Multiple hurdles, such as drug solubility, stability, and physical barriers in the body, hinder bioavailability of many promising therapeutics. Polymeric nanocarriers can encapsulate the therapeutics to protect non-target areas from side effects but also protect the drug from premature degradation for increased circulation and bioavailability. To capitalize on these advantages, the polymer nanoparticle must be properly engineered for increased control in size distribution, therapeutic encapsulation, colloidal stability, and release kinetics. However, each application requires a specific set of characteristics and properties. Being able to tailor these by manipulation of different design parameters is essential to optimize nanoparticles for the application of interest. This study of nanoparticle fabrication and characterization takes us a step closer to building effective delivery systems tailored for specific treatments.
Poly(ethylene oxide)-b-poly(D,L-lactic acid) (PEO-b-PDLLA) based nanoparticles were produced to range from 100-200 nm in size. They were fluorescently labeled with a hydrophobic dye 6-13 bis(triisopropylsilylethynyl) pentacene (TIPS pentacene) at an optimal loading of 0.5 wt% with respect to the core.
Surfaces were successfully coated with streptavidin to be readily functionalized with various biotinylated compounds such as PD-L1 antibodies or A488 fluorophore. Using the same PEO-b-PDLLA, iron oxide and a conjugated polymer poly(2- methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene) (MEH-PPV) were co-encapsulated to form fluorescently labeled magnetic particles. Using poly(lactic-co-glycolic acid), CRISPR-Cas9 plasmids were encapsulated at 1.6 wt% and most of the payload released within the first 24 hours. The incorporated plasmids were intact enough to have mammalian macrophages successfully express the bacterial protein Cas9. Using similar PLGA based particles, the surface was functionalized with streptavidin and bound to the surface of bacteria as an active carrier for increased penetration of solid tumors averaging ~23 particles per bacterium. PEO-b-PLGA based particles were used in conjunction with a hydrophobic salt former to encapsulate a peptide designed to reduce platelet binding to cancer cells and mitigate extravasation. The peptide encapsulated was increased from < 2 wt% without salt former to 8.5 wt% with the used of hexadecyl phosphonic acid. Although the applications across these projects can be broad, the fundamentals and important design parameters considered contribute to the overarching field of effective carriers for drug delivery. / Ph. D. / There are many reasons why many promising pharmaceutical formulations never make it through regulation and onto market, including low solubility of the drug, low absorbance by the body, and harmful side effects, to name a few. Using polymer drug carriers, these difficulties can be overcome by holding the drug in a more soluble carrier, releasing it on a certain timeline or to a specific location to increase absorbance and decrease side effects. When designing a carrier, the requirements for the product are dependent on the application and the disease of interest. This work looks at the material types and conditions during particle formation to see how it affects the final product to better define and understand how these parameters change the performance.
This work shows that the carrier size can be manipulated depending on how much of one material is used versus the other, they can be labeled to fluoresce so they can be tracked during cell and animal studies, and they can be coated with targeting compounds on the surface to increase the specificity of the carrier to localize to a target location of interest. Different particles containing DNA for gene editing, peptides for cancer therapies, and magnetic iron oxides to increase transport across difficult cell barriers have all be fabricated and characterized. The lessons learned through these projects will help guide future work to more effective and efficient delivery of pharmaceuticals to the body.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/97220 |
| Date | 12 September 2018 |
| Creators | Jo, Ami |
| Contributors | Chemical Engineering, Davis, Richey M., Allen, Irving C., Riffle, Judy S., Ducker, William A., Lu, Chang |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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