Polymer-coated magnetic nanoparticles and polymer nanoparticles for the treatment of Mycobacterium tuberculosis (Mtb)

Simple item page
dc.contributor.advisorLutz, Marietjieen_ZA
dc.contributor.authorSmit, Maricaen_ZA
dc.contributor.otherStellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.en_ZA
dc.date.accessioned2022-03-08T16:11:17Zen_ZA
dc.date.accessioned2022-04-29T09:37:35Zen_ZA
dc.date.available2022-03-08T16:11:17Zen_ZA
dc.date.available2022-04-29T09:37:35Zen_ZA
dc.date.issued2022-04en_ZA
dc.descriptionThesis (PhD)--Stellenbosch University, 2022.en_ZA
dc.description.abstractENGLISH ABSTRACT: Tuberculosis (TB) can be classified as a neglected disease where an estimated one fourth of the world’s population could be infected with Mycobacterium tuberculosis (Mtb) in the form of latent TB. Combinations of three or more anti-tuberculosis (anti-TB) drugs are required during a long treatment period (between 6 months and 2 years) to effectively eliminate Mtb. The long treatment duration with concentrated anti-TB drugs has lead to side-effects, low patient adherence and resulting possible drug resistance. Orally administered anti-TB drugs have difficulty effectively reaching the lung and alveolar macrophages. Concentrated anti-TB drugs are thus orally administered daily in tablet form but anti-TB drug loaded polymer nanoparticles could possibly prevent rapid drug degradation via sustained release. There is thus a need to decrease the necessary concentration of the administered anti-TB drugs, which could be achieved via pulmonary inhalation which directly treats TB in the lungs. Polymer coated superparamagnetic iron oxide nanoparticles (SPMNs) could possibly enable targeted drug delivery via injection. The nanoparticles can be controlled with an external magnetic field to Mtb infected areas, followed by drug release from the anti-TB drug loaded polymer coating. In this thesis, biocompatible polymers namely chitosan, carrageenan, alginate, dextran sulfate and poly(lactide-co-glycolide) (PLGA) were utilized for anti-TB drug loading. Quaternary ammonium chitosan (CS-qC12) and quaternary ammonium poly(styrene-alt- maleic anhydride) (SMI-qC12) were also synthesized due to the known improvement in antimicrobial activity and mucoadhesion, due to the quaternary ammonium functional groups, compared to pristine chitosan and poly(styrene-alt-maleic anhydride). Several commonly administered anti-TB drugs such as isoniazid (INH), rifampicin (RIF), ethambutol (EMB), streptomycin (STM), ethionamide (ETA) and ofloxacin (OFX) were utilized for anti-TB drug loading. Chitosan (CS) based anti-TB drug loaded nanoparticles were synthesized via ionic gelation where polymer and anti-TB drug is dissolved, followed by the addition of crosslinking agent or polymer to prepare the nanoparticles (distributing anti-TB drug throughout the polymer matrix). PLGA nanoparticles were prepared via an “oil-in-water” emulsion followed by solvent evaporation. Sustained drug release (aqueous acetic acid solution, pH 5, UV-Vis spectrophotometry) over 7 days was seen for all the drug loaded nanoparticles, except with ofloxacin loading. The SPMNs were produced via co-precipitating with Fe2+ and Fe3+ in one step (CS SPMNs and CS-qC12 SPMNs) or two steps (chitosan-alginate-carrageenan (CS-Al-Car) SPMNs and chitosan-dextran sulfate (CS-DS) SPMNs). PLGA SPMNs and SMI-qC12 SPMNs were synthesized by activating the pristine iron oxide nanoparticles with oleic acid and (3-aminopropyl)triethoxysilane (3-APTES), respectively, before polymer coating. The polymer coated SPMNs were ex situ drug loaded by dispersing the SPMNs in anti-TB drug solution. Sustained drug release over 8 days was observed for the INH, ETA and RIF loaded polymer coated SPMNs. The resazurin microtiter assay (REMA) against TB mimic Mycobacterium Smegmatis (M. Smeg) was utilized to quantify the antimicrobial activity, via minimum inhibition concentration (MIC) determinations. The CS-DS nanoparticles were determined to be the optimal drug carrier with lower MIC values (CS-DS-OFX = 0.2441 μg/mL) compared to the free drugs (OFX = 0.5859 μg/mL).en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Tuberkulose (TB) kan geklassifiseer word as 'n verwaarloosde siekte waar 'n geskatte kwart van die wêreld se bevolking met Mycobacterium tuberculosis (Mtb) besmet kan wees in die vorm van latente TB. Kombinasies van drie of meer anti-tuberkulose (anti-TB) middels is nodig gedurende 'n lang behandelingstydperk (tussen 6 maande en 2 jaar) om Mtb effektief te elimineer. Die lang behandelingsduur met gekonsentreerde anti-TB middels het gelei tot newe-effekte, lae pasiënt nakoming en gevolglik moontlike weerstand teen medisyne. Oraal toegediende anti-TB middels sukkel om effektief die long en alveolêre makrofage te bereik. Gekonsentreerde anti-TB middels word dus daagliks mondelings in tablet vorm toegedien, maar anti-TB middel gelaaide polimeer nanopartikels kan moontlik vinnige middel degradasie deur volgehoue vrystelling voorkom. Daar is dus 'n behoefte om die benodigde konsentrasie van die toegediende anti-TB middels te verminder, wat verkry kan word deur pulmonale inaseming wat TB direk in die longe behandel. Polimeer bedekte superparamagnetiese ysteroksied nanopartikels (SPMNs) kan moontlik geteikende middel toediening via inspuiting moontlik maak. Die nanopartikels kan beheer word deur 'n eksterne magnetiese veld na Mtb geïnfekteerde areas, gevolg deur geneesmiddel vrystelling vanaf die anti-TB middel gelaaide polimeer bedekking. n hierdie tesis is bioversoenbare polimere, naamlik chitosan, karrageenaan, alginaat, dekstransulfaat en poli(laktied-ko-glikolied) (PLGA) gebruik vir die laai van anti-TB middels. Kwaternêre ammonium chitosan (CS-qC12) en kwaternêre ammonium poli(stireen-alt- maleïensanhidried) (SMI-qC12) is ook gesintetiseer as gevolg van die bekende verbetering in antimikrobiese aktiwiteit en mukoadhesie, as gevolg van die kwaternêre ammonium funksionele groepe, in vergelyking met ongerepte chitosan en poli(stireen-alt- maleïensanhidried). Verskeie algemeen toegediende anti-TB middels insluitend isoniazid (INH), rifampicin (RIF), ethambutol (EMB), streptomycin (STM), ethionamide (ETA) en ofloxacin (OFX) was gebruik vir anti-TB middel lading. Chitosan (CS) gebaseerde nanopartikels gelaai met anti-TB middels is gesintetiseer deur middel van ioniese jellering waar polimeer en anti-TB middels opgelos word, gevolg deur die byvoeging van kruisbindingsmiddel of polimeer om die nanopartikels voor te berei (versprei anti-TB middel deur die polimeer matriks). PLGA nanopartikels is voorberei deur middel van 'n “olie-in- water” emulsie, gevolg deur verdamping van oplosmiddels. Volgehoue middel vrystelling (asynsuur oplossing in water, pH 5, UV-Vis spektrofotometrie) oor 7 dae is gesien vir al die middel gelaaide nanopartikels, behalwe met ofloxacin lading. Die SPMNs is geproduseer deur mede-neerslag van Fe2+ en Fe3+ in een stap (CS SPMNs en CS-qC12 SPMNs) of twee stappe (chitosan-alginaat-karrageenaan (CS-Al-Car) SPMNs en chitosan-dextransulfaat (CS-DS) SPMNs). PLGA SPMNs en SMI-qC12 SPMNs is gesintetiseer deur die ongerepte ysteroksied nanopartikels te aktiveer met oleïensuur en 3- aminopropiel(trietoksiesilaan) (3-APTES), onderskeidelik, voor polimeer bedekking. Die polimeer bedekte SPMNs is ex situ middel gelaai deur die SPMNs in anti-TB middel oplossing te versprei. Volgehoue middel vrystelling oor 8 dae is waargeneem vir die INH, ETA en RIF gelaaide polimeer bedekte SPMNs. Die resasurien mikrotiter toets (REMA) teen TB mimiek Mycobacterium Smegmatis (M. Smeg) is gebruik om die antimikrobiese aktiwiteit te kwantifiseer deur middel van minimum inhibisie konsentrasie (MIK) bepalings. Die CS-DS nanopartikels was bepaal om die optimale geneesmiddeldraer te wees met laer MIK waardes (CS-DS-OFX = 0.2441 μg/mL) in vergelyking met die vrye middels (OFX = 0.5859 μg/mL).en_ZA
dc.description.versionDoctoralen_ZA
dc.format.extent182 pagesen_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/124860en_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subjectChitosanen_ZA
dc.subjectPoly(styrene-alt-maleic anhydride)en_ZA
dc.subjectTB treatmenten_ZA
dc.subjectDrug loaded nanoparticlesen_ZA
dc.subjectPolymer coated superparamagnetic iron oxide nanoparticlesen_ZA
dc.subjectDextran -- Sulfatesen_ZA
dc.subjectAlginatesen_ZA
dc.subjectMycobacterium tuberculosis (Mtb) -- Treatmenten_ZA
dc.subjectPolylactic-co-glycolic aciden_ZA
dc.subjectUCTDen_ZA
dc.subjectNanoparticlesen_ZA
dc.titlePolymer-coated magnetic nanoparticles and polymer nanoparticles for the treatment of Mycobacterium tuberculosis (Mtb)en_ZA
dc.typeThesisen_ZA
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
smit_polymer_2022.pdf
Size:
10.24 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Doctoral Degrees (Chemistry and Polymer Science)