Chemical and Biomolecular Engineering Theses and Dissertations
Permanent URI for this collectionhttp://hdl.handle.net/1903/2751
Browse
2 results
Search Results
Item Therapeutic contact lenses for extended drug delivery(2021) Torres Luna, Cesar Eduardo; Wang, Nam Sun; Briber, Robert M; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)There is significant interest in hydrogel-based drug-eluting contact lenses as platforms for topical ocular drug delivery. These devices have shown to provide an increased residence time of drugs at the surface of the eye, leading to enhanced bioavailability (~ 50%) when compared to eye drops (1–5%). One major limitation of contact lenses for drug delivery is that most drugs are released in a few hours, which limits their application for extended delivery. In this dissertation, we develop novel drug-eluting contact lenses that are capable of achieving extended in vitro drug delivery. In our first study, we describe the application of drug-participating catanionic aggregates in poly-(2-hydroxy-ethyl-methacrylate) based contact lenses. Contact lenses embedded with catanionic aggregates can achieve extended delivery of at least 1-week for two anionic drugs. Release kinetics is significantly dependent on the drug’s octanol-water partition coefficient, the hydrocarbon chain length and concentration of the cationic surfactant. Next, we focus on the use of unsaturated fatty acids in commercial contact lenses to extend the release of three cationic drugs. We demonstrate that lenses loaded with oleic acid can extend drug release kinetics to over 1 month. An opposite effect is seen for two anionic drugs, where oleic acid significantly accelerates release kinetics. These studies confirm the dominating impact of coupling charge interactions between drug molecules and fatty acid carrier molecules in contact lenses to adjust drug delivery rates. Finally, we extend the application of fatty acids in contact lenses to evaluate the effect of hydrocarbon chain length, ionic strength, and pH on the release kinetics. It is shown that fatty acids with carbon chain lengths equal or greater than 12 are capable of extending drug release of two cationic drugs, which confirms the importance of hydrophobic interactions with the silicone domain of the gel matrix. By decreasing ionic strength (from 1665 to 167 mM) or increasing the pH of the release media (from 5.5 to 7.4), release kinetics is significantly extended. In summary, the use of fatty acids to control the release of oppositely charged drug molecules represents a versatile tool to modify contact lenses for drug delivery applications.Item Engineering cell-penetrating peptides for translocation and intracellular cargo delivery in Candida species(2017) Gong, Zifan; Karlsson, Amy J; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Fungal infections caused by Candida species, particularly C. albicans and C. glabrata, have become a serious threat to public health. The rising drug resistance has prevented effective treatment and increased the mortal rate. Novel approaches to improve the therapeutic effects of antifungal agents and allow delivery of agents that are not normally cell-permeable are in demand. In order to improve the intracellular delivery of antifungal agents, we have investigated using cell-penetrating peptides as drug carriers for treating fungal infections. CPPs have been widely studied as tools for delivering a variety of molecular cargo into cells, including DNA, RNA, proteins, and nanoparticles. Previous work with CPPs has mainly focused on their uptake in mammalian cells, but CPPs also have potential as drug delivery and research tools in other organisms, including Candida pathogens. We have explored various well-studied CPPs to identify peptides that retain their translocation capability with Candida cells, including pVEC, penetratin, MAP, MPG, SynB, TP-10 and cecropin B. The CPPs pVEC, penetratin, MAP and cecropin B show a higher level in the cytosol adopt direct translocation mechanisms and exhibit toxicity towards C. albicans. Our peptide localization and mechanistic studies allow better understanding of the mode of translocation for different CPPs, which is related to the potential toxicity towards Candida pathogens. To further understand the molecular mechanisms of translocation of CPP, we investigated the biophysical properties of the peptides. CPPs that previously were shown to use direct translocation mechanisms (pVEC, MAP, and cecropin B) exhibit helical conformations upon interaction with cells due to the hydrophobic interaction with the core of bilayers. Membrane associations of peptides that entered cells via endocytosis were controlled by electrostatic forces. Our novel structure characterization methods using circular dichroism with live fungal cells, along with Monte Carlo simulations, allow us to understand how CPPs interact with cell membranes and how the membrane association affects the translocation mechanisms. After beginning to understand the structure-function relationships of CPPs, we engineered two CPPs, pVEC and SynB, to enable better translocation efficacy and manipulation of translocation mechanisms. We tuned the properties of the peptides, including the net charge and the hydrophobicity, to alter intracellular fates and the level of antifungal activity. These results are promising and motivate better peptide engineering for specific purposes. Our work with CPPs and fungal pathogens contributes to the understanding of structure-function relationship of CPPs in Candida species. We have provided the foundation for further peptide engineering and explorations into applications of CPPs in treating fungal infections.