PhD, University of Cincinnati, 2021, Engineering and Applied Science: Chemical Engineering

The complex structure of the eye and the blood-ocular barriers have impeded the drug delivery via conventional administration routes. Innovative on-demand drug delivery system targeted to the eye has been considered as a promising strategy and received great attention in recent years. Hence, we investigated drug nanocarriers which can be activated by near infrared (NIR) laser to release the payload in a controlled manner over a long period. We first evaluated gold nanorod (AuNR)-coated perfluorocarbon (PFC) nanodroplets with two different PFC cores, perfluoropentane (C5F12, PF5) and perfluorohexane (C6F14, PF6). These PFC nanodroplets undergo a liquid-to-gas phase-transition and “burst” to release the payload with NIR laser. The size, encapsulation efficiency, number density, and cytotoxicity were similar between PF5 and PF6 nanodroplets. The feasibility of both PF5 and PF6 nanodroplets on suppressing the in vitro angiogenesis was demonstrated. PF6 nanodroplets performed better in long-term stability at physiological conditions but showed lower phase-transition efficiency than PF5. Subsequently, AuNR-coated nanosized liposomes (diameter˜100 nm) were studied with a focus on structure reversibility. Laser-triggered drug release tests demonstrated that these AuNR-liposomes released drug repetitively with multiple irradiation cycles (5sec per cycle, 1.1W) and the released amounts were proportional to cycle numbers. It was also proved that AuNR prominently increased the temperature of lipid bilayers via plasmonic heating effect and facilitated drug-releasing when irradiated by NIR laser. In addition, the number density of liposomes remained the same after laser irradiation. These results implied that the structures of AuNR-liposomes are likely to be reversible after exposure to NIR laser. Next, we fabricated micron-sized (diameter˜1.5 µm) AuNR-liposomes by reverse-phase evaporation method. Similarly, these micron-sized liposomes showed repetitive drug releases wi (open full item for complete abstract)

Committee: Yoonjee Park Ph.D. (Committee Chair); Jonathan Nickels (Committee Member); Winston Kao Ph.D. (Committee Member); Gregory Beaucage Ph.D. (Committee Member) Subjects: Chemical Engineering

Doctor of Philosophy, University of Akron, 2024, Polymer Science

Polymer-based coacervates can be prepared from a large variety of compositions. This provides versatility to coacervates as a material platform, but can also make them difficult to characterize, especially when other molecules or biologics are used in the same solution. The Joy lab has previously developed a platform to make thermoresponsive coacervating polyesters in a modular fashion. This allows us to make incremental changes to the coacervate structure and thus better observe how the structure affects the properties in various applications. In this work, we look at coacervates for hemostatic materials for non-compressible torso hemorrhage, and as sustained release drug delivery vehicles for colchicine release. Through a variety of experimental methods, our goal is to link structural changes in the coacervating polyester to the performance of the coacervate. The performance of our hemostatic coacervate was evaluated using clotting time tests, hemolysis tests, and rheology to determine how our materials interact with blood components. The trend in this data was further confirmed with in vivo mouse model studies which showed that the coacervates can perform well as hemostatic materials, and that the in vitro studies can effectively screen materials. We have also shown that amines in our coacervates are not effective and contrary to expectations and literature may increase bleeding times. To better predict coacervate properties on drug release, we employ NMR techniques such as STD and DOSY to better understand the strength of interactions between the coacervate and drug. The final drug release study confirms our NMR findings, and while the NMR techniques are not easily quantifiable, they do show an excellent relative predictability which can also be used to screen materials for an application. Ultimately, the tools employed for understanding coacervate performance enhance our understanding of their behavior in applications such as hemostasis and sustained (open full item for complete abstract)

Committee: Abraham Joy (Advisor); James Eagan (Committee Chair); Nita Sahai (Committee Member); Toshikazu Miyoshi (Committee Member); Ge Zhang (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Chemistry; Experiments; Materials Science; Molecular Chemistry; Molecules; Nanotechnology; Organic Chemistry; Pharmaceuticals

Doctor of Philosophy, The Ohio State University, 2022, Chemistry

Peptide self-assembly offers a powerful tool in the development of nanomedicines. We present a CPT based tetrapeptide scaffold, containing cysteines, which offers high stability and controlled release at low concentrations due to the crosslinking disulfides. The inclusion of cysteines allows for crosslinking under oxidative conditions (10% DMSO in PBS). The formation of covalent bonds allows for the structure to remain intact even at low concentrations and provides an opportunity to control the release of CPT. Many cancers are known to overexpress reducing agents, GSH, which would selectively break the disulfide bonds to release the CPT in the presence of cancer cells. Dual drug delivery systems have the potential to be a powerful tool in the treatment of cancers. Currently, combinations of anticancer agents are prescribed together, in many instances, 5-Fu and irinotecan are used together. We present a dual drug scaffold using both 5-Fu and CPT that can quickly release 5-Fu, while a secondary structure forms to afford the slow release of CPT. The initial system is assembled into a nanotube with a diameter of 84 nm, and as the 5-Fu is released, the nanotubes morph into a second assembly with a diameter of 72 nm that allows the CPT to be released more slowly. Previous studies have demonstrated peptide based self-assembled system can have a stabilizing effect on enzymes. We report the use of electro-spun CNCs, graciously given to us by the National Research Council of Canada, to test the long-term stability of Rubisco over the period of 49 days. Further studies are warranted to determine the potential use of PDA as a polymer coat of the CNC scaffolds.

Committee: Jonathan Parquette (Advisor); Christopher Hadad (Committee Member); Jovica Badjic (Committee Member) Subjects: Chemistry

Doctor of Philosophy, University of Akron, 2021, Polymer Science

Protein therapeutics are involved in several diseases, including HIV, cancer, and infectious diseases. However, the major challenge is preserving the activity of the protein outside its native environment. The effectiveness of protein therapeutics would be improved by developing a polymeric shell-like structure to encapsulate and release them sustainably. Our lab has developed a new class of non-ionic, thermoresponsive polyesters (TR-PEs), which can create protein delivery cargos. TR-PEs can undergo reversible temperature-dependent phase separation above lower critical solution temperature (LCST) to form coacervates. To test the ability of this coacervate platform, the encapsulation and release of Doxorubicin (Dox), an anti-cancer drug, were analyzed to understand molecular-level interactions with our TR-PEs. Several spectroscopy techniques, including 2D NMR, were employed to probe the coacervate-Dox interactions, and we have shown specific polymer-Dox interactions that lead to enhanced encapsulation. Although the above approach is promising, efficient protein encapsulation requires tailored protein-TR-PE interactions for each protein-TR-PE pair. However, synthesizing a large number of TR-PEs and examining their interactions with protein can be time-consuming. Therefore, a systematic, ‘fragment-based' approach was applied, similar to the pharmaceutical industry's fragment-based drug discovery process. The monomer ‘fragments' of the TR-PEs, methyl esters of the pendant functionalized diols, were developed for this methodology. A blueprint was established for ideal TR-PE compositions with significant binding affinities towards the protein, ubiquitin, by an iterative fragment identification and optimization of protein-fragment interactions. Advanced NMR techniques were exploited in fragment-based TR-PE discovery strategy. This approach can be transformational in designing polymers with specificity towards protein targets.

Committee: Abraham Joy (Advisor); Toshikazu Miyoshi (Committee Chair); Adam Smith (Committee Member); Nic Leipzig (Committee Member); Junpeng Wang (Committee Member) Subjects: Materials Science; Polymer Chemistry; Polymers

Doctor of Philosophy, The Ohio State University, 2018, Materials Science and Engineering

Electrospun fibers have been extensively studied for drug delivery applications. While fibers made through electrospinning can release a desired drug by engineering various properties, drug loading is typically not sufficient to enable long term release. We explored the use of electrospinning to create polycaprolactone (PCL) capsules sintered to full density allowing encapsulation of both a drug and carriers mainly consisting of hydrophobic or hydrophilic oils, `HPO' and `HPI', respectively. The use of HPO demonstrated undetectable water absorption and release of our model drug. In contrast, having HPI as a carrier allowed water uptake into the PCL capsules and was controlled according to the degree of hydrophilicity imparted by these oils. Mechanical properties of as-spun PCL demonstrated to be significantly different from the sintered specimens. PCL samples fully sintered at 100C under vacuum nonetheless demonstrated memory effects as mechanical failure exhibited features of the as-spun microstructure. This memory behavior was lost when samples treated at 150C were analyzed under tensile strength. After 224 days of in vitro and in vivo exposure the microstructure revealed fiber-based yet dense morphology attributed to the memory effects even after sintering at 100C. The use of non-sintered specimens in cylindrical form proved to be effective as a biomimetic scaffold of natural porcine coronary arteries showing similar failure behavior. Although PCL capsules were strong enough to resist compressive force in small animal models, this was not sufficient to study release on large animals. A weak implant can collapse, resulting in an undesired burst release. The incorporation of polyethylene terephthalate (PET) into PCL electrospun fibers in different ratios to then fully densify the capsule through sintering was studied. These blended fibers demonstrated to be mechanically stronger than PCL alone at any studied ratio. Water absorption was able to be controlled by the (open full item for complete abstract)

Committee: John Lannutti (Advisor); Marco da Silva Coutinho (Other); Heather Powell (Committee Member); Jianjun Guan (Committee Member) Subjects: Biomechanics; Biomedical Research; Chemical Engineering; Design; Engineering; Materials Science; Medicine; Nanoscience; Nanotechnology; Organic Chemistry; Plastics; Polymer Chemistry; Polymers

Doctor of Philosophy, Case Western Reserve University, 2017, Macromolecular Science and Engineering

The objective of this dissertation was to develop polymeric biomaterials for a wide range of biological and biomedical aliments. Chapter 1 introduces the need to develop new therapeutic approaches to combat multidrug resistant microorganisms. Currently, the literature focuses primarily on ESKAPE pathogens, which are all bacterial infections. However, other multidrug resistant microbes, such as Candida albicans, pose an equally daunting threat to public health. In Chapter 2 we combat multidrug resistant C. albicans with photodynamic therapy (PDT) using silicon phthalocyanine Pc 4. PDT utilizes a photosensitizer, light, and cellular O2 to produce reactive oxygen species (ROS), which then induce oxidative stress resulting in apoptosis. The hydrophobic nature of Pc 4, however, poses significant formulation and delivery challenges in the use of this therapy. To mitigate these concerns, a drug delivery vehicle was synthesized to better formulate Pc 4 into a viable PDT agent for treating fungal infections. Utilizing poly(amidoamine) dendrimers as the framework for the vehicle, the amine chain ends were partially PEGylated to promote water solubility and deter non-specific adsorption. In vitro studies with C. albicans demonstrate the potency of Pc 4 was not hindered by the dendrimer vehicle. Encapsulated Pc 4 was able to effectively generate ROS and obliterate fungal pathogens upon photoactivation. Thus, we have developed a nanoparticulate delivery vehicle for Pc 4 that readily kills drug-resistant C. albicans and eliminates solvent toxicity, thereby improving formulation characteristics for the hydrophobic photosensitizer. Though we able to effectively eradicate multidrug resistant C. albicans planktonic cells, the formation of biofilms is what makes Candidal infections truly lethal. Biofilms are colonies of cells encased in a polysaccharide matrix, which acts as a reservoir of pathogens causing persistent infections. To properly obliterate these infections, the plankto (open full item for complete abstract)

Committee: Jonathan Pokorski (Advisor) Subjects: Polymers

Master of Science, Miami University, 2017, Chemical, Paper and Biomedical Engineering

Engineered nanoparticles show great promise as a future medium for drug delivery due to their ability to transport great distances within the human body. Recent studies have shown that some nanoparticles may have the ability to diffuse to the central nervous system by means of the olfactory region of the nasal cavity. Although animal models and human simulations are available, the information they can provide is limited. In order to better test nanoparticles on this possible pathway, this study has created a more advanced respiratory device that incorporates a microfluidic device in a nasal cavity model to mimic the olfactory region through 3D modeling and printing. The unique geometry of the nasal cavity allows for the gathering of more realistic results. This unique respiratory device, in conjunction with an artificial lung apparatus, is able to accurately simulate a breathing human nasal cavity. During this study, the artificial nasal cavity was exposed to particles of varying sizes to determine the dosage reaching the olfactory region, which in turn can be used to determine which types of particles are most likely to travel this pathway. Results show similar trends to that of past studies: smaller nanoparticles are more effective at transporting to the olfactory region. While preliminary results are promising, further modifications to the setup are discussed that might better simulate an actual nasal cavity as well as to incorporate cell culture into the design.

Committee: Lei Kerr PhD (Advisor); Shashi Lalvani PhD (Committee Member); Douglas Coffin PhD (Committee Member) Subjects: Biomedical Engineering; Chemical Engineering

PhD, University of Cincinnati, 2017, Engineering and Applied Science: Chemical Engineering

Cancer is still a major threat to public health worldwide. Thanks to the extensive studies in cancer biology and growing understanding in cancer, many novel and effective therapeutic agents and drug combinations have been discovered and designed. However, many of them are challenged in reaching their targeted site. Nano-scaled drug carriers that target and deliver therapeutic agents to the sites of diseases have shown great promises in cancer treatment. As a starting point, we designed a human epidermal growth factor receptor 2 (HER-2) targeting pH sensitive nanoparticle combining the advantages of polyhistidine (PHis) and Herceptin. This nanoparticle contains a pH sensitive hydrophobic core in which chemotherapeutic drug is loaded and hydrophilic layer which stabilizes the whole nanoparticle while providing active targeting to HER-2. This nanoparticle shows a pH triggered drug release (i.e. fast drug release at acidic condition and sustained release at physiological condition), a capability of endosomal escape which allows delivery of cargo to cytoplasm, and HER-2 targeting which enhances cellular uptake of the nanoparticle. This work is described in detail in chapter 2. In addition, there are growing needs in delivery of micro RNA inhibitor (miRi) for RNA interferences (RNAi). In chapter 3, a novel lipid coated calcium phosphate miRi complex was made to address poor encapsulation of hydrophilic RNA molecules in hydrophobic polymeric core for co-delivery of molecules with different physicochemical properties. This novel complex was co-encapsulated with paclitaxel in nanoparticle to achieve co-delivery. The co-delivery nanoparticle was found effective in regulating gene expression in vitro. The synergistic effects of co-delivery of miRi and paclitaxel were confirmed in culture cells. In the last part of the study, chapter 4-5 were focused on developing drug delivery systems address the unmet needs for systematic sequential delivery of combination th (open full item for complete abstract)

Committee: Joo Youp Lee Ph.D. (Committee Chair); Chia Chi Ho Ph.D. (Committee Member); Yoonjee Park Ph.D. (Committee Member); Susan Waltz Ph.D. (Committee Member) Subjects: Chemical Engineering

Doctor of Philosophy, The Ohio State University, 2009, Pharmacy

Among various drug delivery systems, nanoparticles have shown some unique advantages. In this dissertation, a series of lipid and polymer-based nanoparticle systems were designed and prepared for the objective of improved drug delivery efficiencies and enhanced therapeutic efficacies. The development of nanoparticle formulation for nucleic acid drugs are described in Chapter 2, 3 and 4. In Chapter 2, a lipid-based, transferrin receptor (TfR)-targeted nanoparticle formulation containing protamine (Tf-LN) was developed to deliver antisense oligodeoxynucelotide G3139 against Bcl-2 to leukemia cells. Compared to free G3139 and non-targeted formulation (LN), Tf-LN showed increased cellular uptake and enhanced target gene downregulation. In Chapter 3, the effects of different components and composition on green fluorescence protein (GFP) gene delivery efficiency were investigated and provided useful information for further development of PEI and lipid-containing nanocrystal formulation of G3139 in Chapter 4. Chapter 4 described the development of a novel lipid-based nanoparticle formulation containing cationic lipid, PEI2000 and calcium, designated as nanocyrstal (NC), for delivery of antisense oligonucelotide G3139 to KB cells. ODN G3139 delivery by NC resulted in much higher cellular uptake and target gene downregulation in vitro. However, the downregulation was not observed in treated mice tumor, suggesting the other unknown factors in vivo may affect the antisense effect of G3139 nanocrystal. In this dissertation, we also developed nanoparticle delivery systems for chemotherapy drugs. In Chapter 5, a liposomal formulation of flavopiridol was developed to address the issues of solubility, high plasma protein-binding and side effects. Pharmacokinetic study in mice after i.v. bolus injection showed that the liposomal flavopiridol had an increased elimination phase half-life, decreased clearance and increased area under the plasma concentration-time curve compared to the (open full item for complete abstract)

Committee: Robert Lee (Advisor); Guido Marcucci (Committee Member); Kenneth Chan (Committee Member); L. James Lee (Committee Member) Subjects: Pharmaceuticals

Doctor of Philosophy, Case Western Reserve University, 2011, Chemistry

Gold nanoparticle-drug conjugates have attracted increasing attention in drug delivery for photodynamic cancer therapy. The nanoparticle acts as a water-soluble and bio-compatible platform that allows the delivery of hydrophobic drugs to the site of therapy. Due to the favorable surface area, hundreds of molecules can be attached to a 5 nm gold nanoparticle. More importantly, the versatile nanoparticle surface plays a vital role in targeted drug delivery. In this dissertation, we focus on efficient drug vectors for cancer therapy by synthesizing PEGylated gold nanoparticle-phthalocyanine conjugates. Both covalent and non-covalent drug binding can be achieved by designing the functionality of the nanoparticle surface. Due to the design of the gold nanoparticle carrier, using amphiphilic polymers, the drug delivery can be facilitated based on its size and the enhanced permeability and retention in the tumor tissue. Compared to the covalent approach, the non-covalent delivery approach of the hydrophobic photodynamic therapy drug Pc 4 through gold nanoparticles has provided rapid release and enhanced photocytotoxicity in cancer cells. In vivo studies in cancer bearing mice have shown an efficient deep penetration of the drug into the target tumors by the nanoparticle carriers within hours. In addition, controlled drug delivery system using visible-NIR light is achieved by a masked Pc 4-gold nanoparticle conjugate system. Targeted drug delivery can be achieved by modification of the carrier surface with active targeting ligands. After modification of the gold nanoparticle-Pc 4 conjugates with an EGF peptide, drug uptake into the tumor cells is dramatically improved due to the combination of active and passive targeting compared to untargeted conjugates. A 10-fold increase of the drug accumulation in a brain tumor was observed for the targeted drug delivery system. This shows that the designed gold nanoparticle-based drug delivery vector is able to cross the blood brain (open full item for complete abstract)

Committee: Clemens Burda (Advisor); Robert Salomon (Committee Chair); Malcolm Kenney (Committee Member); Yanming Wang (Committee Member); James Basilion (Committee Member) Subjects: Chemistry

Master of Science in Engineering, University of Akron, 2008, Biomedical Engineering

Intimal hyperplasia is the most common mechanism of failure for interventional and revascularization procedures like coronary artery bypass grafts (CABG), peripheral artery bypass surgery and dialysis access grafts. It is characterized by the thickening of intima within the artery wall. The reason for the thickening is due to the proliferation of medial vascular smooth muscle cells in the intima of the vessel wall. In a previous study, a novel targeted drug delivery system named the PolyRing was devised, using the drug cyclosporin A (CyA). The objective of our present research was to modify the previously established PolyRing system using the drug simvastatin, a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. The research hypotheses were that the loading of simvastatin in the PLGA microspheres could be optimized, and that there was controlled local release of the drug from the PolyRing device over a period of time. In this system, simvastatin was encapsulated within PLGA microspheres, which in turn were entrenched in a PEG block as a polymeric vascular wrap. The microspheres were prepared by an oil-in-water (o/w) emulsion technique. In order to achieve the maximum load, a total of eight runs with various formulation parameters including drug to polymer ratio, surfactant concentration, emulsification time and aqueous volume were conducted. Characterization of the microspheres was then completed to examine the surface morphology, particle size distribution, drug loading, encapsulation efficiency and the device in vitro release behavior. For this study, the null hypothesis was that there were no significant effects of the formulation parameters on encapsulation efficiency. Approximately 100µm size diameter spherical, smooth microspheres were obtained with no appreciable drug loss on the surface. The highest drug loading was observed to be 81.5 ± 6.3 µg drug/mg of microspheres. Only the drug to polymer ratio had significant effect on the encapsulation (open full item for complete abstract)

Committee: Stephanie Lopina Ph.D. (Advisor); Daniel Sheffer Ph.D. (Committee Member); Steven Schmidt Ph.D. (Committee Member); Michelle Evancho-Chapman Ms (Committee Member) Subjects: Biomedical Research

Doctor of Philosophy, University of Akron, 2005, Chemical Engineering

The long-term clinical success of autologous vein and synthetic vascular grafts is limited due to the development of anastomotic intimal hyperplasia (IH). Previously published data suggests that cyclosporine (CyA) (an immunosuppressive drug) may reduce the development of IH in a canine model [1]. However, systemic administration of CyA could create serious adverse effects. Therefore, it is our long-term goal to test the hypothesis that the controlled local release of cyclosporine from a polymeric vascular wrap will prevent the development of IH. In order to test this hypothesis, we developed three controlled release polymeric devices that could be placed around vascular graft anastomotic sites to deliver therapeutic drugs locally. The first device is a poly(ethylene glycol) (PEG) hydrogel sheet. The second device is a composite device consisting of poly(DL-lactide-co-glycolide) (PLGA) microspheres dispersed in the PEG hydrogel sheet. The third device is in the form of a ring (referred to as PolyRing from here on) that can be slipped around the anastomotic sites. PolyRing is a composite polymeric device consisting of PLGA microspheres embedded in a PEG hydrogel. In-vitro studies were conducted on the three devices to evaluate the effects of different sterilization procedures on the properties of the device. It was determined that gamma sterilization was the preferred sterilization method of choice. In-vivo studies were conducted on a swine model to evaluate the biocompatibility, drug optimization and efficacy of PolyRing. The biocompatibility study utilized four (4) domestic swine with non-drug loaded PolyRings harvested at two (2) and four (4) week time points. PolyRings (ID 3-5 mm; OD 7-8 mm; Length 5 mm) were implanted in subcutaneous and muscular tissues and around jugular veins and carotid arteries. The histological findings of gamma sterilized PolyRing implants at two and four weeks demonstrated the biocompatibility of this device. A minimal foreign body reacti (open full item for complete abstract)

Committee: Stephanie Lopina (Advisor) Subjects:

Doctor of Education (Educational Leadership), Youngstown State University, 2025, Department of Teacher Education and Leadership Studies

This study examines the perceptions of alumni regarding the effectiveness of multifaceted high school interventions designed to combat electronic nicotine delivery systems (ENDS) usage and related illicit substance use. The research focused on anti-smoking/vaping educational courses and prevention/detection processes implemented in a Midwestern suburban high school, exploring their effectiveness in curbing habitual vaping or smoking among graduates later in life. While these interventions raised awareness about the dangers of ENDS use, the findings reveal their long-term effectiveness was limited due to challenges such as a lack of sustained understanding and the persistent influence of peer pressure. These results underscore the need for more comprehensive and adaptable strategies to promote lasting behavioral change. The literature review, central to this study, examined preventative measures for schools, encompassing topics such as the background of tobacco products, health concerns with nicotine and Tetrahydrocannabinol (THC), proven cessation programs, school ecology, social media influences, outside barriers, school-based measures, and gateway theory. These multifaceted viewpoints provide a broader understanding of the issues surrounding adolescent drug use. The review also acknowledges the limited availability of information on the long-term health effects of ENDS products, given their relatively recent emergence, and highlights insights from health professionals, educators, and international studies to inform future strategies.

Committee: Jane Beese EdD (Committee Chair); Joseph Hendershott EdD (Committee Member); Robert Marino EdD (Committee Member) Subjects: Educational Leadership; Educational Sociology; Health Sciences; School Administration

Master of Science, The Ohio State University, 2007, Graduate School

Committee: Not Provided (Other) Subjects:

Doctor of Philosophy, Case Western Reserve University, 2022, Biomedical Engineering

Poly(lactic-co-glycolic acid) (PLGA) is a prolific polymer used in many forms of biomedical devices, from bioresorbable sutures to drug delivery carrying microspheres, including as a component in more than a dozen FDA-approved medical devices. This is why the newly discovered affinity between a drug and PLGA reported in this dissertation could have widespread effects on the way we think about polymers used long-term in implanted biomedical devices. The first chapter is devoted to a review of previous strategies used to design and implement refillable, implanted drug delivery devices. These approaches span a wide range of applications, and recent advances in the field have brought more affinity materials-based techniques to the forefront. The key takeaway is that through intentional design, polymer-drug affinity can be harnessed for noninvasive drug homing/refilling to delivery devices to facilitate local drug delivery. In the second chapter, we share the first report of PLGA, a material which has not been “intentionally designed” to possess affinity for any drugs, exhibiting affinity in vivo for the cancer drug doxorubicin, under certain conditions effectively loading with as much drug as an affinity-based polymer which has been intentionally designed. On one hand, this observation led us to imagine that non-trivial interactions between exogenous drug and implanted PLGA biomaterials can be harnessed to refill drug delivery devices in situ multiple times, and extend drug delivery duration, for instance as adjuvant cancer drug delivery method to prevent recurrent tumors. On the other hand, because PLGA is capable of filling/refilling with doxorubicin to a significant extent, this suggests that poly(alphahydroxy esters) may interact with drugs similar to doxorubicin, leading to unexpected drug refilling and release in the body. We propose an “Amphiphilic Molecular Patterning Theory,” designating the structured amphiphilicity of other affinity polymers and PLGA to be th (open full item for complete abstract)

Committee: Horst von Recum (Advisor); Martin Bocks (Committee Member); Agata Exner (Committee Member); Sam Senyo (Committee Chair) Subjects: Biomedical Engineering

Doctor of Philosophy, Case Western Reserve University, 2020, Biomedical Engineering

Glioblastoma multiforme (GBM) is resilient to the current standard of care treatment of surgical resection followed by concurrent radiotherapy and temozolomide (TMZ) chemotherapy. GBM patient responses are poor and variable, resulting in more than 90% tumor recurrence and grim survival. The high mortality of GBM is attributed to its invasive peripheral growth, partially intact blood-brain barrier (BBB), regions of hypoxia, and high cellular heterogeneity that includes brain tumor initiating cells (BTICs) and immunosuppressive cells. These features of GBM work together to restrict the delivery of drugs throughout the tumor, suppress immune recognition of tumor cells, and facilitate tumor progression. Nanoparticles are well-suited to address limitations associated with the treatment of GBM by enhancing drug delivery to the tumor and reducing side effects. The overall objective of the work in this dissertation is to develop systemically administered nanoparticles that overcome barriers to drug distribution and cellular heterogeneity in GBM to improve therapeutic responses. In murine GBM models, the effective delivery of Doxorubicin (DOX) chemotherapy, BTIC inhibitor, and immune-stimulating agonists were evaluated using two distinct mesoporous silica nanoparticles (MSNs): 1) the Fe@MSN particle and 2) the immuno-MSN particle. First, drug release from the Fe@MSN particle was triggered using an external radiofrequency (RF) field to enhance the distribution of DOX and/or BTIC inhibitor across the partially intact BBB and into the tumor interstitium. The effective delivery of drugs facilitated by Fe@MSN particles translated into suppressed GBM growth, depleted stem-like cell phenotypes in hypoxic regions, and prolonged or cancer-free survival. Second, towards further improving GBM treatment strategies, the immuno-MSN particle delivered immune-stimulating agonists to dysfunctional immune cells in GBM to reverse the effects of immunosuppression. Immuno-MSN particles facilitat (open full item for complete abstract)

Committee: Efstathios Karathanasis Ph.D. (Advisor); Agata Exner Ph.D. (Advisor); Dominique Durand Ph.D. (Committee Chair); Jennifer Yu M.D., Ph.D. (Committee Member) Subjects: Biomedical Engineering; Immunology

Doctor of Philosophy, The Ohio State University, 2019, Pharmaceutical Sciences

Ribonucleic acid (RNA) nanotechnology is a rapidly emerging field that focuses on the nanostructure design, construction, and application in biotechnology and biomedicine. Unlike other biomacromolecules, RNA is more flexible in structure and more versatile in functionality. On the other hand, RNA is a naturally-occurring biopolymer, making them more biocompatible compared to other nanomaterials. Thus, RNA can serve as a building block to construct nanoparticles as drug delivery platform for cancer therapy. This dissertation primarily describes a fundamental study that explores the immune-compatibility of RNA nanoparticles, as well as the use of thermostable RNA nanoparticles to specifically deliver therapeutics for efficient cancer therapy without causing toxicity. Firstly, RNA polygons that have identical size but varying shapes, or same shape but with different sizes were constructed as study model. The RNA nanoparticles were found to be immunologically inert, indicating that RNA nanoparticles are safe drug carriers without triggering immune responses. On the other hand, they can elicit significant immunomodulation by extending the nanoparticles with special sequences. Specifically, this immunomodulation was found to be size, shape, sequence-dependent, demonstrating the potential of using RNA nanoparticles in immunotherapy. Secondly, the use of a thermostable RNA nanoparticle for solubilizing and high-density loading chemotherapeutic drugs for cancer inhibition is reported. Small chemotherapeutic drugs possess significant anti-cancer activity, but their clinical applications were greatly limited by the poor biocompatibility such as water-insolubility. By chemically conjugating water-insoluble drugs to RNA, the RNA nanoparticles dramatically improved drug water-solubility. An ultra-thermostable RNA four-way junction nanoparticle was able to covalently load twenty-four copies of paclitaxel without nanoparticle dissociation or unfolding. After intravenous administrat (open full item for complete abstract)

Committee: Yizhou Dong (Advisor); Peixuan Guo (Committee Member); Robert Lee (Committee Member); Mitchell Phelps (Committee Member) Subjects: Nanotechnology

PhD, University of Cincinnati, 2018, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics

Controlled release oral dosage form offers great advantages over conventional dosage form by providing steady drug plasma concentration, decreasing the frequency of administration, and providing enhanced patient compliance. However, orally ingested tablet is exposed to varying pH conditions and fluctuating mechanical agitations during its travel through the gastrointestinal tract (GIT). Selection of materials that provide controlled release mechanism to the oral dosage form is important as they can a) minimize drug release rate fluctuations for ionizable drugs during its travel along the changing pH environment of the GIT and b) maintain the release rate mechanism even when subjected to the physiological mechanical agitation forces. To examine these two important requirements, matrix tablets prepared using low glass transition temperature (Tg) silicone pressure sensitive adhesive (PSA) were evaluated and compared with matrix tablets prepared using high Tg ethyl cellulose (EC). Specifically, the effect of dissolution medium pH on drug release from binary tablets consisting of the polymer and ionizable model drugs verapamil hydrochloride and diclofenac sodium was studied using USP dissolution apparatus (without mechanical stress). The effect of simulated physiological mechanical stress agitation on drug release was studied using dissolution stress test apparatus for non-ionizable model drug acetaminophen. Mechanical properties, physical structures, electrical resistance, water uptake, and contact angle of pure polymer films and of matrix tablets were studied to understand the relationships of these factors to drug release. Our study indicated that increasing polymer amount decreased drug release rate from both silicone PSA and EC tablets using USP dissolution apparatus. However, silicone PSA tablets showed lower friability compared to EC tablets. The application of physiological simulated mechanical stress affected drug release from high Tg EC tablets that resulte (open full item for complete abstract)

Committee: Kevin Li Ph.D. (Committee Chair); Pankaj Desai Ph.D. (Committee Member); Sergey Grinshpun Ph.D. (Committee Member); Gerald Kasting Ph.D. (Committee Member); Gary Kelm Ph.D. (Committee Member); R. Randall Wickett Ph.D. (Committee Member) Subjects: Pharmaceuticals

Doctor of Philosophy, University of Toledo, 2017, Chemical Engineering

Ionically crosslinked chitosan nanocarriers have attracted significant attention as potential drug delivery vehicles due to their biocompatibility, mucoadhesiveness, payload protection ability, and mild formation/payload encapsulation procedures. Despite these advantages, however, most studies on these materials have tuned their drug uptake and release properties by trial and error, and not infrequently reported conflicting results. This dissertation aimed to address some of these issues. To better understand drug uptake properties, we have shown that, besides increasing with the drug/particle binding affinity, protein drug association efficiency (i.e., the fraction of the added protein that was taken up) increased almost linearly with the particle yield (the fraction of the added chitosan that self-assembled into particles). This scaling was explained via a predictive equilibrium binding model and suggested that many of the (often conflicting) variations in protein uptake reported in the literature might stem from the largely ignored variability in particle yield. Because sustained drug release could be affected by particle dissolution stability, ionically crosslinked chitosan particle dissolution was also examined. This revealed hysteresis in the ionic crosslink formation/dissociation cycle (where particle dissolution occurred at lower ionic crosslinker concentrations than those required for particle formation). Also explored was whether drug/particle binding (where the drug molecules served as additional physical crosslinks between the chitosan chains) enhanced the dissolution stability of chitosan/tripolyphosphate (TPP) particles. This indicated that, while protein/chitosan binding was insufficiently strong to generate a stabilizing effect, chitosan/TPP particles could be stabilized against dissolution through the uptake of DNA. Further, it has long been ignored that the in vitro drug release profiles obtained for chitosan particles via the common “s (open full item for complete abstract)

Committee: Yakov Lapitsky (Committee Chair); Constance Schall (Committee Member); Sasidhar Varanasi (Committee Member); Matthew Liberatore (Committee Member); Eda Yildirim-Ayan (Committee Member) Subjects: Biomedical Engineering; Chemical Engineering; Pharmaceuticals; Polymers

Master of Science, The Ohio State University, 2016, Chemical Engineering

DNA origami nanostructure technology allows for the precise control of size and structure formation using the building blocks of life. Here, DNA was not used as the blueprint for protein formation but as a delivery vehicle for chemotherapeutic drugs, such as the anthracycline antibiotic, daunorubicin. By itself, daunorubicin has limited pharmacokinetics and biodistribution profiles when applied in vivo. In addition, daunorubicin, like most small molecule drugs, is ineffective against cancer cells that have acquired multi-drug resistance (MDR). By delivering the chemotherapeutic using DNA origami allows the drug to travel through the endolysosomal pathway, bypassing MDR mechanisms. Here, we were able to overcome MDR mechanisms in a liquid tumor cell line using the “Trojan Horse” DNA origami nanostructure as a drug delivery vehicle. Though promising, there are many barriers to pass before DNA origami nanostructures is a viable option for clinical use. This includes commercial level scale-up, target specificity and testing for immunogenicity and toxicity in vivo. Here, we discuss a method developed for the scale up of DNA origami production by 1500x standard volumetric reaction amounts. In addition, we were able to characterize a multitude of nanostructures for a more universal scaled process. Furthermore, we measured the effects that high concentrations of DNA origami nanostructures have in a mouse model. Lastly, since the binding and subsequent cellular internalization of DNA origami is non-specific, we were able to attached strategically located antibodies allowing for not only targeted drug specificity, but also blocking non-specific cell uptake. With these additions, the hope is that effective chemotherapeutics can be delivered to tumor sites while avoiding undesirable damage to healthy tissues in a clinical setting.

Committee: Carlos Castro (Advisor) Subjects: Biomedical Engineering; Biomedical Research; Chemical Engineering; Nanoscience; Nanotechnology; Oncology; Pharmaceuticals