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Authors: Kang, Biao
Title: Carbohydrate nanocarriers in biomedical application : construction and surface modification
Online publication date: 22-Feb-2017
Language: english
Abstract: Nanomedicine is a key technology for the 21st century. The specific targeting of either tumor cells or immune cells in vivo by carefully designed and properly surface-functionalized nanocarriers may become effective therapeutics for the treatment of a variety of diseases. Carbohydrates, as prominent biomolecules, have shown their outstanding ability in balancing the biocompatibility, stability, biodegradability, and functionality of nanocarriers. As a derivative of starch, hydroxyethyl starch (HES) possesses both high biocompatibility and improved stability against enzymatic degradation, but guarantees final body clearance due to its biodegradability. This thesis investigated the stealth properties of novel HES nanocontainers in vitro and in vivo. The HES nanocontainers were prepared via interfacial polyaddition in a water-in-oil miniemulsion. The synthesized hollow nanocapsules can be loaded with hydrophilic guests and tuned in size, chemically-functionalized in various pathways, and show high shelf life stability. The surface of the HES-NCs is further functionalized with poly(ethylene glycol) via different chemistries, which substantially enhanced blood half-life time (Chapter 3). Importantly, methods for precise and reliable quantification of the degree of functionalization are also introduced, which enable the precise control of the chemistry on the capsules’ surface. The functionalized nanocapsules serve as a modular platform for specific cell targeting, as they show no unspecific up-taken by different cell types and show very long circulating time in blood (up to 72 h, chapter 3). Subsequently, the PEGylated HES-NCs was further functionalized by mannose, and the targeting effect of them in both the absence and presence of protein corona was compared, while the influence of the additional mannose on the protein corona composition around the PEGylated HES-NCs was studied (Chapter 4). Whenever nanoparticles encounter biological fluids like blood, proteins adsorb on their surface, which consequently form a so called protein corona. As its importance is widely accepted, the information on the influence of surface functionalization of nanocarrier on the protein corona is still sparse, especially on the topic that how the functionalization of PEGylated nanocarrier with targeting agent will affect its protein corona formation, and how this protein corona may in turn influence the targeting effect. In chapter 4, hydroxyethyl starch nanocarriers (HES NCs) were prepared, PEGylated, and modified “on top” with mannose to target dendritic cells (DCs). Their interaction with human plasma was studied: low overall protein adsorption with a distinct protein pattern and a high specific DCs binding affinity prove an efficient combination of “stealth” and targeting behavior. Despite the long plasma halftime and specific targeting effect, encapsulation of complex molecules into the above described HES-NCs is difficult as nucleophiles like amines, thiols, or alcohols, and consequently will participate in the polycondensation reaction with the diisocyanate electrophile. New strategies have to be developed, which use bio-orthogonal reactions to generate the nanocarriers allowing the encapsulation of more complex pharmaceutical agents. In chapter 5, azide functionalized HES was prepared, so that capsules can be prepared by the bio-orthogonal copper free click reaction can be used to encapsulate any water-soluble drug or potential therapeutic agent.
Sobald Nanopartikel mit biologischen Flüssigkeiten wie Blut in Kontakt kommen, adsorbieren Proteine auf ihrer Oberfläche, welche die sogenannte Proteinkorona ausbilden. Die Wichtigkeit dieser Proteinhülle ist weitgehend anerkannt, jedoch untersuchen nur wenige Studien den Einfluss von Oberflächenfunktionalisierung der Nanocarrier auf die Proteinkorona. Vor allem die Variation der Proteinkorona von PEGylierten und zusätzlich mit Targeting-Molekülen versehenen Nanoträgern und der Einfluss auf das Targeting sind nicht bekannt. Hydroxyethylstärke-Nanocarrier (HES-NCs) wurden synthetisiert, anschließend PEGyliert und zusätzlich (“on top”) mit Mannose funktionalisiert, um dendritische Zellen (DCs) spezifisch anzusteuern. Die Wechselwirkungen mit menschlichem Plasma wurden untersucht: Niedrige Gesamtproteinabsorption mit einem ähnlichen Proteinmuster und eine hohe spezifische Bindungsaffinität zu DCs zeigen eine leistungsfähige Kombination von “Stealth”- und Targeting-Verhalten.
DDC: 540 Chemie
540 Chemistry and allied sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 09 Chemie, Pharmazie u. Geowissensch.
Place: Mainz
Version: Original work
Publication type: Dissertation
License: in Copyright
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Extent: II, 191 Seiten
Appears in collections:JGU-Publikationen

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