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Designing PoEGylated tyrocidine for improved antiplasmodial chemotherapy
Thesis (PhD) -- Stellenbosch University, 2019
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2019
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| _version_ | 1867614083310682112 |
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| access_status_str | Open Access |
| author | Begum, Nusrat Mutta |
| author2 | Klumperman, Bert |
| author_browse | Begum, Nusrat Mutta Klumperman, Bert |
| author_facet | Klumperman, Bert Begum, Nusrat Mutta |
| author_sort | Begum, Nusrat Mutta |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD) -- Stellenbosch University, 2019 |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/106935 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:46:23.902Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2019 |
| publishDateRange | 2019 |
| publishDateSort | 2019 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/106935 Designing PoEGylated tyrocidine for improved antiplasmodial chemotherapy Begum, Nusrat Mutta Klumperman, Bert Gule, Nonjabulo Prudence Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Malaria – Chemotherapy Antimalarials Drug resistance Peptides Polymers -- Synthesis Thesis (PhD) -- Stellenbosch University, 2019 ENGLISH ABSTRACT: Advancement of antiplasmodial drugs is of great interest due to the thousands of deaths in malaria-endemic countries annually, particularly in African children under the age of five. The drug-resistant strains of Plasmodium falciparum are overshadowing the enormous success of antiplasmodial chemotherapy. The use of peptides such as tyrocidine (Trc) to combat malaria infection has attracted interest in chemotherapy since peptides have proven to slow down the occurrence of resistance. Trc is a hydrophobic cyclodecapeptide which was established around the 1940s to destroy the blood stage of the malaria parasite. Due to Trc’s haemolytic activity, its application particularly for intracellular delivery was limited. To circumvent the haemolytic activity, Trc can be PEGylated for drug delivery purposes. Comb-like poly[oligo(ethylene glycol) methoxy methacrylate] (PoEGMA) is an attractive hydrophilic biocompatible polymer, that is resistant to protein interaction compared to non-linear PEG. The main objective of this study was to conjugate PoEGMA with Trc in order to improve pharmacological properties of Trc upon its delivery. This dissertation utilizes reversible addition-fragmentation chain transfer (RAFT) mediated polymerization as a robust synthetic tool for the preparation of well-defined functional PoEGMA polymers for designing the desired PoEGylated Trc as a strategy to improve malaria chemotherapy. In order to attain good control over polymerization and to retain the targeted functionality, a library of RAFT agents were synthesized and evaluated for the polymerization of oEGMA. A stable functional RAFT agent was subsequently employed for the preparation of well-defined heterotelechelic PoEGMAs with Mn values ranging between 3 000 Da and 13 000 Da. A malaria targeting ligand and a fluorescence marker were conjugated on the α-chain end of the resultant polymer via reductive amination. Subsequently, Trc was modified to a Michael acceptor prior to being conjugated on the ω-chain end of the polymer via the thiol-Michael addition reaction. This strategy afforded a pH-labile linker between the polymer and the Trc, for the release of Trc at malaria infected blood cells. The amphiphilic conjugates readily self-assemble into micellar nanovehicles in aqueous media, where the Trc selectively occupy the inner core that is stabilized by the corona PEG brushes. The spherical-like architectures were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). The PoEGylated micellar Trc conjugates were subsequently monitored in acidic aqueous media for drug release. A slow pulsatile-like drug release profile during kinetics study was observed with increasing molar masses of the micellar PoEGylated Trc conjugates increases. Trc haemolytic activity in all the conjugates is low, particularly declines with increase in molar mass. As the molar mass increases, compactness of the corona from the PEG brushes increases, which in turn increases the stealth property. The micellar PoEGylated Trc conjugates, possesses the ability for application in drug delivery systems as it overcame the inherent Trc haemolysis. These PoEGylated Trc offer a promising design of improving delivery pharmacological profiles of Trc as a solution towards antiplasmodial chemotherapy. AFRIKAANS OPSOMMING: Die bevordering van antiplasmodiale middels is van groot belang as gevolg van die duisende sterftes in malaria-endemiese lande jaarliks, veral in Afrika-kinders onder die ouderdom van vyf jaar oud. Die dwelm bestande stamme van Plasmodium falciparum oorskadu die enorme sukses van antiplasmodiale chemoterapie. Die gebruik van peptiede soos tyrocidine (Trc) om malaria infeksie te bekamp, het belangstelling in chemoterapie aangetrek, aangesien peptiede bewys het dat die voorkoms van weerstand vertraag kan word. Trc is 'n hidrofobiese siklodekapeptied wat ongeveer in die 1940's gestig is om die bloedstadium van die malariaparasiet te vernietig. As gevolg van Trc se hemolitiese aktiwiteit, was die toepassing veral vir intraselulêre aflewering beperk. Om die hemolitiese aktiwiteit te omseil, kan Trc gePEGuleer word vir dwelmafleweringsdoeleindes. Kam-soorte poli[oligo(etieleengliekol) metoksiemetakrilaat] (PoEGMA) is 'n aantreklike hidrofiliese biokompatiebare polimeer, wat bestand is teen proteïeninteraksie in vergelyking met nie-lineêre PEG. Die hoofdoel van hierdie studie was om PoEGMA met Trc te verbind om die farmakologiese eienskappe van Trc te verbeter met die aflewering daarvan. Hierdie proefskrif gebruik omkeerbare addisie-fragmentasie kettingoordrag (RAFT) gemedieërde polimerisasie as 'n robuste sintetiese instrument vir die voorbereiding van goed gedefinieërde funksionele PoEGMA-polimere vir die ontwerp van die verlangde gePoEGeleerde Trc as 'n strategie om malaria chemoterapie te verbeter. Om ten einde goeie beheer oor polimerisasie te behaal en die geteikende funksionaliteit te behou, is 'n biblioteek van RAFT-agente gesintetiseer en geëvalueer vir die polimerisasie van oEGMA. ‘n Stabiele funksionele RAFT-agent is vervolgens aangewend vir die voorbereiding van goed gedefinieërde heterotelekeliese PoEGMAs met Mn waardes wat wissel tussen 3 000 Da en 13 000 Da. ‘n Malaria-teikende ligand en ‘n fluoresente merker is via reduktiewe aminering op die α-ketting einde van die resulterende polimeer gebuig. Vervolgens is Trc aangepas na 'n Michael-aanvaarder voordat hy via die tiol-Michael addisiereaksie op die ω-kettingkant van die polimeer gebuig is. Hierdie strategie bied 'n pH-labiele skakelaar tussen die polimeer en die Trc, wat sal toelaat vir die vrylating van Trc by malaria besmette bloedselle. Die amfifiliese konjugate kan maklik selfmonteer in miselêre nanovoertuie in waterige media, waar Trc selektief die binneste kern beset, wat deur die Corona PEG-borsels gestabiliseer word. Die sferiese argitektuur is gekenmerk deur transmissie-elektronmikroskopie (TEM), dinamiese ligverspreiding (DLS) en nanopartikelopsporinganalise (NTA). Die gePoEGeleerde miselêre Trc-konjugate is daarna in suurwaterige media vir geneesmiddelvrystelling gemonitor. 'n Stadige pulsatiele-soort dwelm vrystelling profiel tydens kinetika studie is waargeneem met toenemende molêre massas van die miselêre gePoEGeleerde Trc-konjugate verhoog. Doctoral 2019-11-15T15:16:02Z 2019-12-11T06:39:34Z 2022-05-17T03:00:14Z 2019-12 Thesis http://hdl.handle.net/10019.1/106935 en_ZA Stellenbosch University xxiii, 115 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Malaria – Chemotherapy Antimalarials Drug resistance Peptides Polymers -- Synthesis Begum, Nusrat Mutta Designing PoEGylated tyrocidine for improved antiplasmodial chemotherapy |
| title | Designing PoEGylated tyrocidine for improved antiplasmodial chemotherapy |
| title_full | Designing PoEGylated tyrocidine for improved antiplasmodial chemotherapy |
| title_fullStr | Designing PoEGylated tyrocidine for improved antiplasmodial chemotherapy |
| title_full_unstemmed | Designing PoEGylated tyrocidine for improved antiplasmodial chemotherapy |
| title_short | Designing PoEGylated tyrocidine for improved antiplasmodial chemotherapy |
| title_sort | designing poegylated tyrocidine for improved antiplasmodial chemotherapy |
| topic | Malaria – Chemotherapy Antimalarials Drug resistance Peptides Polymers -- Synthesis |
| url | http://hdl.handle.net/10019.1/106935 |
| work_keys_str_mv | AT begumnusratmutta designingpoegylatedtyrocidineforimprovedantiplasmodialchemotherapy |