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Amine end-functional poly(N-vinylpyrrolidone) as amMacroinitiator for L-lysine N-carboxyanhydride polymerization - towards the preparation of pH-responsive micelles for drug delivery
Thesis (PhD)--Stellenbosch University, 2015.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2015
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| _version_ | 1867614102607626240 |
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| access_status_str | Open Access |
| author | Ilchev, Alexander |
| author2 | Klumperman, Bert |
| author_browse | Ilchev, Alexander Klumperman, Bert |
| author_facet | Klumperman, Bert Ilchev, Alexander |
| author_sort | Ilchev, Alexander |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2015. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/96634 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:46:42.610Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2015 |
| publishDateRange | 2015 |
| publishDateSort | 2015 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/96634 Amine end-functional poly(N-vinylpyrrolidone) as amMacroinitiator for L-lysine N-carboxyanhydride polymerization - towards the preparation of pH-responsive micelles for drug delivery Ilchev, Alexander Klumperman, Bert Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Cancer Tumour Phthalimidomethyl RAFT Doxorubicin Polymerization UCTD Thesis (PhD)--Stellenbosch University, 2015. ENGLISH ABSTRACT: Cancer is a notorious affliction that knows no age, gender, ethnic, racial, or species bounds and is responsible for over 14% of annual worldwide human deaths. There is no universal cure and the treatments that exist have poor probabilities of success. Chemotherapy is often considered the staple for cancer treatment as it can enter areas of the body that are unsafe for surgery and can treat tumors that are too small to be detected, even with modern imaging techniques. However, chemotherapy can induce many harmful and fatal side-effects. It can also lose its therapeutic effect if the cancer mutates to become multi-drug resistant. These shortcomings can be linked to the poor selectivity and pharmacokinetics of conventional chemotherapy drugs. Modern research focusses on improving these aspects of existing chemotherapy regimens through the incorporation of drug delivery principles. This dissertation focusses on the development of a novel, polymeric, pHresponsive drug delivery system for chemotherapy that incorporates the chemotherapeutic drug as well as a cell-penetrating peptide in a prodrug formulation. The system was designed to inhibit the release of its components into healthy tissues while selectively accumulating, through the enhanced permeability and retention effect, and releasing its payload, through reversible hydrolysis of imine bonds, within tumor tissues. Poly(L-lysine) was chosen as the cell-penetrating peptide since it is able to form imine bonds through its ε-amine functional groups on its residues. It was prepared by the primary amine-initiated ring-opening polymerization of Nε-(benzyloxycarbonyl)-L-lysine Ncarboxyanhydride at 0 °C and pressures lower than 1 mbar as these conditions allow for a controlled, living polymerization to occur. The benzyloxycarbonyl end-group was removed by acidolysis with HBr in a mixture of dichloromethane and 1,4-dioxane at 0 °C. The initiator used for the ring-opening polymerization was poly(N-vinylpyrrolidone) with a primary amine end-group, prepared by RAFT-mediated polymerization with O-ethyl-S-(phthalimidylmethyl)xanthate. This RAFT agent was shown to display slow pre-equilibrium kinetics which was linked to the lower relative stability of the phthalimidylmethyl radical compared to the poly(N-vinylpyrrolidone) propagating radical. The pre-equilibrium and main equilibrium kinetics of the RAFT polymerization were optimized by performing the polymerization in semi-batch mode. During the semi-batch polymerization, the monomer to RAFT agent ratio could be controlled by adjusting the monomer feed. This ratio was shown to be inversely proportional to the probability of radical transfer from the propagating radical to the phthalimidylmethyl radical. The phthalimide end-group could be converted to a primary amine both by reacting with hydrazine in methanol as well as reduction with sodium borohydride in water followed by hydrolysis in 1 M HCl at 60 °C. Doxorubicin and benzaldehyde could be conjugated, via imine bonds, to the poly(N-vinylpyrrolidone-block-L-lysine) copolymer spontaneously in methanol. Both types of conjugates would self-assemble into micelles when dispersed in water. However, the Doxorubicin conjugates were unstable, precipitating out of solution within 24 hours. The benzaldehyde conjugates were stable in water for over 24 hours. This suggested that a formulation of Doxorubicin and benzaldehyde conjugated to the block copolymer may be sufficiently stable under the physiological conditions of blood plasma. AFRIKAANSE OPSOMMING: Kanker is 'n berugte toestand wat geen ouderdom, geslag, etniese, ras- of spesiegrense ken nie en is verantwoordelik vir meer as 14% van die jaarlikse wêreldwye menslike sterftes. Daar is geen universele kuur vir hierdie siekte nie en die behandelings wat bestaan het swak waarskynlikhede van sukses. Chemoterapie is handig want dit behandel tumore waar operasies nie as veilig beskou word nie of as dit te klein is om te spoor, selfs met moderne beeldingstegnieke. Chemoterapie kan egter skadelike en dodelike newe-effekte tot gevolg hê. Dit kan ook die terapeutiese effek verloor as die kanker muteer en multi-middelweerstandig word. Hierdie tekortkominge kan gekoppel word aan die swak selektiwiteit en farmakokinetika van konvensionele chemoterapiemiddels. Moderne navorsing probeer om hierdie probleme op te los deur die inlywing van geneesmiddel-leweringsbeginsels. Hierdie proefskrif fokus op die ontwikkeling van 'n nuwe, polimeriese, pH-reaktiewe geneesmiddelleweringstelsel vir chemoterapie wat die chemoterapeutiese middel sowel as 'n sel-indringende peptied in 'n progeneesmiddel formulering inkorporeer. Die stelsel is ontwerp om die ophoping of vrystelling van die medikasie en die peptied in gesonde weefsel te inhibeer. Terselftertyd word die medikasie deur middel van gevorderde deurlatings en terughoudings in die tumor vrygestel deur omgekeerde hidrolise van die imienbindings. Poli (L-lisien) is gekies as die sel-indringerpeptied omdat dit imienbindings kan vorm deur middel van die ε-amien funksionele groep en ook omdat dit bioafbreekbaar is. Die reaksie is daargestel deur die primêre amien-geïnisieerde ring-openingpolimerisasie van Nε-(bensieloksikarboniel)-L-lisien N-karboksianhidried. Die temperatuur is by 0 °C en die druk onder 1 mBar gehou aangesien hierdie omstandighede gekontroleerde lewende polimerisasie toelaat. Die bensieloksikarboniel eindgroep is verwyder deur middel van HBr in 'n mengsel van dichlorometaan en 1,4-dioksaan by 0 °C. Die inisieerder wat gebruik word vir die ringopeningpolimerisasie is poli(N-vinielpirrolidoon) met 'n primêre amien eindgroep. Dit is berei deur RAFT-bemiddelde polimerisasie van N-vinielpirrolidoon met O-etiel-S-(ftalimidielmetiel)xantaat. Hierdie RAFT-agent het stadige voorewewig kinetika getoon as gevolg van die laer relatiewe stabiliteit van die ftalimidielmetielradikaal in vergelyking met die poli(N-vinielpirrolidoon) voortsettingsradikaal. Die voorewewig en hoofewewig kinetika van die RAFT-polimerisasie is geoptimaliseer deur die polimerisasie in ‘n semi-bondel manier uit te voer. Doctoral 2015-05-20T09:13:09Z 2015-05-20T09:13:09Z 2015-03 Thesis http://hdl.handle.net/10019.1/96634 en_ZA Stellenbosch University 213 pages application/pdf application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Cancer Tumour Phthalimidomethyl RAFT Doxorubicin Polymerization UCTD Ilchev, Alexander Amine end-functional poly(N-vinylpyrrolidone) as amMacroinitiator for L-lysine N-carboxyanhydride polymerization - towards the preparation of pH-responsive micelles for drug delivery |
| title | Amine end-functional poly(N-vinylpyrrolidone) as amMacroinitiator for L-lysine N-carboxyanhydride polymerization - towards the preparation of pH-responsive micelles for drug delivery |
| title_full | Amine end-functional poly(N-vinylpyrrolidone) as amMacroinitiator for L-lysine N-carboxyanhydride polymerization - towards the preparation of pH-responsive micelles for drug delivery |
| title_fullStr | Amine end-functional poly(N-vinylpyrrolidone) as amMacroinitiator for L-lysine N-carboxyanhydride polymerization - towards the preparation of pH-responsive micelles for drug delivery |
| title_full_unstemmed | Amine end-functional poly(N-vinylpyrrolidone) as amMacroinitiator for L-lysine N-carboxyanhydride polymerization - towards the preparation of pH-responsive micelles for drug delivery |
| title_short | Amine end-functional poly(N-vinylpyrrolidone) as amMacroinitiator for L-lysine N-carboxyanhydride polymerization - towards the preparation of pH-responsive micelles for drug delivery |
| title_sort | amine end functional poly n vinylpyrrolidone as ammacroinitiator for l lysine n carboxyanhydride polymerization towards the preparation of ph responsive micelles for drug delivery |
| topic | Cancer Tumour Phthalimidomethyl RAFT Doxorubicin Polymerization UCTD |
| url | http://hdl.handle.net/10019.1/96634 |
| work_keys_str_mv | AT ilchevalexander amineendfunctionalpolynvinylpyrrolidoneasammacroinitiatorforllysinencarboxyanhydridepolymerizationtowardsthepreparationofphresponsivemicellesfordrugdelivery |