Behavior and effect of nanoparticles in the pulmonary microcirculation

Li, Chenxi (2024): Behavior and effect of nanoparticles in the pulmonary microcirculation. Dissertation, LMU München: Medizinische Fakultät

Abstract

The lung, with its large surface area and thin air-blood barrier, presents an ideal site for drug delivery and serves as the main entry portal for inhaled particles. Additionally, the abundant pulmonary capillary bed provides an important surface for interactions with particles suspended in the bloodstream. Therefore, engi- neered nanoparticles (NPs) offer promising prospects for precision drug delivery to the lung. However, despite the potential benefits of NPs, their interactions and possible adverse effects in the pulmonary microcirculation under both healthy and pathophysiological conditions remain largely unknown. Understanding these in- teractions is crucial for harnessing the full potential of NPs in lung-specific drug delivery and ensuring their safety and efficacy for clinical applications. To visualize and quantify the real-time dynamics of intravenously delivered or injected NPs and their interactions with the pulmonary vascular innate immune system, we utilized intra-vital microscopy of the alveolar region in mice. The NPs used in the study were divided into two distinct subsets: one usually considered of a low potential for interacting with biomolecules and cells (PEG-amine-QDs, referred to as aQDs), and the other with a high potential for such interactions (carboxyl-QDs, referred to as cQDs). In vitro experiments demonstrated that cQDs were taken up more efficiently by Human Umbilical Vein Endothelial Cells compared to aQDs. In vivo experiments revealed that intravenously applied cQDs interacted with endothelial cells and might be taken up by them. In contrast, aQDs tended to form clusters in pulmo- nary vessels over time and induced stronger inflammation compared to cQDs, indicating that the PEG modification of QDs did not fully protect against their po- tential effects in the pulmonary microcirculation. Under healthy conditions, i.v. injection of aQDs induced neutrophil recruitment, but did not significantly alter the immune responses under pathological conditions, such as LPS-induced acute inflammation and Bleomycin-induced fibrosis. The initiation of neutrophil recruitment induced by aQDs was found to require cellular degranulation and release of TNF-α. Furthermore, neutrophil response to aQDs appeared to involve the release of damage-associated molecular patterns (DAMPs), particularly extracellular ATP (eATP). This process also involved the upregulation of relevant selectins (such as E-selectin) and the involvement of in- tegrins (such as LFA-1 and MAC-1) on endothelial cells and neutrophils. These, in turn, resulted in a slowdown of the crawling velocity of neutrophils on the vas- cular surface. The blockage of selectins and integrins or the use of an eATP an- tagonist prevented recruitment of neutrophils and partially restored their reduced crawling velocity. Furthermore, the accumulation and retention of neutrophils in the pulmonary microcirculation led to a decrease in local blood flow velocity. Ac- cordingly, when factors involved in neutrophil recruitment, such as cellular degranulation, DAMPs, and TNF-α release, as well as the upregulation of se- lectins and integrins, were diminished, blood perfusion could be restored to base- line levels. Overall, this study unveils a detailed mechanism underlying the neutrophil re- sponse to aQDs, involving cellular degranulation, DAMPs and TNF-α release, as well as the upregulation of selectins and integrins. This intricate cascade ulti- mately leads to a reduced velocity of crawling neutrophils and a slowdown in blood perfusion. These insights pave the way for further exploration and optimi- zation of NP-based drug delivery strategies, aiming to enhance efficacy and safety in medical applications.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 23. Januar 2024
• 1. Bericht­erstatter:in: Rehberg, Markus