Conventional methods of cancer therapy have been severely limited by inefficient delivery of therapeutic doses without incidence of harsh and toxic side effects in normal tissues. Consequently, countless new methods for early detection and drug delivery have been investigated in the area of nanoparticles and hydrogels. Although many of these methods are promising, the complex nature of cancer increases the difficultly for the development of the perfect system.
Cellulose nanocrystals (CNCs) have been studied widely for a variety of applications. Despite their advantages, investigations of their abilities in the biomedical field have not been explored. The goal of this project is to delve into the potential uses of CNCs in detection, targeted drug delivery, and potentiation of irreversible electroporation (IRE)-induced cell death in folate receptor (FR)-positive cancers. To accomplish this task we have prepared stable and reproducible CNCs from wood pulp via sulfuric acid hydrolysis. Furthermore, we have functionalized the surface of these nanoparticles and conjugated them with the targeting ligand folic acid (FA) and the fluorescent imaging agent fluorescein-5\'-isothiocyanate (FITC) to create FITC-CNC-FA; CNCs have also been conjugated with doxorubicin (DOX), a potent chemotherapeutic (DOX-ALAL-CNC-FA). We have determined FITC-CNC-FA's and DOX-ALAL-CNC-FA's ability to specifically target FR-positive cancer cells in vitro; meanwhile non-targeted CNCs (FITC-CNC) were shown unable to bind to these cell types. In addition, we have investigated FITC-CNC-FA's pharmacokinetic activity in vivo. To properly model the CNC conjugate's activity in vivo, a physiologically based pharmacokinetic (PBPK) model has been constructed.
We have also examined CNCs' ability to potentiate a new technique for tumor ablation, IRE. Pre-incubation with FA-conjugated CNCs (CNC-FA) have shown an increase in cytotoxicity in FR-positive cancer cells induced by IRE. In addition, CNC-FA did not potentiate IRE-induced cytotoxicity in a FR-negative cancer cell type. For a more comprehensive understanding of CNC-FA's ability to potentiate IRE induced cytotoxicity, we optimized a 3D in vitro hydrogel system. Preliminary data suggest this method of experimentation will be more realistic to in vivo studies to be completed in the future. Together, these studies showcase CNCs as efficient and effective nano-carriers in tumor detection and treatment. / Ph. D.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/51212 |
| Date | 01 August 2013 |
| Creators | Colacino, Katelyn |
| Contributors | Biomedical Engineering, Lee, Yong Woo, Achenie, Luke E. K., Roman, Maren, Rylander, M. Nichole, Robertson, John L. |
| 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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