Cellulose ethers are valuable matrices for drug-delivery systems (DDS), namely amorphous solid dispersions (ASD). ASD are efficient vehicles that can solubilize and stabilize poorly soluble drugs by increasing the time that it takes for drugs to crystallize, thereby allowing higher drug concentrations and providing increased bioavailability. However, most commercially available cellulose derivatives were not specifically designed for this application, leading to gaps in understanding the key mechanisms by which ASD operate. This creates the need for polysaccharide derivatives specifically conceptualized for ASD and for elucidating structure-property relationships. In this dissertation, I successfully demonstrated regioselective and chemoselective techniques to functionalize cellulose to prepare new ASD as well as smart tracking devices. I efficiently and successfully create complex structures via appending bile salt substituents using olefin cross-metathesis. I ascertained that high performance crystallization inhibitors can be achieved with enhanced hydrophilicity by the marriage of two classes crystallization inhibitors (cellulose and bile salts), as illustrated with the commercial, fast crystallizing prostate cancer drug, enzalutamide.
I obtained ketone-functionalized cellulose derivatives using oxidation chemistry to produce fluorescent poly- and oligosaccharides (hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl beta cyclodextrin). Schiff-base chemistry was then explored to append a commercially available fluorescent label, Nile Blue. Due to the dynamic nature and hydrolytic lability of Schiff-bases, I applied reductive-amination chemistry with either one pot, or two-step techniques and evaluated the efficiency of these approaches. I characterized the new fluorescent polymers, and with the objective of elucidating ASD mechanisms, I investigated their response in solvents of different polarities to probe environment-sensitivity.
Flavonoids are interesting drug candidates; they have been explored for many biomedical applications, including as inducers of apoptosis and functioning as antioxidants by radical scavenging. I prepared high-performance ASD polymer candidates, then prepared and characterized ASDs with different loadings of the flavonoids, genistein and quercetin. I explored the performance of polymers with different functionalities, hydrophilicity/hydrophobicity, and carboxylic acid content (cellulose acetate glutarate, 5-carboxypentyl hydroxypropyl cellulose, and hydroxypropyl methyl cellulose acetate succinate as positive control) by using in vitro dissolution studies. In this screening process, I determined that cellulose acetate glutarate provides the most advantageous enhancement, possessing the appropriate amphiphilicity to increase drug concentration in this study, supported by the similarity of the polymer and drug solubility parameters. I was further able to confirm via polarized light microscopy that advantageous nanodroplet formation occurs during the drug-release process. / Doctor of Philosophy / As sources for future ecofriendly materials, derivatives from nature offer fertile ground. One group of natural materials that attracts increasing attention to fulfill both performance and sustainability are polysaccharides, long chains of carbohydrates, that can be found in plant cell walls, exoskeletons of bugs or oceanic bottom feeders, algae, and indeed in all living things. Cellulose derivatives provide biologically safe materials that are biomedically relevant, including in the field of oral drug delivery. While most orally administered drugs are not 100% effective or absorbable, a class of drug delivery systems named amorphous solid dispersions can improve drug absorption with the aid of polysaccharide derivatives. Although amorphous solid dispersions are highly effective, there is still much room for improvement, and important opportunities to learn about the precise mechanisms that make such systems work. With fluorescent markers, I can also explore the surrounding environment of the drug delivery systems in preliminary studies. By understanding the environment of such polysaccharides, I determined important insight into how they improve oral drug availability and performance. Herein, I explored new amorphous solid dispersion polysaccharide derivatives, and how I have attached fluorescent labels to track them to learn how they work.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/116264 |
| Date | 11 September 2023 |
| Creators | Novo, Diana Cecilia |
| Contributors | Chemistry, Edgar, Kevin J., Taylor, Lynne S., Matson, John, Riffle, Judy S. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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