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Lopez, Aguilar Aime. "Peptides as therapeutics." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:d893e962-5cb9-4d50-bbe1-c5183418295c.
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Peptides have attracted increasing attention as therapeutics in recent years, at least partially as a consequence of the widespread acceptance of protein therapeutics; but also as possible solutions to problems such as short half-life and delivery of molecules, and as therapeutics in their own right. The current work presents three projects that involve applications of peptides in a therapeutic environment. The first project studies the use of ER retaining peptides and CPPs (Cell penetrating peptides) in enhancing the effective concentration of DNJ (1-deoxynojirimycin), an α-glucosidase inhibitor, in cells. DNJ constructs with ER retaining peptides (6-[N-(1-deoxynojirimycino)]-hexanoyl-KDEL and 6-[N-(1-deoxynojirimycino)]-hexanoyl-KKAA) and CPPs (6-[N-(1-deoxynojirimycino)]-hexanoyl-TAT and 6-[N-(1-deoxynojirimycino)]-hexanoyl-MAP) were synthesised and analysed for their inhibitory activity against α-glucosidase I and II in vitro. The constructs were then analysed in a cell-based assay to determine their inhibitory activity on α¬-glucosidase-mediated hydrolysis of N-linked oligosaccharides. FITC-labelled ER retaining peptides were also synthesised to determine the internalisation and trafficking of the constructs by FACS and IF-microscopy. While none of the DNJ-constructs showed higher cellular inhibition than NB-DNJ (N-butyl DNJ; Miglustat), the CPP construct 6-[N-(1-deoxynojirimycino)]-hexanoyl-TAT showed comparable activity and the ER retaining construct 6-[N-(1-deoxynojirimycino)]-hexanoyl-KDEL showed a small but significant increase in activity following long-term administration. The second project focuses on beauveriolides, a cyclic depsipeptide family shown to have activity as ACAT inhibitors and thus a possible treatment for Alzheimer’s disease by the decrease in the production of Amyloid β (Aβ). A published total synthetic method was improved by the use of a cross-metathesis to reduce the total synthesis by 5 steps and increase its flexibility to allow the production of analogues. The synthesised beauveriolide III was used in attempts to develop an IF-FACS-based assay to measure the intracellular concentrations of Aβ. However, the location of γ-secretase in the used cell-line meant that levels of intracellular Aβ were not sufficient to track any decrease caused by ACAT inhibition. The third project involves the design of a cyclic peptide that could block the binding site for the influenza virus in the host cell. The cyclic peptide (cGSGRGYGRGWGVGA) was developed from a comparative study of four different sialic acid-binding proteins and synthesised by solution cyclisation of the linear peptide synthesised by traditional solid phase peptide synthesis (SPPS). An in silico study showed that the cyclic peptide allowed overlap with the binding site of Hemagglutinin. A 1H NMR titration determined the dissociation constant of the cyclic peptide to sialic acid. The KD corresponded to a low binding affinity, however the observed binding seemed to be specific and caused by a single bound conformation.
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Balivada, Sivasai. "Cell mediated therapeutics for cancer treatment: tumor homing cells as therapeutic delivery vehicles." Diss., Kansas State University, 2013. http://hdl.handle.net/2097/16890.
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Doctor of Philosophy<br>Department of Anatomy and Physiology<br>Deryl L. Troyer<br>Many cell types were known to have migratory properties towards tumors and different research groups have shown reliable results regarding cells as delivery vehicles of therapeutics for targeted cancer treatment. Present report discusses proof of concept for 1. Cell mediated delivery of Magnetic nanoparticles (MNPs) and targeted Magnetic hyperthermia (MHT) as a cancer treatment by using in vivo mouse cancer models, 2. Cells surface engineering with chimeric proteins for targeted cancer treatment by using in vitro models. 1. Tumor homing cells can carry MNPs specifically to the tumor site and tumor burden will decrease after alternating magnetic field (AMF) exposure. To test this hypothesis, first we loaded Fe/Fe3O4 bi-magnetic NPs into neural progenitor cells (NPCs), which were previously shown to migrate towards melanoma tumors. We observed that NPCs loaded with MNPs travel to subcutaneous melanoma tumors. After alternating magnetic field (AMF) exposure, the targeted delivery of MNPs by the NPCs resulted in a mild decrease in tumor size (Chapter-2). Monocytes/macrophages (Mo/Ma) are known to infiltrate tumor sites, and also have phagocytic activity which can increase their uptake of MNPs. To test Mo/Ma-mediated MHT we transplanted Mo/Ma loaded with MNPs into a mouse model of pancreatic peritoneal carcinomatosis. We observed that MNP-loaded Mo/Ma infiltrated pancreatic tumors and, after AMF treatment, significantly prolonged the lives of mice bearing disseminated intraperitoneal pancreatic tumors (Chapter-3). 2. Targeted cancer treatment could be achieved by engineering tumor homing cell surfaces with tumor proteases cleavable, cancer cell specific recombinant therapeutic proteins. To test this, Urokinase and Calpain (tumor specific proteases) cleavable; prostate cancer cell (CaP) specific (CaP1 targeting peptide); apoptosis inducible (Caspase3 V266ED3)- rCasp3V266ED3 chimeric protein was designed in silico. Hypothesized membrane anchored chimeric protein (rCasp3V266ED3, rMcherry red) plasmids were constructed. Membrane anchoring and activity of designed proteins were analyzed in RAW264.7 Mo/Ma and HEK293 cells in vitro. Further, Urokinase (uPA) mediated cleavage and release of rCasp3V266ED3 from engineered cells was tested (Chapter-4). Animal models for cancer therapy are invaluable for preclinical testing of potential cancer treatments. Final chapter of present report shows evidence for immune-deficient line of pigs as a model for human cancers (Chapter-5)
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Gunnam, Mallikarjunareddy. "Novel anti-norovirus therapeutics." Thesis, Wichita State University, 2013. http://hdl.handle.net/10057/6818.
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Noroviruses are the most common cause of acute gastroenteritis, accounting for over 23 million cases annually in the U.S. alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this thesis, (a) structure-activity relationship studies were carried out using the acyclic sulfamide scaffold. Several derivatives based on this scaffold were found to inhibit norovirus in a cell-based replicon system and, (b) a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and ?-ketomides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED50 of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition inhibitors in the inhibition of norovirus 3CL protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as ?-ketoheterocycles and ?-ketoesters. Taken together, this thesis describes the discovery of two novel classes of inhibitors of noroviruses.<br>Thesis (M.S.)--Wichita State University, Fairmount College of Liberal Arts and Sciences, Dept. of Chemistry
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Hill, Jonathan B. "Deoxyvariolins and polymer therapeutics." Thesis, University of Canterbury. Chemistry, 2005. http://hdl.handle.net/10092/6695.
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Polymeric carrier molecules have been shown to improve the pharmacokinetics and pharmacological profile of small-molecule anticancer drugs. The variolins are a group of marine natural product-derived cytotoxins whose clinical efficacy may be improved through conjugation with a polymer backbone.
This thesis first describes the optimisation of a synthesis of the non-natural analogue deoxyvariolin B, a synthesis that was devised by Anderson and Morris immediately prior to the commencement of this project. The synthesis, comprised of six linear steps, was refined to give an overall yield of 25%.
As part of a much larger structure-activity relationship investigation being carried out by Pharma Mar, SA (a Spanish pharmaceutical company specialising in marine natural products), a small library of deoxyvariolin analogues, numbering approximately fifteen, was also synthesised and tested in vitro against the P388 murine leukaemia cell line. All analogues synthesised showed an appreciable loss of bioactivity (typically around an order of magnitutude) compared to that of deoxyvariolin B,
Attempts at acylating deoxyvariolin B with the tetrapeptide biolinker were hampered by DVB's awkward reactivity and the low stability of some of the products. A more suitable deoxyvariolin analogue, in terms of its bioactivity as well as chemical reactivity, was therefore chosen for development into a polymer therapeutic. This analogue was successfully conjugated with a tetrapeptide biolinker to give a compararably bioactive conjugate that was to be reacted with an activated polymer backbone.
The final part of this thesis, however, describes work that was carried out with the polymeric starting material, in which it was revealed that two unforeseen side reactions were taking place. These side reactions ultimately precluded the synthesis of the target constructs.
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Reynolds, Francis M. M. B. A. Massachusetts Institute of Technology. "InVivo Therapeutics® Corporation." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/37231.
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Thesis (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management, 2006.<br>Includes bibliographical references (leaf 100).<br>To date, the primary treatment for spinal cord injuries has been the use of spinal fixation devices to create a stable environment for the spinal cord to heal. The second treatment option is to remove soft tissue near and around the spinal cord intended to reduce pressure on the spinal cord and allow the spinal cord to heal on its own. InVivo Therapeutics Corporation is a startup founded to commercialize novel science and technology that was developed through a collaborative effort between the Massachusetts Institute of Technology's Langer labs, and the department of Neuroscience at Harvard Medical School. Together they have created a patent pending medical device that will provide the first "Neuro-Tissue Engineered" implantable device for the immediate treatment of spinal cord injuries. We expect to have our first product on the market in 2010, and we will continue to work in our labs to develop a portfolio of three to four product categories in order to meet the systemic needs of the spinal cord injury patient. This thesis presents the first business plan, to commercialize this innovative treatment option.<br>(cont.) It is always challenging to be first to market with such an innovative product, so we have meticulously explored all relevant strategic initiatives, and tactical tasks required to bring our products to market. As the result we have developed a comprehensive business plan to ensure InVivo's success. Key components of the plan are: Introduction to InVivo Therapeutics, InVivo's business model, critical strategic analysis, functional strategies, financial analysis, and an integrative strategic framework. We have created a vision, mission, and strategic model that will lead to InVivo Therapeutics becoming a global leader in the treatment of neurological disease.<br>by Francis M. Reynolds.<br>M.B.A.
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O'Malley, Jennifer A. "Improving therapeutics for Parkinson's disease." Cincinnati, Ohio : University of Cincinnati, 2009. http://rave.ohiolink.edu/etdc/view.cgi?acc_num=ucin1259079683.
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Thesis (Ph.D.)--University of Cincinnati, 2009.<br>Advisor: Kathy Steece-Collier. Title from electronic thesis title page (viewed Apr. 26, 2010). Keywords: Parkinson; dopamine; dyskinesia; levodopa; dendritic spine; medium spiny neuron. Includes abstract. Includes bibliographical references.
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Langford, Nigel James. "Beta-receptor pharmacology and therapeutics." Thesis, University of Birmingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404060.
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Derfus, Austin Matthew. "Toward multifunctional nanoparticle-based therapeutics." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2006. http://wwwlib.umi.com/cr/ucsd/fullcit?p3254426.
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Thesis (Ph. D.)--University of California, San Diego, 2006.<br>Title from first page of PDF file (viewed May 3, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 121-135).
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Sutter, Julianne V. "ASSESSING IMPACT OF AFFECT RECOGNITION ON THERAPEUTIC RELATIONSHIP." UKnowledge, 2010. http://uknowledge.uky.edu/gradschool_theses/14.
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Therapeutic alliance and its relationship to client nonverbal behavior, specifically facial expressions, were examined. Therapist interpretation of the client nonverbal behavior, or affect, influences the therapeutic alliance and process. Based on a sample of clients from a graduate school therapy training facility, results suggest therapist training in facial expressions, and how they relate to client emotion, improve the therapeutic alliance between therapist and client. After a micro-expression training for therapists, clients reported higher life functioning on the Outcome Rating Scale (ORS) and an improved therapeutic alliance on the Session Rating Scale (SRS). Overall, these findings support the benefit of incorporating micro-expression training into therapy instruction.
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Chiu, Shih-Jiuan. "Receptor-mediated DNA-based therapeutics delivery." Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1127403022.
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Bashar, A. M. A. Emran. "Cell based therapeutics for retinal degenerations." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58180.
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Vision loss, due to retinal degeneration, is one of the major disabilities in the developed world. Cell based therapeutics showed promising results in preventing retinal degenerations. Here, mesenchymal stem cells have been used to develop therapeutics for two different disorders. First, the innate paracrine activity of the Mesenchymal Stem Cells (MSCs) has been utilized to prevent neurodegeneration in a rodent model (S334ter-4) of Retinitis Pigmentosa. To deliver a significant number of cells to the rodent retina, a novel magnetic targeting approach was applied. The MSCs were pre-labelled with superparamagnetic iron oxide nanoparticles (SPIONs) and targeted to the eye by surgically placing a disc magnet in the orbit after systemic delivery. The magnetically guided MSCs provided better neuroprotection and functional responses (electroretinography and optokinetic tracking response) when compared to control and non-magnetic MSCs. The effect of magnetic nanoparticles on the paracrine secretion profile of MSCs was also analyzed. The concentration of the nanoparticles, used for the magnetic targeting study, had no significant effect on MSC’s paracrine activity; however, higher concentrations displayed varying effects for different factors. In the next project MSCs were employed as a vector for an ex vivo gene therapy approach for X linked retinoschisis (XLRS). MSCs were genetically modified to secrete an extracellular protein, retinoschisin (RS1), which is either nonfunctional or absent in XLRS. The RS1 expression from the MSCs was controlled in both constitutive (cMSC) and inducible (iMSC) manners. Cells, with both modifications, provided significant structural and functional benefits after intravitreal delivery in a RS1 knock-out mouse model when compared to unmodified MSCs, sham injection and no treatment controls. Among the two genetically modified cell lines, iMSC displayed better response compared to cMSC. These results from the MSC based therapeutic approaches in two different disease models show the potential of MSCs as a resourceful cell type for a number of retinal degenerations as well as diseases of other organs.<br>Medicine, Faculty of<br>Experimental Medicine, Division of<br>Medicine, Department of<br>Graduate
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Smith, Mathew Wayne. "Phage display and experimental brain therapeutics." Thesis, Cardiff University, 2009. http://orca.cf.ac.uk/55853/.
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Phage display, a powerful polypeptide display technology, affords the rapid identification of peptides and proteins that interact with a target of interest The aims of the project were the phage display identification of peptides that interact with a druggable target in a brain disorder (glioblastoma multiforme) and the identification of peptides that serve as targeting vectors for brain delivery. Validation studies were undertaken to qualify the use of a cyclic 7-mer peptide phage library against targets including streptavidin and paracetamol chosen as examples of a large complex and small simple molecule, respectively. With the aim of identifying peptide phages that bind to the luminal surface of brain micro vasculature, a primary in-vitro porcine model of the blood-brain barrier (BBB) comprising primary brain capillary endothelial cells was established and characterised. An in-vivo phage display was undertaken in the rat with the aim of identifying peptide sequences that mediated translocation across the BBB into brain grey matter. A 7-mer cyclic peptide was identified with sequence AC-SYTSSTM-CGGGS that enhanced the uptake of phages into brain grey matter by 4-fold compared to control wild-type phages. This peptide may serve as a novel targeting vector for the delivery of a therapeutic cargo to the brain. Caveolin-1 was identified as a potential new therapeutic target in in-vitro models of grade IV astrocytomas (glioblastoma multiforme), with siRNA knockdown of caveolin-1 associated with reduced glioma cell proliferation and invasiveness. With the caveolin-1 scaffolding domain (aa 81-101 in the caveolin-1 protein) as a target, an in-vitro peptide phage selection was undertaken and identified a series of peptides that bind the scaffolding domain with high affinity. These peptides will serve as a template for the development of low molecular weight peptidomimetics that inhibit caveolin-1 function. In conclusion, the studies in this thesis have demonstrated the utility of phage display in experimental therapeutics of brain disorders.
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Watson, Judy J. "Neurotrophins and their receptors as therapeutics." Thesis, University of Bristol, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431610.
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Woffindale, Caroline A. "RNA-based therapeutics for Alzheimer's disease." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:8abb9f7b-9e49-4063-8395-83a57e9b14f7.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised pathologically by the accumulation of amyloid-β plaques and neurofibrillary tangles within the brain. Currently, there are no disease-modifying therapeutic interventions available. This thesis describes the development and delivery of novel RNA-based therapeutics for AD. Recently, significant advances have occurred in the field of RNA interference (RNAi)-based therapeutics, allowing targeted silencing of disease-relevant genes through the use of short interfering RNAs (siRNAs) or microRNAs (miRNAs). However, development has been impeded by poor penetrance of the blood-brain-barrier (BBB) in vivo. Exosomes, as secreted extracellular vesicles (EVs), may overcome this problem as they naturally deliver RNA between cells and cross the BBB. Furthermore, recent evidence suggests that they may be loaded with exogenous RNA and preferentially targeted to neuronal tissue. Thus, this study investigated EV-mediated delivery of RNAi-based therapeutics shown to regulate AD-relevant genes. A comparison of EV-loading methods revealed that electroporation was confounded by the formation of large siRNA aggregates and indicated that endogenous loading strategies may be preferable. Endogenous loading of RNAi molecules was shown to be enhanced by co-expression with RNA-binding proteins, particularly following inclusion of an acylation domain. These findings highlight the potential for EV-mediated delivery of RNAi-based therapeutics. A combinatorial therapeutic approach is increasingly recognised to hold the most promise for the future of AD. Thus, this study also focused upon the development of novel multi-gene targeting locked nucleic acid-modified antisense oligonucleotides (LNA-ASOs) as a combinatorial approach towards AD therapy. Two multi-gene LNA-ASOs each produced potent silencing of two separate target genes simultaneously, resulting in a significant reduction in amyloid-β production in vitro. A murine-specific multi-gene LNA-ASO was also identified, paving the way for future in vivo studies. These findings suggest that multi-gene targeting LNA-ASOs may represent a promising novel therapeutic strategy for AD. In summary, this thesis has investigated novel strategies for both RNA delivery and multi-gene targeting, demonstrating the potential of RNA-based therapeutics for the treatment of AD.
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Ordway, Gregory A. "The Norepinephrine Transporter: Biology and Therapeutics." Digital Commons @ East Tennessee State University, 2007. https://dc.etsu.edu/etsu-works/8647.
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Chiu, Shihjiuan. "Receptor-mediated DNA-based therapeutics delivery." The Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1127403022.
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Hill, Marcus Peter. "Design of novel tobramycin loaded therapeutics." Thesis, Queen's University Belfast, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.706976.
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Telussa, Rallya. "Reclaiming the Activity of Lost Therapeutics." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6411.
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ESKAPE pathogens are notorious in causing nosocomial infections and escaping current antibiotic treatments. There has been a dramatic increase in nosocomial infections accompanied with a decrease in the number of antibiotics developed, leading to significant increase in morbidity and mortality among patients. In an attempt to combat this problem, derivatives of ciprofloxacin, rifabutin and beta-lactam antibiotics were synthesized and tested against the ESKAPE pathogens. From minimum inhibitory concentration assays, 4 ciprofloxacin analogs and 8 beta-lactam analogs were found to be effective against multiple bacterial species. Additionally, 12 rifabutin analogs and 23 beta-lactam analogs were potent against single bacterial species, primarily toward methicillin-resistant Staphylococcus aureus (MRSA) at a concentration of ≤ 25 µg mL-1. Based on the effectiveness against methicillin-resistant Staphylococcus aureus (MRSA), three rifabutin analogs were selected for further testing. Two rifabutin analogs (DU644 and DU645) were found to possess between a one to twofold mean increase of inhibitory activities, while the other rifabutin analogs (DU650) demonstrated up to a twofold decrease of inhibitory activity when compared to the parent drug. These compounds were then examined for their bactericidal and antibiofilm activities against MRSA. From these assays, we found that DU644 and DU645 were 4 times more bactericidal and antibiofilm against MRSA when compared to the parent drug. In addition, rpoB mutation validation results confirmed that modification of these rifabutin derivatives at the C3 and C4 positions, and bearing an imidazolyl ring carrying substituted spiropiperidyl ring, did not change their mechanism of action towards the beta-subunit of RNA polymerase. Cytotoxicity testing performed using human hepatocellular carcinoma epithelial cells (hepG2) showed that at concentrations ranged from 1.25 µg mL-1 to 25 µg mL-1, DU644 and DU645 showed very low toxicity. Collectively, structural drugs modifications of these obsolete drugs are able to restore their antibacterial activities against MRSA, which is notable as the most infectious nosocomial pathogen. Therefore, further development and application of rifabutin analogs might be beneficial for medical use to combat MRSA infections.
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Southwell, Amber L. Schuman Erin Margaret Patterson Paul H. "Intrabodies as therapeutics for Huntington's disease /." Diss., Pasadena, Calif. : California Institute of Technology, 2009. http://resolver.caltech.edu/CaltechETD:etd-06082009-164212.
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Kohler, Nathan. "Superparamagnetic nanoparticles for cancer diagnostics and therapeutics /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/10565.
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Dahl, Kjell. "Human colorectal cancer : experimental staging and therapeutics /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-154-8/.
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Shonk, David Knight. "An investigation into the therapeutics of architecture." Thesis, Georgia Institute of Technology, 1990. http://hdl.handle.net/1853/21736.
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Alkhamesi, Nawar Abdul-Hadi Saleh. "Intraperitoneal delivery of therapeutics in laparoscopic surgery." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438982.
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Deacon, Samuel Philip Edward. "Bioresponsive polymer therapeutics containing coiled-coil motifs." Thesis, Cardiff University, 2009. http://orca.cf.ac.uk/55819/.
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Polyethyleneglycol (PEG) conjugates of peptides, proteins and an aptamer are in routine clinical use as first generation nanomedicines. Here a new family of polymer therapeutics based on PEG conjugates containing a coiled-coil peptide motif as a molecular switch are proposed. The coiled-coil motif is adopted by many naturally occurring proteins/peptides, including transcription factors key to cancer progression (E2F1/AP-1) and Ebola virus proteins (VP35/GP2). These were chosen as the first targets, however there is potentially a much wider role for this novel family of therapeutics. First studies selected coiled-coil motif peptide sequences (using computational prediction software and published literature) that were then synthesised using a solid phase approach, purified and characterised. To facilitate subsequent PEGylation, peptides were engineered to include an N-terminal cysteine residue. mPEG-maleimide (-5,500 g mol 1) was then conjugated site-specifically via the cysteine thiol. A purification method optimised using cation-exchange chromatography enabled the removal of both unreacted mPEG-maleimide and free peptide purity was > 95 % for each conjugate. Proof of concept was obtained with mPEG-FosWc, which was designed to inhibit coiled-coil heterodimerisation of native c-Jun and c-Fos proteins (AP-1). 1H, 15N HSQC spectroscopy confirmed target hybridisation of heterodimeric coiled-coils FosWc : c-Jun and mPEG-FosWc : c-Jun. In addition, both NMR and CD spectroscopy showed that both heterodimers adopted very similar structures under physiological conditions, irrespective of the presence or absence of PEG. Further studies using fluorescently labelled conjugates investigated cellular uptake in MCF-7 cells, and biological activity was assessed using the MTT assay with and without the use of a cationic transfection reagent. These studies demonstrate the potential of mPEG-coiled-coil motifs as therapeutic agents. However, demonstrating reproducible biological activity was not possible with the intracellular targets. Investigating the biological activity of the conjugates designed to target the extracellular Ebola virus fusion proteins remains an exciting prospect.
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Petrilli, Guinart Alejandra. "Target validation for Neurofibromatosis Type 2 therapeutics." Doctoral diss., University of Central Florida, 2013. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/6339.
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Neurofibromatosis type 2 (NF2) is a benign tumor disease of the nervous system. Development of bilateral vestibular schwannomas is characteristic of NF2; however patients frequently present schwannomas on other nerves, as well as meningiomas and ependymomas. Currently, there are no drug therapies for NF2. There is an urgent need for development of NF2 therapeutics and this dissertation presents two independent potential therapeutic targets.
The disease is caused by mutations in the NF2 gene that encodes a tumor suppressor called merlin. Loss of merlin function is associated with increased activity of Rac and p21-activated kinases (PAK) and deregulation of cytoskeletal organization. LIM domain kinases (LIMK1 and 2) are substrates for Cdc42/Rac-PAK, and modulate actin dynamics by phosphorylating cofilin, an actin severing and depolymerizing agent. LIMKs also translocate into the nucleus and regulate cell cycle progression. Here we report that mouse Schwann cells (MSCs) in which merlin function is lost as a result of Nf2 exon2 deletion (Nf2 delta Ex2) exhibited increased levels of LIMK1, LIMK2, and active phospho-Thr508/505-LIMK1/2, as well as phospho-Ser3-cofilin, compared to wild-type normal MSCs. Similarly, levels of LIMK1 and 2 total protein and active phosphorylated forms were elevated in human vestibular schwannomas compared to normal human Schwann cells (SCs). Reintroduction of wild-type NF2 into Nf2delta Ex2 MSC reduced LIMK1 and LIMK2 levels. Pharmacological inhibition of LIMK with BMS-5, decreased the viability of Nf2?delta Ex2 MSCs in a dose-dependent manner, but did not affect viability of control MSCs. Similarly, LIMK knockdown decreased viability of Nf2delta Ex2 MSCs. The decreased viability of Nf2delta Ex2 MSCs was due to inhibition of cell cycle progression as evidenced by accumulation of cells in G2/M phase. Inhibition of LIMKs arrest cells in early mitosis by decreasing Aurora A activation and cofilin phosphorylation.
To increase the search for NF2 therapeutics, we applied an alternative approach to drug discovery with an unbiased pilot high-throughput screen of the Library of Pharmacologically Active Compounds. We assayed for compounds capable of reducing viability of Nf2delta Ex2 MSC as a cellular model for human NF2 schwannomas. AGK2, a SIRT2 (sirtuin 2) inhibitor, was identified as a candidate compound. SIRT2, a mammalian sirtuin, is a NAD+-dependent protein deacetylase. We show that Nf2delta Ex2 MSC have higher expression levels of SIRT2 and lower levels of overall lysine acetylation than wild-type control MSC. Pharmacological inhibition of SIRT2 decreases Nf2delta Ex2 MSC viability in a dose dependent manner without substantially reducing wild-type MSC viability. Inhibition of SIRT2 activity in Nf2delta Ex2 MSC causes cell death accompanied by release of the necrotic markers lactate dehydrogenase and high mobility group box 1 protein into the medium in the absence of significant apoptosis, autophagy, or cell cycle arrest.
Overall this work uncovered two novel potential therapeutic targets, LIMK and SIRT2 for NF2 and tumors associated with merlin deficiency.<br>Ph.D.<br>Doctorate<br>Molecular Biology and Microbiology<br>Medicine<br>Biomedical Sciences
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Campbell, Sarah Elizabeth. "Targeting gene-based therapeutics for canine osteoarthritis." Thesis, University of Glasgow, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419179.
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Scotti, F. "Novel potential peptide therapeutics for tuberculosis therapy." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1544707/.
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Despite the existence of vaccinations, diagnostic tools and treatments, tuberculosis (TB) prevalence is increasing because of the circulation of people and misuse of antibiotics, giving rise to growing numbers of drug resistant strains of Mycobacterium tuberculosis. There is therefore a pressing need to look for new strategies against TB, in the hope of finding new drugs with novel mechanisms of anti-tubercular action or ways to potentiate the activity of already existing drugs and reduce treatment duration. This thesis explores the employment of peptides in anti-tuberculosis therapy. The project was initiated by the identification of a novel therapeutic target in M. tuberculosis: murein peptide ligase (Mpl, Rv3712), an enzyme involved in the bacterial peptidoglycan recycling process. The aim is to synthesise its putative natural substrates (peptidoglycan peptide fragments) to characterise its activity and synthesise sequence analogues. These analogues were tested on the whole-cell and will be evaluated for inhibitory activity on the recombinant Mpl enzyme and eventually could be used in combination with existing or new drugs to see whether they increase anti-tubercular potency and thus combat resistance. Attainment of the putative substrate required the synthesis of mDAP, an unusual amino acid unique to peptidoglycan. Its synthesis was successfully completed and it was incorporated in the tripeptide Mpl putative substrate. Solid-phase synthesis has been used successfully and proved effective for rapid synthesis of multiple short peptide analogues in parallel. In addition it was used to synthesise anti-tuberculosis lasso peptides, lariatins A and B, lassomycin and analogues, to evaluate the structural requirements for biological activity. The method for the heterologous expression and purification of recombinant Mpl from M. tuberculosis has been confirmed as successful, and the enzyme is available for future target-based evaluation using the synthesised mDAP-containing tripeptide and eventually for other mDAP-containing PG fragments and analogues.
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Collins, Patrick. "The Galectins as Targets for Cancer Therapeutics." Thesis, Griffith University, 2013. http://hdl.handle.net/10072/365234.
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The galectins are the most ancient and widely expressed family of glycan-binding protein, and have been found in all metazoans examined to date. Galectins recognise and bind to carbohydrate ligands, specifically those that contain β-galactosides, and it is via these interactions, and through direct protein–protein interactions, that the galectins perform their highly diverse collection of activities. In humans, the galectins are found in both the intracellular and extracellular environments, and have important roles in many aspects of cellular homeostasis, cell signalling, and cell adhesion. Of importance for this project is that most of the functions of galectins, even those involving direct protein–protein interactions, are found to be inhibitable by carbohydrate ligands.
Many galectin functions are related to important aspects of tumour progression and cancer, and it has emerged that the galectins are playing many negative roles in disease processes. Some galectins are found to be involved in tumour growth, adhesion, migration, and immune escape, with galectin expression levels in tumour cells often correlating with tumour aggressiveness, metastatic potential, and poor patient prognosis. The most extensively studied members of the galectin family, and for which there exists the most detailed evidence regarding their roles in disease, are galectins -1 and -3. As
such, these two proteins have been identified as promising targets for cancer therapy, and are under investigation in this project.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>Institute for Glycomics<br>Science, Environment, Engineering and Technology<br>Full Text
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Sklepari, Meropi. "Stability and biophysical characterisation of protein therapeutics." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/98558/.
Full textAbstract:
For the past two decades, the development of protein therapeutics has significantly expanded with numerous biopharmaceutical and biosimilar products entering the medicine market every year, and even more queuing in the pipeline globally. Biologics are very complex molecules and therefore extremely sensitive to minor changes in the manufacturing process, which can result in heterogeneity and affect the stability, potency and immunogenicity of the final product. Public health organisations, such as EMA (European Medicines Agency), require that biological products should be extensively tested for their similarity to the original drug (in the case of a biosimilar) as well as to products from different batches (batch-to-batch comparison). The issued guidelines focus, among other tests, on physicochemical characterisation of these molecules. The suggested analytical techniques, however, are only vaguely named in the specifications, leaving the final decision to the manufacturers. The present work focuses on the use of different combinations of analytical techniques with an aim to demonstrate similarity or dissimilarity between two or more samples. The selected instrumental techniques are characterised by their simplicity and are able to detect structural differences and microheterogeneity of the active ingredient in different samples, aggregation, degradation and post-translational modifications (PTMs). Seven studies were completed in total, each one to a different extent, and these included protein therapeutics such as insulin and monoclonal antibodies. The applied techniques served for primary (MS),* secondary (far-UV CD, FT-IR) and tertiary structure (near-UV CD, fluorescence) comparison of the examined samples. Particle size comparability and detection of aggregation was achieved with DLS, and higher-order structure comparison with 1D 1 H-NMR. Coupling of the techniques with temperature-dependent measurements enabled further comparison on the thermal stability of the samples and provided confidence in the observed (at room temperature) results. The acquired empirical experience pointed out the advantages and disadvantages of each technique compared to the rest of the techniques, possible solutions to the encountered challenges, and the cases that one technique can be used instead of another or as complementary to it. Finally, a potential SOP is suggested, advising on which biophysical techniques should be used depending on the structure of the protein that is examined and its formulation.
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Spagnolli, Giovanni. "Folding, Misfolding and Therapeutics in Prion Diseases." Doctoral thesis, Università degli studi di Trento, 2021. http://hdl.handle.net/11572/308935.
Full textAbstract:
Prion diseases are rare neurodegenerative disorders affecting humans and other animals, caused by a proteinaceous infectious agent named prion. The pivotal event in these pathologies is the conversion of PrPC, a physiologically expressed protein of poorly characterized function, into a misfolded conformer, named PrPSc, which is capable of replicating its conformationally-encoded information by inducing the conversion of its physiological counterpart. The aggregates resulting from this misfolding process accumulate in the central nervous system of affected organisms leading to neuronal death. Prion diseases are always fatal and no therapy is currently available. The lack of an effective therapeutic strategy to tackle such conditions is the result of the poor available information regarding many aspects of PrPSc, such as its structure, pathogenicity, and its replication mechanism. To complicate things further, PrPSc can appear as a set of distinct conformers, named strains, characterized by the capacity to evolve through modification and selection of their conformations, promoting resistance to treatments. In this work, we focus on two main aspects of prion biology, the elucidation of prion structure and propagation, and the development of a novel pharmacological strategy to tackle prion diseases. In both projects, we exploited the potential of integrative schemes combining computational methods and experimental data. Such approaches allowed us to build a plausible atomistic model of PrPSc and to propose a propagation mechanism describing the series of events underlying prion propagation. Moreover, the application of advanced computational schemes enabled us to identify a PrP folding intermediate displaying unique druggability properties. By exploiting the structural information of this protein conformer we identified a compound capable of acting as a pharmacological degrader for PrP by interfering with its folding pathway. Overall, this work highlights how the integration of computational and experimental methods is an extremely valuable scheme to answer complex biological questions, such as unraveling the mechanisms of protein misfolding and providing the tools to design pharmacological strategies for untreatable diseases.
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Spagnolli, Giovanni. "Folding, Misfolding and Therapeutics in Prion Diseases." Doctoral thesis, Università degli studi di Trento, 2021. http://hdl.handle.net/11572/308935.
Full textAbstract:
Prion diseases are rare neurodegenerative disorders affecting humans and other animals, caused by a proteinaceous infectious agent named prion. The pivotal event in these pathologies is the conversion of PrPC, a physiologically expressed protein of poorly characterized function, into a misfolded conformer, named PrPSc, which is capable of replicating its conformationally-encoded information by inducing the conversion of its physiological counterpart. The aggregates resulting from this misfolding process accumulate in the central nervous system of affected organisms leading to neuronal death. Prion diseases are always fatal and no therapy is currently available. The lack of an effective therapeutic strategy to tackle such conditions is the result of the poor available information regarding many aspects of PrPSc, such as its structure, pathogenicity, and its replication mechanism. To complicate things further, PrPSc can appear as a set of distinct conformers, named strains, characterized by the capacity to evolve through modification and selection of their conformations, promoting resistance to treatments. In this work, we focus on two main aspects of prion biology, the elucidation of prion structure and propagation, and the development of a novel pharmacological strategy to tackle prion diseases. In both projects, we exploited the potential of integrative schemes combining computational methods and experimental data. Such approaches allowed us to build a plausible atomistic model of PrPSc and to propose a propagation mechanism describing the series of events underlying prion propagation. Moreover, the application of advanced computational schemes enabled us to identify a PrP folding intermediate displaying unique druggability properties. By exploiting the structural information of this protein conformer we identified a compound capable of acting as a pharmacological degrader for PrP by interfering with its folding pathway. Overall, this work highlights how the integration of computational and experimental methods is an extremely valuable scheme to answer complex biological questions, such as unraveling the mechanisms of protein misfolding and providing the tools to design pharmacological strategies for untreatable diseases.
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Lang-Hua, Bich Hue, and 梁許碧蕙. "Decision-making in dental treatment planning: to maintain or to extract compromised teeth." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B50534282.
Full textAbstract:
Background: A number of systematic reviews provide the basis for decision-making in treatment planning of the reconstruction of mutilated dentitions. This includes identifying teeth difficult to treat/save and decisions on replacement such teeth if extracted.
Aims:
1) To assess attitudes of general dental practitioners (GDPs) in a community where provision of dental implants is a widely practiced treatment; and to determine variations in attitudes with respect to dentists’ factors, training factors and implant-provision factors (Study 1): and
2) To determine treatment decision making with respect to maintaining periodontally compromised teeth among dentists with and without postgraduate qualifications in implant dentistry (Study 2).
Methods:
Study 1:A cross-sectional survey was conducted on a random sample of registered dentists in Hong Kong regarding their attitudes towards implant dentistry with respect to (1) perceived superiority, (2) perceived outcomes, (3) perceived complications and maintenance issues and (4) placement issues. In addition, information was collected on dentists’ factors, training factors and implant provision factors. Variations in attitudes towards implant dentistry were explored.
Study 2: A series ofpatient scenarios with varying degrees of periodontal disease levels was presented to selected dentists. Information on their decision-making outcomes, and their intention to retain compromised teeth was analysed in bivariate and regression analyses; accounting for postgraduate implant training, gender, years in dental practice and implant placement experience.
Results:
Study 1: Among eligible practitioners (n=246), the response rate was 46.3%. Most dentists’perceived implants to be superior to conventional prostheses for the replacement of a single missing posterior tooth (80%) and likewise, for the replacement of a single missing anterior tooth (67%). Variations in attitudes existed with respect to dentists’ factors: years in practice (p<0.05), place of graduation (p<0.05); implant training factors (p<0.05), number of days of training (p<0.05) and implant experience factors (p<0.05).
Study 2:This study involved 30 dentists with postgraduate implant qualifications (GDPP), 33 dentists without postgraduate implant qualifications (GDP) and 27 dentists undergoing postgraduate training for implant qualifications (GDPT). Variations in treatment decision-making were evident between the three groups (p<0.05). Differences in treatment approaches to retaining compromised teeth were apparent(p<0.05). Furthermore, variations in rehabilitation of extracted scenarios existed in terms of use of implants and number of implants needed for rehabilitation. Accounting for dentist and practice factors in regression analyses, compared to GDP, GDPP/GDPT were three times as likely to retain periodontally compromised upper molars with painwith pain (OR 3.08, 95%CI 1.09, 8.14 p=0.03), or without pain (OR 3.10, 95%CI 1.04, 10.62 p=0.04).
Conclusions:
Study 1:In a community where provision of dental implants is widespread the attitudes of GDPs are not wholly in line with evidence-based knowledge. Variations in their attitudes exist with respect to dentist factors, training and experience issues.
Study 2: Variations in treatment decision making with respect to retaining periodontally compromised teeth exist between dentists with and dentists without postgraduate training in implant dentistry. Furthermore, there are differences in their management approaches.<br>published_or_final_version<br>Dentistry<br>Master<br>Master of Philosophy
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Parfitt, Natalie Rae. "Investigations of the assessment of bioequivalence of topical clotrimazole products using a dermatopharmacokinetic approach." Thesis, Rhodes University, 2010. http://hdl.handle.net/10962/d1007659.
Full textAbstract:
The specialised nature of the stratum corneum makes it an efficient barrier to foreign substances, including drug molecules. Therefore, cutaneous drug absorption is a slow and complex process of which stratum corneum penetration is the rate limiting step. The rate and extent of stratum corneum penetration by a drug compound depends greatly on the presence of penetration enhancing/retarding excipients and therefore the clinical outcomes of a product rely greatly on the components and quality of the formulation. Hence, establishing bioequivalence between topical products is crucial to ensure that patients receiving multisource drug products are assured of the same efficacy and safety as the brand product. Since locally acting topical formulations do not target the systemic circulation, conventional methods of assessing bioequivalence using plasma levels are not appropriate. Consequently, the current regulatory guidelines require comparative clinical trials to be carried out to show bioequivalence between topical products. As these studies are very expensive and time consuming, the development of a more direct and relatively rapid and inexpensive method for determining bioequivalence between topical products is required. Clotrimazole is an anti-fungal agent where the target site of action is in the stratum corneum. In this work, tape stripping, which involves the sampling of stratum corneum, was investigated as a tool for the determination of bioequivalence between topical clotrimazole products. The tape stripping method involved the analysis of each tape strip individually and standardization of stratum corneum thickness between subjects was carried out using TEWL measurements. This approach provided detailed information regarding the amount of clotrimazole present in the stratum corneum as well as the extent of drug penetration. Prior to the tape stripping studies an HPLC method was developed for the quantitative analysis of clotrimazole from the tape strip samples. This method was shown to be accurate and reproducible across the required range. It was also shown to be selective for clotrimazole in the presence of possible interfering substances such as those present in the tape adhesive and also skin components. The bioequivalence studies were conducted using a single “uptake” time point. In order to determine an appropriate dose duration for these studies a novel approach was employed, involving a preliminary dose duration study. For the bioequivalence investigations, Canesten® Topical cream was used as both test and reference products to determine if the method was capable of showing bioequivalence. Subsequently, Canesten® Topical cream was also compared to a 1% gel formulation to determine if the method could detect formulation differences. The conventional BE limits of 0.8 – 1.25 were used for the assessment of BE, however, the clinical relevance of using these limits for dermal studies is debatable since they are derived from oral pharmacokinetic studies. Therefore, the data from the tape stripping investigations were also assessed using more realistic limits of 0.75 – 1.33 and even 0.7 – 1.44. In addition to the tape stripping studies a novel method of determining the amount of drug present in the stratum corneum, the “Residual Method”, was investigated. This method involved assaying the amount of clotrimazole found in the residual formulation after a specified dose duration had elapsed and subtracting that amount from the amount of clotrimazole initially applied. The results of tape stripping investigations showed that, if the study is sufficiently powered, tape stripping may be used to determine bioequivalence according to the conventional limits, as well as possibly detect formulation differences between different clotrimazole products. Bioequivalence assessment using the widened intervals showed that fewer subjects were required to achieve a sufficient statistical power. The variability associated with this method was acceptable and tape stripping may therefore have the potential to be used as a BE tool in a regulatory setting for clotrimazole or other antifungal topical formulations. The “Residual Method” also showed promising results as a bioequivalence tool, but further investigation and extensive validation of this method is required before it can be suggested as a regulatory method. The results of these studies have clearly indicated that tape stripping has the potential to be used as an alternative to comparative clinical trails for the assessment of bioequivalence between clotrimazole formulations and also to assess bioequivalence between other antifungal products.
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Fraser, Andrew Gordon. "The elimination of susceptibility bias in the study of adult female class II division 1 cases treated either with orthognathic surgery or orthodontics : a project report submitted as partial fulfilment for the degree of Master of Dental Surgery /." Title page, contents and summary only, 1997. http://web4.library.adelaide.edu.au/theses/09DM/09dmf841.pdf.
Full text
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Rafiq, Sarwish. "Evaluation of Antibody-based Therapeutics in B cell Malignancies." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338321515.
Full text
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McCrudden, Maeliosa Theresa Christine. "Characterisation of small protease inhibitors as potential therapeutics." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492028.
Full textAbstract:
Neutrophil-derived serine proteases provide one of the first lines of defense against infection in innate immunity. However, in some disease states, the activity of these proteases becomes excessive and prolonged and so novel lead molecules with the potential to inhibit the excessive activity of these proteases in disease states are constantly being sought. In the current study, three proteinaceous protease inhibitors were chosen for characterisation. The specificity of the Escherichia coli trypsin inhibitor (ecotin) was modulated by site-directed mutagenesis studies; the elastase and cathepsin G-like inhibitor (eglin C) from Hirudo medicinalis was used as a positive control recombinant protein and the functional characteristics of the epididymal protease inhibitor (eppin) were examined. Eppin's anti-bacterial activity had been partially characterised but beyond this, very little functional information was available for the protein. Composed of the Whey acidic protein (WAP) and Kunitz inhibitor motifs, eppin was postulated to have anti-protease and immunomodulatory properties. Expression vectors were constructed for eppin and each of its consensus inhibitor domains and recombinant proteins were subsequently expressed in and purified from E. coli cells. The proteins all had elements of a-helix and p-sheet in their secondary structure, deduced by circular dichrosim (CD) analysis. Eppin and its domains were found to kill E. coli cells via a mechanism of permeabilisation of bacterial membranes resulting in uncoupling of respiratory electron transport but the two domains were required to achieve maximal effect. The Kunitz domain inhibited human neutrophil elastase to a similar extent as the intact protein but the.WAP domain exhibited no such activity. In a model of lipopolysaccharide (LPS)-induced inflammation in a monocytic cell line, eppin was shown 'to inhibit the expression of three pro-inflammatory cytokines. The mechanism of inhibition, in the case of one of the cytokines, was via down-regulation of transcription ofthe cytokine.
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Chen, Sam. "Lipid nanoparticles for delivery of nucleic acid therapeutics." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58637.
Full textAbstract:
Nucleic acid therapies have the potential to enable the treatment of disorders previously untreatable. However, significant barriers prevent the rapid development of nucleic acid therapeutics and necessitate the use of sophisticated delivery systems. The overall objective of this dissertation is to develop more effective and tolerable lipid nanoparticles (LNPs) for nucleic acid delivery. Specifically, LNP that vary in size, stability and composition were tested for activity after subcutaneous and intravenous injection in order to optimize LNP properties. Furthermore, the incorporation of novel lipophilic pro-drugs co-delivered with nucleic acids was explored as a means to improve tolerability.
The first part of this dissertation explores the use of subcutaneous administration for LNP-siRNA. There are compelling reasons to develop LNP-siRNA that can be administered subcutaneously. These include the potential for self-administration, a prolonged therapeutic window due to a depot effect and access to cell types that are in contact with the lymphatic system, in addition to tissues available through the circulation. We found that particle size and PEG steric barrier are both important for drainage from the injection site and subsequent accumulation in the liver.
Although small LNP exhibited improved drainage and access to the systemic circulation, activity was impaired. The second part of this dissertation addresses this issue. The decrease in LNP activity can be attributed to the pronounced size dependent instability of LNP. By altering the amino-lipid content and the PEG-lipid used, the activity and stability of these systems can be greatly improved.
The previous two parts of this dissertation identified limitations to existing LNP systems. First, administration of LNP containing nucleic acids could result in immune stimulation. Second, efforts to improve LNP activity must go beyond existing components. The last part of this dissertation proposes a general pro-drug strategy for enabling direct incorporation of additional compounds into the LNP. As an example dexamethasone, a corticosteroid commonly used to minimize infusion-related reactions, was used. Direct incorporation greatly improved the ability of dexamethasone to ameliorate immune stimulation by LNP containing nucleic acids. This work shows that when appropriately designed, LNP systems can have improved activity and tolerability, potentially expanding its clinical utility.<br>Medicine, Faculty of<br>Biochemistry and Molecular Biology, Department of<br>Graduate
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Conrad, David Paul. "Development of Vesiculovirus-based Therapeutics for Acute Leukemia." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31743.
Full textAbstract:
Outcomes for most patients with acute leukemia remain dismal. In-vitro, vesiculovirus members induced rapid apoptosis of acute leukemia cells. Intravenous injection of lymphoblastic leukemia cells infected ex-vivo with attenuated Vesicular Stomatitis Virus or Maraba Virus followed by gamma-irradiation, controlled leukemic progression in murine recipients. Essential properties of this autologous vaccine [immunotherapy by Leukemia-Oncotropic Virus (iLOV)] and the host’s immune system were characterized. iLOV durability was restricted to the leukemia used to manufacture the vaccine. At administration, virion cell-entry was required but vesiculovirus lifecycle completion was not essential. Apoptotic or necrotic leukemia cells, with/without co-injection of virus, were ineffective vaccines. Similarly ineffective were leukemia cells activated by, or injected with, Toll-like receptor agonists. Naïve recipients of adoptive splenocyte transfer from vaccine-treated immunocompetent donors were protected from leukemic challenge. Efficacy was notably diminished following matched allogeneic bone marrow transplantation; this correlated with isolated depletion of cytotoxic T-cells. iLOV was ineffective in athymic mice. Taken together, iLOV therapy relies on immediate spaciotemporal interactions between infected-dead/dying leukemia cells and the immune system; this promotes adaptive anti-tumor responses. Clinical translation could target patients in remission to control relapse.
During the above I discovered that under specific conditions, live vesiculovirus exposed to a precise window of UV fluence reproducibly generates unique “non-replicating rhabdovirus-derived particles” (NRRPs) that maintain cell-entry and cytopathic properties. A gamut of leukemia cells, including multidrug-resistant blasts, underwent rapid NRRPs-induced apoptosis. Normal cell lines and healthy bone marrow mononuclear cells were resistant, in part through interferon-mediated signaling responses. Administering NRRPs intravenously was curative in a murine acute leukemia model, versus uniform disease progression using maximal tolerated dose of replicating virus. Serum levels of an array of immunomodulatory cytokines were significantly elevated after injection of NRRPs. iLOV prepared with NRRPs protected recipients from otherwise lethal leukemia. Intracranial administration of NRRPs proved nonlethal as opposed to neurotoxic live vesiculovirus. Following treatment, neutralizing antibodies were diminished with NRRPs compared to replicating virus. Together, NRRPs exhibit enhanced therapeutic index over replication-competent vesiculovirus. Leukemocidal activity of NRRPs is exerted through a plurality of immune-related and direct cytotoxic effects. This novel approach now extends vesiculovirus-based therapeutics into upfront treatment for acute leukemia.
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Tan, Ee Lyn. "Drug and Therapeutics Committees: Studies in Australian hospitals." University of Sydney. Pharmacy Practice, 2005. http://hdl.handle.net/2123/711.
Full textAbstract:
Australia�s policy on Quality Use of Medicines (QUM) aims to achieve appropriate use of medicines and improved health outcomes. Drug and Therapeutics Committees (DTCs) are educators, policy makers as well as financial gatekeepers in matters relating to medicine use. Increasingly, DTCs are also involved in risk management and clinical governance. As such, DTCs could be considered to be QUM advocates in the institutions in which they function. In a health care arena where there are escalating demands on high standards of clinical practice, quality assessment and improvement is essential in ensuring safe and effective patient care. Given the role DTCs play in safeguarding the interests of the stakeholders of the health care system, research into ways in which DTC performance could be enhanced is required. Although indicators specific to DTCs exist, the literature does not seem to provide straightforward answers to the question of what is currently being done in terms of quality assessment and quality improvement of DTCs. In the absence of such data, an opportunity for research is clearly identified. The first aim of this research project was to gain insight into the current activities undertaken by, and challenges facing Australian DTCs. Following this, the second aim was to explore ways in which DTC performance could be augmented. In addressing the first aim of this project, a national survey of Australian DTCs was conducted. These findings reinforce the evidence in the literature about the roles, structure and stakeholder expectations of DTCs. Our research also documents DTCs� quality improvement initiatives and barriers to DTC activities. It appears that there is little support available to Australian DTCs. Further, a case study was undertaken in order to gain an understanding of the depth and detail of DTC operations. An audit of a DTC in an Australian hospital was conducted. This study revealed that DTC decisions are being implemented in an ad hoc manner. In fact, there were no strategies (or action) planned to implement the majority of their decisions. This could have an impact on DTC performance. In view of this finding, qualitative methods were used to explore stakeholder opinions regarding the implementation of DTC decisions and policies. Stakeholders believed that strategies used to implement DTC policies should be targeted (to the audience as well as the type of decision/policy being implemented), timely, and delivered at the point of care. Face-to-face strategies were perceived to be more effective than printed materials, particularly when an influence on clinical practice was desired. Stakeholders also felt that the lack of resources was a significant barrier to DTC performance augmentation. This probably contributed to a lack of follow-up (or review) of implemented policies. According to stakeholders, other barriers to policy implementation include a lack of ownership of policies, low DTC profile, and an over-reliance on pharmacy to implement DTC decisions. Stakeholders felt one of the ways in which DTC performance could be improved was to prioritise DTC decisions for implementation. In pursuit of a method to prioritise DTC decisions, a survey was conducted. Stakeholders identified patient safety, cost, and the practice of evidence-based medicine as domains of important DTC decisions. The results also suggest that stakeholders recognise the need for the prioritisation of DTC decisions for implementation. Stakeholders implied that higher priority would be assigned to DTC decisions considered to be important. In a follow-up survey, stakeholders (including doctors, nurses, pharmacists, and DTC members) seemed to have agreement of the primary domains of DTC decisions. Higher levels of importance and higher priority were assigned to decisions involving the primary domains of patient safety and cost. However, level of importance and priority assignment were not consistently correlated. The work presented in this thesis suggests that there are ways to improve DTC performance. Although conducted primarily on hospital-based DTCs, it is anticipated that the lessons learnt could be applied to state-based, or even, Area Health-based DTCs. In conclusion, this research found that there was a range of views regarding �importance� and prioritisation for implementation. Social, organisational, as well as environmental factors may contribute to this. Future research should examine other possible factors contributing to the importance and priority of DTC decisions, so that DTC policy could be appropriately implemented into practice.
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Scott, Lauren. "Multifunctional pro-ligands as potential Alzheimer’s disease therapeutics." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/10317.
Full textAbstract:
Alzheimer’s disease is the most common form of dementia, affecting more than 24 million individuals worldwide. Although the exact causes of disease development and progression are unknown, the amyloid hypothesis links the observed pathologies of elevated metal ion levels (Cu²⁺, Fe³⁺, Zn²⁺), deposition of amyloid peptide in senile plaques, oxidative stress and neurodegeneration in a cohesive manner. As part of a possible intervention for this process, a series of multifunctional pyridinone pro-ligands were designed and synthesised. 3-Hydroxy-4-pyridinones display a high affinity for metal ions - particularly Fe³⁺ and Cu²⁺ - and are readily functionalised by variation of the N-substituent on the heterocyclic ring. The alpha-hydroxyketone functionality serves not only to bind metal ions, but as an antioxidant via phenolic hydrogen donation; in addition, these activities may be masked by glycosylation at the 3-hydroxy position.
Seven pyridinone pro-ligands were synthesised, each containing a pyridinone moiety and a second aromatic ring. Five of these pro-ligands incorporate structural features of amyloid imaging agents: 2-methyl-3-hydroxy-1-(4-dimethylaminophenyl)-4(1H)-pyridinone (Hdapp), 2-methyl-3-hydroxy-1-(4-methylaminophenyl)-4(1H)-pyridinone (Hsapp), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (Hzapp), 1-(6-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (Hbt6p) and 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (Hbt2p). The final two compounds, 3-hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone (Hppp) and 1-benzyl-3-hydroxy-2-methyl-4(1H)-pyridinone (Hnbp), were synthesised and compared to probe the impact of linker length modification between the two aromatic rings. In addition to pro-ligand synthesis, their activities were assessed using a number of in vitro assays. Ability to interfere with metal ion-induced amyloid peptide aggregation in solution, antioxidant activity, cytotoxicity, coordination of Cu²⁺ and binding to amyloid fibrils were all assayed on this series. This was done as a preliminary screen to identify promising lead compounds for further development. The compounds displayed marked ability to resolubilise metal ion-aggregated amyloid-beta, excellent antioxidant activity comparable to that of alpha-tocopherol and acceptable cytotoxicity levels. Furthermore, the ligands coordinate Cu²⁺ in the bis, square planar, tetracoordinate fashion typical of 3-hydroxy-4-pyridinones, and their binding to amyloid-beta fibrils was found to be dependent on ring structure.
This work incorporates the first examples of rationally-designed small-molecule Alzheimer’s therapeutics incorporating such multifunctionality, and it is expected that the combination will promote more effective Alzheimer’s intervention than current metal ion-binding therapeutics such as clioquinol and other 8-hydroxyquinoline derivatives in development.
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Srivastava, Vinit. "Response of medulloblastoma cell lines to experimental therapeutics." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=66723.
Full textAbstract:
Medulloblastoma is the most common malignant childhood brain tumour. The discovery of stem-like cells in malignant cancers has provided an alternative hypothesis for tumour initiation and progression. Given the toxicities associated with conventional therapies, developing therapies targeting aberrant molecular pathways or stem-like cells in medulloblastoma may improve overall survival and quality of life. Numerous reports have indicated that stem-like cells also exist in long-established cultured cell lines. Therefore, we first determined whether the DAOY medulloblastoma cell line contained a stem-like population and how this subset of cells responded to therapeutic modalities. The literature suggests that self-renewal is associated with the CD133 and side population (SP; Hoechst 33342 efflux) phenotypes. However, our results revealed clonogenicity even in the absence of these markers (CD133- and non-SP cells). Furthermore, each compartment demonstrated asymmetric division by regenerating not only itself but the other compartment as well. Expression of the two stem cell markers did not entirely overlap as CD133 expression was present in both SP and non-SP compartments. These results were also supported by decreased cell viability in both the SP and total cell compartments and similar susceptibility of both compartments to chemotherapeutic treatment. Although histone deactylase (HDAC) inhibitors significantly reduced in vitro tumour cell clonogenicity and increased survival of medulloblastoma-bearing mice, the relationship between HDAC inhibitor treatment and stem-like cell markers was not evident. These results highlight the fact that care must be used in interpreting preclinical therapeutic studies targeting the stem cell compartment of cancer cell lines. With a view to developing combinations of targeted therapies, we examined the potential role of transcription factor-based therapies for medulloblastoma. Our results demo<br>Le médulloblastome est la tumeur cérébrale maligne la plus fréquente chez les enfants. La découverte de cellules quasi similaires aux cellules souches dans des cancers malins a permis de fournir une autre hypothèse au développement d'une lésion et à sa progression. Compte tenu des toxicités associées aux thérapies conventionnelles, le développement de thérapies qui ciblent des voies moléculaires aberrantes, ou les cellules quasi similaires aux cellules souches du médulloblastome, peut améliorer la survie générale et la qualité de vie. Dans de nombreux rapports, on a indiqué que les cellules quasi similaires aux cellules souches existent également dans les lignées cellulaires cultivées longuement établies. Par conséquent, nous avons tout d'abord déterminé si la lignée cellulaire des DAOY du médulloblastome contenait une population quasi similaire aux cellules souches et la façon dont ce sous-ensemble de cellules réagissait aux modalités thérapeutiques. La documentation semble suggérer que l'autorenouvellement est associé à des phénotypes CD133 et de population isolée (« side population » ou SP; sortie Hoechst 33342). Toutefois, nos résultats ont permis de révéler une clonogénicité même en l'absence de ces marqueurs (cellules CD133 et non-SP). De plus, chaque compartiment a démontré une division asymétrique en se régénérant non seulement lui-même, mais aussi l'autre compartiment. L'expression de deux marqueurs de cellules souches ne s'est pas entièrement chevauchée, car l'expression du CD133 était présente dans les compartiments SP et non-SP. Ces résultats étaient également appuyés par une diminution de la viabilité cellulaire dans les compartiments SP et de cellule totale, et dans la susceptibilité similaire des deux compartiments au traitement chimiothérapeutique. Même si les inhibiteurs d'histone désacétylase (HDAC) ont réduit de façon importante la clon
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Guillemard, Véronique. "Design and chemical synthesis of selective cancer therapeutics." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85073.
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The clinical use of chemotherapeutic agents against malignant tumors is successful in many cases but suffers from major drawbacks. One drawback is the lack of selectivity which leads to severe side effects and limited efficacy, and another is the emergence/selection of drug-resistance. To limit non-specific toxicity and to improve the efficiency of cancer therapy, "tumor markers", which are proteins generally overexpressed on the surface of tumor cells, can be selectively targeted.<br>Growth factor receptors are one of the most extensively studied groups of tumor markers. The implication of growth factor receptors in the pathogenesis of cancer has clearly been established and therefore, provides a rationale for therapeutic intervention. The targeting of cytotoxic substances to defined cell populations with "magic bullets" is an old idea that raised high expectations but also disappointment. Over the past decade, newly gained understanding of mechanisms for targeted therapy have brought new hopes. Pharmacological agents that selectively target and block the action of growth factors and their receptors have been attempted, such as monoclonal antibodies (mAbs) (whole molecule or fragments), bispecific antibodies, mAbs conjugated to drugs, toxins or radioisotopes, small peptidic and peptidomimetic molecules in free form or conjugated to drugs, anti-sense oligonucleotides, immunoliposomes-encapsulated drugs, and small molecule inhibitors. We designed, synthesized and characterized new chemotherapeutic agents consisting of Paclitaxel or Doxorubicin as anti-cancer drugs chemically coupled to growth factor receptor-selective monoclonal antibodies or small peptides as targeting agents. We show that the conjugates were selective and specific towards the targeted receptors, and had significant increased efficiency compared to parent drugs. More importantly, the conjugates were able to bypass p-glycoprotein-mediated resistance both in vitro and in vivo. These findings have considerable importance since drug resistance is a major cause of cancer treatment failure.
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Attard, Gerhardt. "Novel therapeutics and biomarkers for human prostate cancer." Thesis, Institute of Cancer Research (University Of London), 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511508.
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Magnusson, Johannes Pall. "Smart" polymer therapeutics towards new architectures and applications." Thesis, University of Nottingham, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.523592.
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Wong, Xing-Wei. "Model-Based Therapeutics for Type 1 Diabetes Mellitus." Thesis, University of Canterbury. Mechanical Engineering, 2008. http://hdl.handle.net/10092/1573.
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The incidence of Type 1 diabetes is growing yearly. Worryingly, the aetiology of the disease is inconclusive. What is known is that the total number of affected individuals, as well as the severity and number of associated complications are growing for this chronic disease. With increasing complications due to severity, length of exposure, and poor control, the disease is beginning to consume an increasingly major portion of healthcare costs to the extent that it poses major economic risks in several nations. Research has shown that intensive insulin therapy aimed at certain minimum glycosylated haemoglobin threshold levels reduces the incidence of complications by up to 76% compared to conventional insulin therapy. Moreover, the effects of such intensive therapy regimes over a 6.5y duration persists for at least 10y after, a so called metabolic memory. Thus, early intervention can slow the momentum of complications far more easily than later intervention. Early, safe, intensive therapy protocols offer potential solutions to the growing social and economic effects of diabetes. Since the 1970s, the artificial endocrine pancreas has been heralded as just this type of solution. However, no commercial product currently exists, and ongoing limitations in sensors and pumps have resulted in, at best, modest clinical advantages over conventional methods of insulin administration or multiple daily injection. With high upfront costs, high costs of consumables, significant complexity, and the extensive infrastructure and support required, these systems and devices are only used by 2-15% of individuals with Type 1 diabetes. Clearly, there is an urgent need to address the large majority of the Type 1 diabetes population using conventional glucose measurement and insulin administration. For these individuals, current conventional or intensive therapies are failing to deliver recommended levels of glycaemic control. This research develops an understanding of clinical glycaemic control using conventional insulin administration and glucose measurement techniques in Type 1 diabetes based on a clinically validated in silico virtual patient simulation. Based on this understanding, a control protocol for Type 1 diabetes that is relatively simple and clinically practical is developed. The protocol design incorporates physiological modelling and engineering techniques to adapt to individual patient clinical requirements. By doing so, it produces accurate, patient-specific recommendations for insulin interventions. Initially, a simple, physiological compartmental model for the pharmacokinetics of subcutaneously injected insulin is developed. While the absorption process itself is subject to significant potential variability, such models enable a real-time estimation of plasma insulin concentration. This information would otherwise be lacking in the clinical environment of outpatient Type 1 diabetes treatment due to the inconvenience, cost, and laboratory turnaround for plasma insulin measurements. Hence, this validated model offers significant opportunity to optimise therapy selection. An in silico virtual patient simulation tool is also developed. A virtual patient cohort is developed on patient data from a representative cohort of the broad diabetes population. The simulation tool is used to develop a robust, adaptive protocol for prandial insulin dosing against a conventional intensive insulin therapy, as well as a controls group representative of the general diabetes population. The effect on glycaemic control of suboptimal and optimal, prandial and basal insulin therapies is also investigated, with results matching clinical expectations. To gauge the robustness of the developed adaptive protocol, a Monte Carlo analysis is performed, incorporating realistic and physiological errors and variability. Due to the relatively infrequent glucose measurement in outpatient Type 1 diabetes, a method for identifying the diurnal cycle in effective insulin sensitivity and modelling it in retrospective patient data is also presented. The method consists of identifying deterministic and stochastic components in the patient effective insulin sensitivity profile. Circadian rhythmicity and sleep-wake phases have profound effects on effective insulin sensitivity. Identification and prediction of this rhythm is of utmost clinical relevance, with the potential for safer and more effective glycaemic control, with less frequent measurement. It is thus a means of further enhancing any robust protocol and making it more clinically practical to implement. Finally, this research presents an entire framework for the realistic, and rapid development and testing of clinical glycaemic control protocols for outpatient Type 1 diabetes. The models and methods developed within this framework allow rapid and physiological identification of time-variant, patient-specific, effective insulin sensitivity profiles. These profiles form the responses of the virtual patient and can be used to develop and robustly test clinical glycaemic control protocols in a broad range of patients. These effective insulin sensitivity profiles are also rich in dynamics, specifically those circadian in nature which can be identified, and used to provide more accurate glycaemic prediction with the potential for safer and more effective control.
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Qiao, Boling. "Lead compounds for prion therapeutics from Chinese herbs." Thesis, University of Sheffield, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445123.
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Tomlinson, Ryan. "Degradable polyacetals for the development of polymer therapeutics." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408018.
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Rowley, Laura Elizabeth. "Determining the cellular localisation of novel cancer therapeutics." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6179/.
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Three areas of investigation regarding a novel class of anti-cancer therapeutics, triple-helicate dinuclear compounds known as ‘cylinders’, have been addressed. An improved protocol for the synthesis of a ruthenium cylinder has been developed, utilising microwave synthesis rather than reflux techniques. The use of Sephadex C-25 as a solid phase for column chromatography led to shorter purification protocols. Experiments to determine the cellular localisation of fluorescent ruthenium cylinder using confocal microscopy showed fluorescence within MDA-MB-231 cells, but not within SKOV-3 cells, suggesting preferential uptake between cell lines. Co-localisation experiments suggested localisation of the cylinder within cell nuclei. Synchrotron radiation has been used to image iron cylinder within SKOV-3 cells. High levels of iron are found near the cell membrane, corresponding to areas of high calcium concentration. XANES spectra show that the iron is in an environment closer to that of ferric iron as opposed to the ferrous iron found within the cylinder. The cellular effects of cylinder treatment have been imaged, showing that cell motility is compromised by cylinder treatment. Iron cylinder causes production of NO within MDA-MB-231 cells. Control images showed low levels of fluorescence within MDA-MB-231 cells, suggesting the presence of endogenous NO, which had been debated within literature.
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Ren, Yin Ph D. Massachusetts Institute of Technology. "Tumor-penetrating delivery of small interfering RNA therapeutics." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/72914.
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Thesis (Ph. D. in Medical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2012.<br>Vita. Cataloged from PDF version of thesis.<br>Includes bibliographical references (p. 234-250).<br>Efforts to sequence cancer genomes have begun to uncover comprehensive lists of genes altered in cancer. Unfortunately, the number and complexity of identified alterations has made dissecting the underlying biology of cancer difficult, as many genes are not amenable to manipulation by small molecules or antibodies. RNA interference (RNAi) provides a direct way to assess and act on putative cancer targets. However, the translation of RNAi into the clinic has been thwarted by the "delivery" challenge, as small interfering RNA (siRNA) therapeutics must overcome clearance mechanisms and penetrate into tumor tissues to access cancer cells. This thesis sought to develop nanotechnology-based platforms to rapidly discover and validate cancer targets in vivo. First, we developed versatile surface chemistries for nanoparticle tumor targeting. Leveraging new discoveries in amplified transvascular transport, we designed a siRNA delivery system that integrates the tumor specificity and tissue-penetrating ability of tumor-penetrating peptides with membrane penetration properties of protein transduction domains to direct siRNA to tumors in vivo. Second, we utilized this delivery system to bridge the gap between cancer genomic discovery and in vivo target validation. Comprehensive analysis of ovarian cancer genomes identified candidate targets that are undruggable by traditional approaches. Tumor-penetrating delivery of siRNA against these genes potently impeded the growth of ovarian tumors in mice and improved survival, thereby credentialing their roles in tumor initiation and maintenance. Lastly, we described efforts extending this platform for clinical translation. Mechanistic studies identified functional properties that favored receptor-specific siRNA delivery. We also explored a strategy to improve the microdistribution of successively dosed siRNA therapeutics through modulating the tumor microenvironment. Finally, we investigated the utility of the system in primary human tumors derived from patients with ovarian cancer. Together, these findings illustrate that the combination of cancer genomics with the engineering of siRNA delivery nanomaterials establishes a platform for discovering genes amenable to RNAi therapies. As efforts in genome sequencing accelerate, this platform illustrates a path to clinical translation in humans.<br>by Yin Ren.<br>Ph.D.in Medical Engineering
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Rifai, Bassel. "Cavitation-enhanced delivery of therapeutics to solid tumors." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:374b2ee1-0711-4994-8434-bf90358d9e47.
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Poor drug penetration through tumor tissue has emerged as a fundamental obstacle to cancer therapy. The solid tumor microenvironment presents several physiological abnormalities which reduce the uptake of intravenously administered therapeutics, including leaky, irregularly spaced blood vessels, and a pressure gradient which resists transport of therapeutics from the bloodstream into the tumor. Because of these factors, a systemically administered anti-cancer agent is unlikely to reach 100% of cancer cells at therapeutic dosages, which is the efficacy required for curative treatment. The goal of this project is to use high-intensity focused ultrasound (HIFU) to enhance drug delivery via phenomena associated with acoustic cavitation. ‘Cavitation’ is the formation, oscillation, and collapse of bubbles in a sound field, and can be broadly divided into two types: ‘inertial’ and ‘stable’. Inertial cavitation involves violent bubble collapse and is associated with phenomena such as heating, fluid jetting, and broadband noise emission. Stable cavitation occurs at lower pressure amplitudes, and can generate liquid microstreaming in the bubble vicinity. It is the combination of fluid jetting and microstreaming which it is attempted to explore, control, and apply to the drug delivery problem in solid tumors. First, the potential for cavitation to enhance the convective transport of a model therapeutic into obstructed vasculature in a cell-free in vitro tumor model is evaluated. Transport is quantified using post-treatment image analysis of the distribution of a dye-labeled macromolecule, while cavitation activity is quantified by analyzing passively recorded acoustic emissions. The introduction of exogenous cavitation nuclei into the acoustic field is found to dramatically enhance both cavitation activity and convective transport. The strong correlation between inertial cavitation activity and drug delivery in this study suggested both a mechanism of action and the clinical potential for non-invasive treatment monitoring. Next, a flexible and efficient method to simulate numerically the microstreaming fields instigated by cavitating microbubbles is developed. The technique is applied to the problem of quantifying convective transport of a scalar quantity in the vicinity of acoustically cavitating microbubbles of various initial radii subject to a range of sonication parameters, yielding insight regarding treatment parameter choice. Finally, in vitro and in vivo models are used to explore the effect of HIFU on delivery and expression of a biologically active adenovirus. The role of cavitation in improving the distribution of adenovirus in porous media is established, as well as the critical role of certain sonication parameters in sustaining cavitation activity in vivo. It is shown that following intratumoral or intravenous co-injection of ultrasound contrast agents and adenovirus, both the distribution and expression of viral transgenes are enhanced in the presence of inertial cavitation. This ultrasound-based drug delivery system has the potential to be applied in conjunction with a broad range of macromolecular therapeutics to augment their bioavailability for cancer treatment. In order to reach this objective, further developmental work is recommended, directed towards improving therapeutic transducer design, using transducer arrays for treatment monitoring and mapping, and continuing the development of functionalized monodisperse cavitation nuclei.