A. James Clark School of Engineering
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The collections in this community comprise faculty research works, as well as graduate theses and dissertations.
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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 Protein-based vehicles for biomimetic RNAi delivery(Springer Nature, 2019-02-26) Pottash, Alex Eli; Kuffner, Christopher; Noonan-Shueh, Madeleine; Jay, Steven M.Broad translational success of RNA interference (RNAi) technology depends on the development of effective delivery approaches. To that end, researchers have developed a variety of strategies, including chemical modification of RNA, viral and non-viral transfection approaches, and incorporation with delivery vehicles such as polymer- and lipid-based nanoparticles, engineered and native proteins, extracellular vesicles (EVs), and others. Among these, EVs and protein-based vehicles stand out as biomimetically-inspired approaches, as both proteins (e.g. Apolipoprotein A-1, Argonaute 2, and Arc) and EVs mediate intercellular RNA transfer physiologically. Proteins specifically offer significant therapeutic potential due to their biophysical and biochemical properties as well as their ability to facilitate and tolerate manipulation; these characteristics have made proteins highly successful translational therapeutic molecules in the last two decades. This review covers engineered protein vehicles for RNAi delivery along with what is currently known about naturally-occurring extracellular RNA carriers towards uncovering design rules that will inform future engineering of protein-based vehicles.Item Protein-based vehicles for biomimetic RNAi delivery(BioMed Central, 2019-02-26) Pottash, Alex Eli; Kuffner, Christopher; Noonan-Shueh, Madeleine; Jay, Steven M.Broad translational success of RNA interference (RNAi) technology depends on the development of effective delivery approaches. To that end, researchers have developed a variety of strategies, including chemical modification of RNA, viral and non-viral transfection approaches, and incorporation with delivery vehicles such as polymer- and lipid-based nanoparticles, engineered and native proteins, extracellular vesicles (EVs), and others. Among these, EVs and protein-based vehicles stand out as biomimetically-inspired approaches, as both proteins (e.g. Apolipoprotein A-1, Argonaute 2, and Arc) and EVs mediate intercellular RNA transfer physiologically. Proteins specifically offer significant therapeutic potential due to their biophysical and biochemical properties as well as their ability to facilitate and tolerate manipulation; these characteristics have made proteins highly successful translational therapeutic molecules in the last two decades. This review covers engineered protein vehicles for RNAi delivery along with what is currently known about naturally-occurring extracellular RNA carriers towards uncovering design rules that will inform future engineering of protein-based vehicles.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.Item BIOMIMETIC NANOSTRUCTURES FOR THERANOSTIC APPLICATIONS(2015) Kuo, Yuan-Chia; D'Souza, Warren D; Raghavan, Srinivasa R; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Theranostic nanostructures are those that have both therapeutic as well as diagnostic function, e.g., due to having a combination of drugs as well as imaging agents in them. Such structures, especially those that can selectively home in on cancer tumors, have received considerable attention recently. Although many different structures have been synthesized, their complexity, high cost, and poor biocompatibility have limited their clinical application. In this study, we focus on creating new classes of theranostic nanostructures using simple routes (via self-assembly) and utilizing inexpensive and biocompatible materials. In our first study, we describe a class of liposomal probes that can allow certain tumors to be imaged by magnetic resonance imaging (MRI). Tumors, such as those of head and neck cancer, are known to over-express the epidermal growth factor receptor (EGFR). Our liposomal probes bear anti-EGFR antibodies as well as chelated gadolinium (Gd), a positive (image-brightening) contrast agent for MRI. To synthesize these probes, we use a strategy that is carefully designed to be simple and scalable: it employs two steps that each involve self-assembly. The resulting probes bind in vitro to EGFR-overexpressing tumor cells compared to controls. Moreover, cancer cells with bound probes can be tracked by MRI. In the future, these probes could find clinical use for tracking the efficacy of cancer treatment in real-time. Next, we report a class of microscale (3 to 5 µm) containers derived from erythrocytes (red blood cells). Micro-erythrosomes (MERs) are produced by emptying the inner contents of these cells (specifically hemoglobin) and resuspending the empty structures in buffer. We have developed procedures to functionalize the surfaces of the MERs with targeting moieties (such as anti-EGFR antibodies) and also to load solutes (such as fluorescent dyes and MRI contrast agents) into the cores of the MERs. Thus, we show that MERs are a versatile class of microparticles for biomedical applications. In our final study, we show that the MERs from the previous study can be sonicated to yield nanoscale structures, termed nano-erythrosomes (NERs), with average sizes around 120 nm. NERs are membrane-covered nanoscale containers, much like liposomes. They show excellent colloidal stability in both buffer as well as in serum at room temperature, and they are able to withstand freeze-thaw cycling. Moreover, NER membranes can be decorated with fluorescent markers and antibodies, solutes can be encapsulated in the cores of the NERs, and NERs can be targeted towards mammalian cells. Thus, NERs are a promising and versatile class of nanostructures for use in nanomedicine.