Publication:
Development and characterisation of star-shaped nanoparticles to deliver therapeutic siRNA to medulloblastoma

dc.contributor.advisor McCarroll, Josh en_US
dc.contributor.advisor Kavallaris, Maria en_US
dc.contributor.author Forgham, Helen en_US
dc.date.accessioned 2022-03-23T12:40:50Z
dc.date.available 2022-03-23T12:40:50Z
dc.date.issued 2020 en_US
dc.description.abstract Brain cancer kills more children in Australia than any other disease. Medulloblastoma (MB) accounts for approximately 20% of all childhood brain tumours. Chemoresistance, relapse and treatment related toxicity are common for this disease. There is an urgent need to develop new effective and less toxic treatments. Gene therapies which use short-interfering RNA (siRNA) to silence the expression of a target gene have great potential for the treatment of a host of human diseases including cancer. However, a major hurdle for the clinical translation of siRNA drugs is the need for a delivery vehicle to allow siRNA to internalise into cells. Nanoparticles may offer a solution to this problem and can be used as delivery vehicles for siRNA. No studies have examined the potential of star nanoparticles for the treatment of MB. The aims of this study were to: 1) define the biological conditions for di-block copolymer nanoparticles (star nanoparticles) to deliver siRNA to MB cells in vitro to silence the expression of a gene (Polo-Like Kinase 1, PLK1) which is highly expressed in MB cells and plays a major role in promoting tumour growth; 2) determine whether star nanoparticles could deliver siRNA to solid tumours in mice; and 3) examine whether Star nanoparticle-siRNA (star-siRNA) could penetrate a blood-brain barrier (BBB). Results from this thesis demonstrate that star-siRNA form monodisperse nanoparticles with a size of 19 nm. Star-siRNA is internalised into MB cells in vitro and can silence PLK1 expression leading to mitotic arrest, DNA damage and apoptosis. Star-siRNA was non-toxic to mice and siRNA could be effectively delivered to subcutaneous MB tumours to silence PLK1 expression which induced apoptosis. Finally, using in vitro and in vivo models we showed that star-siRNA could penetrate the BBB. Importantly, star nanoparticles delivered siRNA to the brains of mice with growing orthotopic MB tumours. Collectively, results presented in this thesis demonstrate for the first time the potential of star nanoparticles to deliver siRNA to induce apoptosis in MB cells in vitro and in vivo. Star-siRNA nanodrugs may be a novel therapeutic strategy to inhibit MB growth and increase patient survival. en_US
dc.identifier.uri http://hdl.handle.net/1959.4/67079
dc.language English
dc.language.iso EN en_US
dc.publisher UNSW, Sydney en_US
dc.rights CC BY-NC-ND 3.0 en_US
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/3.0/au/ en_US
dc.subject.other siRNA en_US
dc.subject.other Medulloblastoma en_US
dc.subject.other Nanoparticles en_US
dc.title Development and characterisation of star-shaped nanoparticles to deliver therapeutic siRNA to medulloblastoma en_US
dc.type Thesis en_US
dcterms.accessRights open access
dcterms.rightsHolder Forgham, Helen
dspace.entity.type Publication en_US
unsw.accessRights.uri https://purl.org/coar/access_right/c_abf2
unsw.identifier.doi https://doi.org/10.26190/unsworks/21868
unsw.relation.faculty Medicine & Health
unsw.relation.originalPublicationAffiliation Forgham, Helen, Children's Cancer Institute Australia for Medical Research, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation McCarroll, Josh, Children's Cancer Institute Australia for Medical Research, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Kavallaris, Maria, Children's Cancer Institute Australia for Medical Research, Faculty of Medicine, UNSW en_US
unsw.relation.school Childhood Cancer Research *
unsw.thesis.degreetype PhD Doctorate en_US
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