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Polymeric delivery of miRNA therapeutics
Thesis (PhD)--Stellenbosch University, 2018.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2018
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| _version_ | 1867613878180904960 |
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| access_status_str | Open Access |
| author | Kargaard, Annette |
| author2 | Klumperman, Bert |
| author_browse | Kargaard, Annette Klumperman, Bert |
| author_facet | Klumperman, Bert Kargaard, Annette |
| author_sort | Kargaard, Annette |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2018. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/103842 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:43:08.148Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2018 |
| publishDateRange | 2018 |
| publishDateSort | 2018 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/103842 Polymeric delivery of miRNA therapeutics Kargaard, Annette Klumperman, Bert Sluijter, Joost Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Polymers in medicine Biomedical polymers Polymeric drug delivery systems Gene therapy Thesis (PhD)--Stellenbosch University, 2018. ENGLISH ABSTRACT: RNA interference therapeutics are regarded as having a crucial role in gene regulation and play an integral role in diseases, e.g. cancer, neurological diseases and heart disease. However, the lack of success in using non-coding RNAs as therapeutics lies in the absence of efficient, safe and reliable tools for targeted delivery. Although polymeric vectors have yielded some success in gene delivery, there are still major downfalls related to toxicity, endosomal escape and cytoplasmic delivery. Herein, two classes of novel delivery vehicles have been synthesized and their gene regulation efficiency tested, in an effort to address the difficulties in endosomal escape and cytoplasmic release. The first type of system is a diblock-copolymer conjugated via a pH- labile linker to enhance endosomal escape. The first block is poly(N-vinylpyrrolidone) (PVP) which was synthesized via RAFT–mediated polymerization. The second block is composed of either hydrolysable poly(2-(N,N-dimethylamino)ethyl acrylate-co-butylmethacrylate) (p(DMAEA-co-BMA)) or non-hydrolysable poly(2-(N,N-dimethylamino)ethyl methacrylate- co-butylmethacrylate) (p(DMAEMA-co-BMA)), which are both capable of RNA complexation. The hydrolysable properties of the p(DMAEA-co-BMA) causes decationization, releasing the RNA within the cytoplasm. Neither of the diblock-copolymer conjugates caused significant cytotoxicity. Although gene regulation for both systems was greater than or equivalent to poly(ethylamine), the gold standard in gene regulation, they do not effectively escape the endosome. Interestingly, p(DMAEMA-co-BMA)-b-PVP is more efficient at regulating gene expression than p(DMAEA-co-BMA)-b-PVP. Ring opened and closed DMAPA-modified poly(styrene-co-maleic anhydride) derivatives were synthesized as the second class of zwitterionic polymer vectors. Although the ring- closed derivative was more efficient in condensing the RNAs, the ring-open analogue is more effective at delivering gene regulation. Both systems cause no cytotoxicity, erythrocyte aggregation or hemolysis. The ring-opened analogue, in particular, provides a platform from which potentially effective and safe gene delivery vectors can be designed AFRIKAANSE OPSOMMING: RNA-obtrusieterapeutiesemiddels speel 'n belangrike rol in geenregulering asook in behandeling van siektes soos bv. kanker, neurologiesesiektes en hartsiektes. Die gebrek aan sukses in die gebruik van nie-koderende-RNAs as terapeutiese middels lê egter in die afwesigheid van doeltreffende, veilige en betroubare sisteme vir geteikende-aflewering. Alhoewel polimeriesevektore 'n mate van sukses behaal het in geenaflewering, is daar steeds groot tekortkominge wat verband hou met toksisiteit, endosomale ontsnappings en sitoplasmiese aflewering. Hierin is twee klasse nuwe afleweringsvoertuie gesintetiseer en hulle geenregulasie doeltreffend getoets in 'n poging om die probleme in endosomale ontsnapping en sitoplasmiese vrystelling aan te spreek. Die eerste tipe stelsel is die van 'n diblok-kopolimeer wat via 'n pH-sensitiewekoppelaar verbind is om endosomale ontsnapping te verbeter. Die eerste blok bestaan uit poli(N-vinielpyrolidoon) (PVP) wat deur RAFT-gemedieerde polimerisasie gesintetiseer is. Die tweede blok is saamgestel uit óf hidroliseerbare poli(2-(N, N-dimetielamien)etielakrilaat-ko-butielmetakrilaat) (p(DMAEA-ko-BMA)) óf nie-hidroliseerbare poli(2-(N,N-dimetielamien)etielmetakrilaat-ko-butielmetakrilaat p(DMAEMA-ko-BMA)), wat beide in staat is tot RNA-kompleksasie. Die hidroliseerbare eienskappe van die p(DMAEA-ko-BMA) veroorsaak dekationisasie wat die RNA binne die sitoplasma vrystel. Nie een van die diblok-kopolimeergekonjugeerde sisteme het beduidende sitotoksisiteit veroorsaak nie. Alhoewel geenregulering vir beide stelsels groter is as of ekwivalent is aan poli(etielamien) (die goudstandaard in geenregulering) ontsnap hulle nie die endosoom effektief genoeg nie. Interessant genoeg is dat p(DMAEMA-ko-BMA)-b-PVP meer doeltreffend is om geenuitdrukking te reguleer as p(DMAEA-ko-BMA)-b-PVP. Ring-oop en ringgeslote DMAPA-gemodifiseerde poli(stireen-ko-maleïenanhidried) afgeleides is gesintetiseer as die tweede klas van zwitterioniese polimeervektore. Alhoewel die ringgeslote afgeleide meer doeltreffend was om die RNAs te kondenseer, is die ring-oop vorm meer doeltreffend in geenregulering. Beide sisteme veroorsaak geen sitotoksisiteit, eritrosiete-aggregasie of hemolise nie. Die besondere analoog bied 'n platform waarvan potensiële, effektiewe en veilige geenafleweringsvektore ontwerp kan word. Doctoral 2018-01-31T17:40:59Z 2018-04-09T10:52:35Z 2021-03-23T03:00:09Z 2018-03 Thesis http://hdl.handle.net/10019.1/103842 en_ZA Stellenbosch University 202 pages application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Polymers in medicine Biomedical polymers Polymeric drug delivery systems Gene therapy Kargaard, Annette Polymeric delivery of miRNA therapeutics |
| title | Polymeric delivery of miRNA therapeutics |
| title_full | Polymeric delivery of miRNA therapeutics |
| title_fullStr | Polymeric delivery of miRNA therapeutics |
| title_full_unstemmed | Polymeric delivery of miRNA therapeutics |
| title_short | Polymeric delivery of miRNA therapeutics |
| title_sort | polymeric delivery of mirna therapeutics |
| topic | Polymers in medicine Biomedical polymers Polymeric drug delivery systems Gene therapy |
| url | http://hdl.handle.net/10019.1/103842 |
| work_keys_str_mv | AT kargaardannette polymericdeliveryofmirnatherapeutics |