Uptake, distribution and elimination of intranasally-delivered immunoglobulin G in vivo and suggestions for intranasal drug formulations tailored for the olfactory mucosa
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Date
2025-04-16
Authors
Gänger, Stella
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Publication Type
Dissertation
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Abstract
Neurological diseases such as Multiple Sclerosis, Alzheimer's, Parkinson's, and psychiatric disorders impact the central nervous system (CNS), necessitating effective therapies to enhance patient health. Therefore, the development of pharmacologically active drugs that modulate the pathophysiological processes of these diseases is crucial. However, targeting CNS disorders poses significant challenges. The blood-brain barrier (BBB) is a formidable protective system that prevents up to 95% of molecules from reaching the CNS, complicating the delivery of therapeutically effective drug concentrations via oral or intravenous routes. Intrathecal administration on the other hand carries infection risks and can deter patient compliance.
To address these challenges, a new approach for effective CNS disorder treatment is needed. Nose-to-brain (N2B) drug delivery offers a promising solution. Unlike traditional methods, the nose-to-brain pathway bypasses the BBB, facilitating drug uptake directly into the CNS. This method not only enhances patient compliance but also supports long-term therapy administration.
To develop pharmacologically active drugs for nose-to-brain transport, a thorough understanding of drug delivery pathways is essential. Prior to this thesis, the nose-to-brain transport mechanism of immunoglobulin G (IgG) was not well elucidated. Therefore, a primary objective of this study was to investigate the uptake, distribution and the elimination of IgG antibodies from the olfactory mucosa to the CNS.
This work has made a significant contribution by analyzing the Fc receptor-mediated nose-to-brain pathway for IgG in vivo and providing insights into the uptake and degradation of intranasally administered IgG. Key findings from the study include the transport of IgG along the olfactory sensory neurons (OSNs) through bulk-flow processes. It is hypothesized that IgG navigates through the spaces between neuronal bundles and the surrounding olfactory ensheathing cells (OECs) to enter the CNS from the lamina propria without requiring active transport. Once in the olfactory bulb, IgG are distributed throughout the CNS via passive flow in the cerebrospinal fluid until they reach their target sites.
The study also investigated IgG uptake in the olfactory mucosa, with a focus on receptor-mediated uptake. It was confirmed that the Fc receptor FcRn is significantly involved in the uptake of both wild-type and deglycosylated IgG. The FcRn receptor is thought to trigger endosomal uptake, enabling transcytotic transport. While imaging methods have not conclusively demonstrated this, it is proposed that FcRn has a stronger affinity for deglycosylated IgG. This may account for the increased presence of deglycosylated IgG observed in the CNS.
The expected role of FcγR could not be validated in this study, as no substantial co-localization of FcγR and IgG was detected. However, this is not necessarily a drawback, as FcγRs are linked to immune system activation, which should ideally be minimized during drug delivery. Consequently, further exploration of FcγR’s involvement in IgG transport is still needed.
The study also found that IgGs are degraded within lysosomal compartments in the CNS and eliminated via cerebrospinal fluid drainage. A greater amount of deglycosylated IgG was detected in lysosomes compared to wild-type IgG. This may be due to the reduced stability of deglycosylated IgG, leading to faster degradation, or it could suggest that more deglycosylated IgG is taken up by the CNS, resulting in its higher concentration in lysosomes. From a medical perspective, this implies that higher or more frequent dosing of deglycosylated IgG may be needed to compensate for its accelerated degradation.
Additionally, this thesis successfully applied a systematic approach, including data mining and expression analysis of tissue samples, to thoroughly examine the olfactory mucosa. It was predicted that the olfactory environment consists of a watery mucosal barrier with low salt concentration and neutral pH, which was confirmed by a small study using postmortem porcine tissue. This information is crucial for optimizing drug formulations.
As a result, recommendations for suitable drug formulations were made, and the challenges of effective nose-to-brain drug delivery were addressed. Predictions regarding the ideal hydrogel patch formulation were meanwhile validated in a preclinical study with mini pigs, which confirmed the accuracy of the predictions. The patch exhibited good long-term stability and no toxic effects. Future research can now focus on establishing the dose-response curve for intranasally administered IgG.
Description
Faculties
Fakultät für Naturwissenschaften
Institutions
Institut für Experimentelle und Klinische Pharmakologie, Toxikologie und Naturheilkunde
Citation
DFG Project uulm
EU Project THU
Other projects THU
License
CC BY 4.0 International
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DOI external
Institutions
Periodical
Degree Program
DFG Project THU
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Keywords
Nose-to-brain, Nervenkrankheit, Nervendegeneration, Targeted drug delivery, Nasale Applikation, Riechepithel, Immunglobulin G, Intranasal medication, Neurodegenerative diseases; Therapy, Nervous system diseases; Therapy, Olfactory receptor neurons, Olfactory mucosa, Drug delivery systems, Administration, Intranasal, Immunoglobulin G, DDC 570 / Life sciences, DDC 610 / Medicine & health