific endogenous proteins because of the nanoparticles' chemical makeup) to effect organ tropism. For lung tropism, the use of a permanently charged cationic lipid introduced into the formulation allows for this targeting. For both methods, it has not been fully understood what cell types in the lung take up these nanoparticles and what effects this may have on therapeutic translation of these modalities and if it changes in the context of acute lung injury (ALI). Here, we answer both questions and show that for both antibody-mediated and physicochemical targeting, the marginated neutrophils of the lung are avid players in the uptake of these nanoparticles. We further show that these marginated neutrophils actively take up these nanoparticles, effectively achieving co-equal uptake, underscoring their role as part of the reticuloendothelial system (RES). In models of acute lung injury, we go on to show that our lung-targeted nanoparticles are cleared faster likely due to activated marginated neutrophils. Exploration of these mechanisms show that for antibody-mediated targeting, complement activation as well as non-specific recognition of the fragment crystallizable region (Fc) region on the antibodies covalently conjugated on the LNPs drove this uptake. However, for physicochemical targeted LNPs, thrombosis and coagulation was the key driving force in lung localization. This work further proposes methods to help reduce uptake by marginated neutrophils and prevent undesired side effects in these nano particles. This work provides insights into these mechanisms and their implications for therapeutic translation of LNPs.
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Details
- Title
- Engineering out the side effects of lipid nanoparticles
- Creators
- Marco Eduardo Zamora
- Contributors
- Kara L. Spiller (Advisor)Jacob S. Brenner (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 10, 248 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 991021934313804721