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Title: Polymer coating for the systemic delivery of oncolytic adenoviruses
Author: Francini, Nora
ISNI:       0000 0004 6347 2937
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2016
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Oncolytic adenoviruses have demonstrated great potential in terms of activity and safety when administered directly to confined solid tumors. However, the lack of routes to systemically deliverthese viruses safely and efficiently, restricts their clinical application, due to host immune response, undesired interactions with blood components and a hepatic tropism, thus decreasing their bioavailability at the tumor sites and so their efficacy. Efficacy of systemically administered viruses has been improved by masking viral surface proteins with polymeric materials, through modulation of viral pharmacokinetic profile and accumulation in tumors in vivo. Although some promising results have been achieved within this area, a clear understanding of the polymer features required to obtain the desired "stealthing" without compromising the activity of the virus is still lacking. In this thesis we sought to elucidate structure-activity relationship of N-(2-hydroxypropyl) methacrylamide (PHPMA) co-polymers and their ability to efficiently circumvent neutralization of ColoAd1, a chimeric oncolytic virus, as a mean to improve systemic virotherapy. Firstly, suitable synthetic strategies were developed that gave access to libraries of novel PHPMA functional copolymers which share identical macromolecular features but differ for the relative amount of reactive functionalities. Polymer coating covalently bound to viral surface proteins enhanced protection against neutralizing Page | ii Abstract antibodies in vitro. In vitro and in vivo viral infectivity was found to be inversely proportional to the coating efficacy. We demonstrated that a loss in viral infectivity resulting from polymer coating is not due to hampered cell entry and may not be a permanent inactivation of the virus. Preliminary observations suggest that virus activity may be restored by tailoring the polymer design, without compromising the virus "stealthing" effect.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available