Dissertation
Uptake and distribution of ultrafine nanoparticles and microemulsions from the nasal mucosa
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2017
DOI: 10.17077/etd.h0z4bv8z
Abstract
<p>Various colloidal delivery systems, including polymeric nanoparticles, metal colloids, liposomes, and microemulsions have been reported to enhance the delivery of therapeutic agents following intranasal administration. However, the mechanisms involved in the uptake of these nanomaterials, especially those in the ultrafine size ranges (diameter < 20 nm) through nasal mucosa and their subsequent biodistribution in the body are not well characterized. The objectives of this study address the knowledge gap regarding ultrafine nanoparticle transfer in the nasal mucosa by quantifying nanoparticle uptake and biodistibution patterns in the presence and absence of known inhibitors of endocytic processes.</p>
<p>The uptake of ~ 10 nm fluorescent quantum dots (QDs) was investigated by measuring the concentration of QDs following exposure to bovine respiratory and olfactory mucosal explants. An inductively coupled optical emission spectroscopy method was developed to measure the amount of QDs within the tissues. The results demonstrated that carboxylate-modified QDs (COOH-QDs) show ~2.5 fold greater accumulation in the epithelial and submucosal regions of the olfactory tissues compared to the respiratory tissues. Endocytic inhibitory studies showed that in respiratory tissues clathrin-dependent, macropinocytosis and caveolae-dependent endocytosis process were all involved in the uptake of COOH-QDs. Whereas in olfactory tissues, clathrin-dependent endocytosis was the major endocytic pathway involved in uptake of COOH-QDs. Additional energy-independent pathways appeared to also be active in the transfer of COOH-QDs into the olfactory mucosa. Interestingly, PEGylated quantum dots (PEG-QDs) of similar size ~15 nm were not internalized into the bovine nasal tissues.</p>
<p>In vivo fluorescence imaging was used to study the biodistribution of quantum dots following nasal instillation in mice. These studies showed that majority of COOH-QDs remain in the nasal tissues for relatively long periods of time (up to 24 h) whereas PEG-QDs showed no such accumulation. Biodistribution studies of gold nanoparticles (~15 nm) in mice using micro-CT showed that gold nanoparticles were transferred to the posterior turbinate region and a fraction of the administered dose distributed to regions in close proximity to the olfactory bulb. Both NIR imaging and micro-CT imaging were useful tools for visualization of in vivo nanoparticle distribution.</p>
<p>A diazepam-containing microemulsion (dispersed phase ~40 nm) was formulated to investigate the uptake mechanisms utilized for fluid-phase colloidal dispersions in the nasal mucosa. The resulting diazepam-containing microemulsion showed enhanced transfer of the drug into the bovine nasal respiratory and olfactory tissues. It is unclear if endocytosis of the fluid-phase nanodispersions played a role in drug absorption from the microemulsions in a manner similar to the uptake of solid-phase nanoparticles, however, since there was significant loss of the epithelial cell layer following exposure to the microemulsion formulation which likely altered the barrier properties of the epithelium.</p>
<p>These studies have increased the fundamental understanding of ultrafine nanoparticle uptake in the nasal tissues and the resulting nanoparticle biodistribution patterns. While ultrafine nanoparticles may have limited application in the development of efficient drug delivery systems, an understanding of the size-dependent and tissue-dependent processes responsible for the uptake of particulates into mucosal tissues will contribute to the rational development of nanoparticulate drug delivery strategies investigating the nasal and other routes of administration.</p>
Details
- Title: Subtitle
- Uptake and distribution of ultrafine nanoparticles and microemulsions from the nasal mucosa
- Creators
- Bhanu Chander Bejgum - University of Iowa
- Contributors
- Maureen D. Donovan (Advisor)Douglas R. Flanagan (Committee Member)Aliasger K. Salem (Committee Member)Lewis L. Stevens (Committee Member)Laura B. Ponto (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy (Pharmaceutics)
- Date degree season
- Summer 2017
- DOI
- 10.17077/etd.h0z4bv8z
- Publisher
- University of Iowa
- Number of pages
- xxi, 183 pages
- Copyright
- Copyright © 2017 Bhanu Chander Bejgum
- Language
- English
- Date submitted
- 09/27/2017
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 151-168).
- Public Abstract (ETD)
A variety of ultrafine nanomaterials including metals, engineered nanoparticles, and viruses have been reported to be transported from the nasal tissues into either the brain or the blood. The mechanisms involved in the uptake of these nanomaterials, especially those in the ultrafine size range (diameter < 20 nm), through nasal mucosa and their subsequent biodistribution in the body are not well characterized. The objective of this study is to investigate the mechanisms involved in the uptake of quantum dots (a model for ultrafine nanoparticles) into the nasal tissues and to characterize their biodistribution patterns using mice as an animal model.
The uptake of these ultrafine nanoparticles was observed to depend on their surface characteristics; negatively charged, carboxylate quantum dots were shown to be taken up by the nasal tissues to a greater extent (2-5 % in 120 min) than with a near-neutral surface charge PEGylated QDs which showed negligible uptake into the tissues. The ultrafine nanoparticles were internalized into the nasal tissues using multiple pathways including micropinocytosis, clathrin-mediated and caveolae-mediated endocytosis. Additional energy-independent pathways were involved in the uptake into olfactory tissues. Following intranasal administration in mice, ultrafine gold nanoparticles and carboxylate quantum dots were observed to migrate from the anterior region of the nasal cavity to posterior regions, including near the olfactory regions, due to mucociliary clearance and some particles were appeared to be retained in the posterior regions for periods of time at least up to 24 h.
- Academic Unit
- Pharmacy; Craniofacial Anomalies Research Center
- Record Identifier
- 9983776988702771
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