Development of miRNA-mimic nanoparticles for the treatment of brain tumours
Glioblastoma are aggressive brain tumours with a median survival of 15 months even with the best currently available treatment options. microRNAs (miRNA) are ~23 nucleotide natural silencing RNAs that have great potentials to improve cancer treatment outcomes. Lack of a safe, stable and efficient de...
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| Format: | Thesis (University of Nottingham only) |
| Language: | English English |
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2017
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| Online Access: | https://eprints.nottingham.ac.uk/39449/ |
| _version_ | 1848795838795481088 |
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| author | Anithiya Ramamoorthi Gopalram, Shubaash |
| author_facet | Anithiya Ramamoorthi Gopalram, Shubaash |
| author_sort | Anithiya Ramamoorthi Gopalram, Shubaash |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Glioblastoma are aggressive brain tumours with a median survival of 15 months even with the best currently available treatment options. microRNAs (miRNA) are ~23 nucleotide natural silencing RNAs that have great potentials to improve cancer treatment outcomes. Lack of a safe, stable and efficient delivery system has, however, hindered the use of miRNAs in clinical applications. The aim is therefore to develop a miRNA delivery system adapted to glioblastoma using linear chain cationic polyamidoamine (PAA) polymers. The first part involved the development of luciferase assay that combined the measurement of gene-knockdown efficiency and cytotoxicity of miRNA nanoparticles. The simple two-step procedure was more effective and sensitive compared to the conventional protein-based normalization method. The second part was focused on the development of miRNA nanoparticles. In the initial phase, conditions required for maximum miRNA-polymer binding was achieved, however, the newly developed miRNA-PAA-nanoparticles did not produce significant functional gene-knockdown after cell treatment. The second stage was focused on the optimization of nanoparticle formulation as a function of stability in physiological ionic concentration. Stable PAA-nanoparticles displaying moderate cellular uptake and gene-knockdown were obtained. The final stage of development was focused on PAA-nanoparticle tagging with biotin, which improved their cellular uptake. This work developed simple and informative luciferase assay; the stability of miRNA-PAA-nanoparticles was improved by thiol-crosslinking and the cellular uptake was enhanced by a simple but smart method of ligand tagging. Further optimizations are needed to increase the functional performance of these potential and clinically relevant thiol-stabilized RNAi vectors. |
| first_indexed | 2025-11-14T19:38:27Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-39449 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English English |
| last_indexed | 2025-11-14T19:38:27Z |
| publishDate | 2017 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-394492025-02-28T13:38:03Z https://eprints.nottingham.ac.uk/39449/ Development of miRNA-mimic nanoparticles for the treatment of brain tumours Anithiya Ramamoorthi Gopalram, Shubaash Glioblastoma are aggressive brain tumours with a median survival of 15 months even with the best currently available treatment options. microRNAs (miRNA) are ~23 nucleotide natural silencing RNAs that have great potentials to improve cancer treatment outcomes. Lack of a safe, stable and efficient delivery system has, however, hindered the use of miRNAs in clinical applications. The aim is therefore to develop a miRNA delivery system adapted to glioblastoma using linear chain cationic polyamidoamine (PAA) polymers. The first part involved the development of luciferase assay that combined the measurement of gene-knockdown efficiency and cytotoxicity of miRNA nanoparticles. The simple two-step procedure was more effective and sensitive compared to the conventional protein-based normalization method. The second part was focused on the development of miRNA nanoparticles. In the initial phase, conditions required for maximum miRNA-polymer binding was achieved, however, the newly developed miRNA-PAA-nanoparticles did not produce significant functional gene-knockdown after cell treatment. The second stage was focused on the optimization of nanoparticle formulation as a function of stability in physiological ionic concentration. Stable PAA-nanoparticles displaying moderate cellular uptake and gene-knockdown were obtained. The final stage of development was focused on PAA-nanoparticle tagging with biotin, which improved their cellular uptake. This work developed simple and informative luciferase assay; the stability of miRNA-PAA-nanoparticles was improved by thiol-crosslinking and the cellular uptake was enhanced by a simple but smart method of ligand tagging. Further optimizations are needed to increase the functional performance of these potential and clinically relevant thiol-stabilized RNAi vectors. 2017-07-17 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en cc_by_nc_nd https://eprints.nottingham.ac.uk/39449/1/Final%20Thesis%20UoN%20SA.pdf application/pdf en arr https://eprints.nottingham.ac.uk/39449/2/00-Comments%20and%20Actions%20Taken.pdf Anithiya Ramamoorthi Gopalram, Shubaash (2017) Development of miRNA-mimic nanoparticles for the treatment of brain tumours. PhD thesis, University of Nottingham, UK and University of Angers, FR. miRNA Delivery Glioblastoma Poly(amidoamine) thiol crosslinking ligand targeting nanomedicine luciferase assay RNA interference. |
| spellingShingle | miRNA Delivery Glioblastoma Poly(amidoamine) thiol crosslinking ligand targeting nanomedicine luciferase assay RNA interference. Anithiya Ramamoorthi Gopalram, Shubaash Development of miRNA-mimic nanoparticles for the treatment of brain tumours |
| title | Development of miRNA-mimic nanoparticles for the treatment of brain tumours |
| title_full | Development of miRNA-mimic nanoparticles for the treatment of brain tumours |
| title_fullStr | Development of miRNA-mimic nanoparticles for the treatment of brain tumours |
| title_full_unstemmed | Development of miRNA-mimic nanoparticles for the treatment of brain tumours |
| title_short | Development of miRNA-mimic nanoparticles for the treatment of brain tumours |
| title_sort | development of mirna-mimic nanoparticles for the treatment of brain tumours |
| topic | miRNA Delivery Glioblastoma Poly(amidoamine) thiol crosslinking ligand targeting nanomedicine luciferase assay RNA interference. |
| url | https://eprints.nottingham.ac.uk/39449/ |