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An investigation of curcumin-loaded nanoparticles to treat pathological hallmarks of Parkinson's disease
Thesis (PhD)--Stellenbosch University, 2025.
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Stellenbosch : Stellenbosch University
2025
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| access_status_str | Open Access |
| author | Burns, Jessica |
| author2 | Bardien, Soraya |
| author_browse | Bardien, Soraya Burns, Jessica |
| author_facet | Bardien, Soraya Burns, Jessica |
| author_sort | Burns, Jessica |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2025. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/134555 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:46:28.519Z |
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| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
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| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/134555 An investigation of curcumin-loaded nanoparticles to treat pathological hallmarks of Parkinson's disease Burns, Jessica Bardien, Soraya Dube, Admire Smith, Liezel Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics. Parkinson’s disease -- Treatment Curcumin -- Therapeutic use Parkinson’s disease -- Pathophysiology Nanoparticles -- Therapeutic use Thesis (PhD)--Stellenbosch University, 2025. Burns, J. 2025. An investigation of curcumin-loaded nanoparticles to treat pathological hallmarks of Parkinson's disease. Unpublished doctoral dissertation. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/d7720075-92d5-4047-bd9a-f06c19558f49 ENGLISH ABSTRACT: Parkinson’s disease (PD) is the fastest-growing neurological disorder worldwide, with environmental and genetic factors, as well as ageing, being linked to its development. PD is characterised by the death of dopaminergic neurons in the substantia nigra. This neurodegeneration is thought to be a multifaceted process, with α-synuclein aggregation and mitochondrial dysfunction playing key roles. Improved disease-modifying treatments are necessary, as only palliative therapies associated with severe side effects are currently available. One candidate drug target is the polyphenol curcumin, which has been shown to exhibit neuroprotective properties in several PD models. Specifically, curcumin has been shown to protect cells from toxic α -synuclein aggregates as well as mitochondrial dysfunction. Unfortunately, curcumin has poor pharmacokinetic properties, such as decreased stability in bodily fluids and low bioavailability, which reduces its blood-brain barrier (BBB) permeability. To overcome these shortcomings, nanoparticles (NP) can be utilised as a drug delivery system. Therefore, the main focus of this study was to select three different NPs (polycaprolactone (PCL), PCL-Lecithin and stearic acid/poloxamer 188) and encapsulate curcumin to examine their effects in cellular models of PD. Empty and curcumin-loaded NPs (CurNP) were successfully synthesised and characterised by dynamic light scattering and scanning electron microscopy and found to be non-toxic. As the stearic acid CurNPs were irregularly shaped and had a variable size distribution, these NPs were excluded from further experiments. Drug loading studies revealed that the PCL NPs had a significantly higher curcumin loading capacity (8.3%) compared to PCL-Lecithin NPs (4.6%). Both NPs had a sustained release profile, but the PCL-Lecithin NPs had a slower release profile. Additionally, fluorescent microscopy revealed that both CurNPs were taken up by SH-SY5Y cells. The effect of the CurNPs on BBB integrity as well as their BBB permeability, was evaluated in a transwell in vitro model of the BBB. The transendothelial electrical resistance across the bEnd.5 cell monolayers was assessed to confirm that the monolayer was indeed formed and whether the treatments affected the integrity of the monolayer. Furthermore, the amount of curcumin that crossed the bEnd.5 monolayer was quantified by liquid chromatography/mass spectrometry. Free curcumin, PCL and PCL-Lecithin CurNPs did not affect the BBB integrity and were all found to cross the BBB. However, no significant differences were observed in the BBB permeability between the free curcumin (0.13%) and the CurNPs (PCL: 0.14% and PCL-Lecithin: 0.17%). The ability of the CurNPs to reduce α-synuclein aggregation was investigated in patient-derived primary dermal fibroblasts harbouring a SNCA triplication. Fibroblasts were pretreated with CurNPs, followed by α-synuclein preformed fibrils. Dot blot analysis revealed that pretreatment with the CurNPs significantly decreased total α-synuclein levels (both 1.8-fold) compared to Epigallocatechin-3-gallate (EGCG) (1.6-fold), a known α-synuclein aggregation inhibitor. Furthermore, pretreatment with EGCG, PCL and PCL-Lecithin CurNPs decreased the number of α-synuclein puncta (2.8-, 1.8- and 4.9-fold, respectively) assessed using immunocytochemistry. The protective effects of free curcumin and CurNP pretreatment against paraquat-induced mitochondrial dysfunction in SH-SY5Y cells were compared using the Seahorse XF Mito Stress Test on the XF96e analyser. Free curcumin and PCL-lecithin CurNPs rescued maximal respiration, while free curcumin and PCL CurNPs improved spare respiratory capacity, though neither effect was significantly different from free curcumin. In conclusion, PCL and PCL-lecithin CurNPs were successfully synthesised with acceptable characteristics, and were able to cross the BBB, reduce the levels of toxic α-synuclein aggregation and protect cells from aspects of paraquat-induced mitochondrial respiratory dysfunction. Even though the CurNPs were not better than free curcumin at crossing the BBB and protecting against paraquat-induced respiratory defects, these findings underscore the potential of NP-based drug delivery systems in overcoming curcumin’s pharmacokinetic limitations. Although additional investigation is needed to improve the size and zeta potential of the NPs, and to evaluate their pharmacokinetic properties and drug-drug interactions in in vivo models, this study provides a solid platform for future studies in this field. The implications of this study extend beyond PD to other α-synucleinopathies and disorders where mitochondrial dysfunction is implicated. Moreover, this study provides a basis for future work using these NP formulations to encapsulate other phytomedicines for the treatment of brain disorders. AFRIKAANSE OPSOMMING: Parkinson’ssiekte (PD) is die vinnigste groeiende neurologiese versteuring wêreldwyd met omgewings- en genetiese faktore, en veroudering wat aan die ontwikkeling daarvan gekoppel word. PD word gekenmerk deur die dood van dopaminerge neurone in die substantia nigra. Hierdie neurodegenerasie word beskou as 'n veelvlakkige proses met a-sinukleinsamevoeging en mitochondriale disfunksie wat sleutelrolle speel. Verbeterde siektemodifiserende behandelings is nodig aangesien slegs palliatiewe sorg wat verband hou met ernstige newe-effekte tans beskikbaar is. Een kandidaat-medikasieteiken is die polifenolcurcumin, wat getoon is dat dit neurobeskermende eienskappe in verskeie PD-modelle vertoon. Daar is spesifiek getoon dat curcumin selle beskerm teen giftige α-sinuklein samevoeging sowel as mitochondriale disfunksie. Ongelukkig het curcumin swak farmakokinetiese eienskappe soos verminderde stabiliteit in liggaamsvloeistowwe en lae biobeskikbaarheid wat sy bloed-breinversperring (BBB) deurlaatbaarheid verminder. Om hierdie tekortkominge te oorkom, kan nanopartikels (NP) as 'n dwelling aflewering stelsel gebruik word. Die hoof fokus van hierdie studie was om drie verskillende NP's (polycaprolactone (PCL), PCLLecithin en steariensuur/poloxamer 188) te kies en curcumin te inkapsuleer om hul effekte in sellulêre modelle van PD te ondersoek. Leë en curcumin-gelaaide NPs (CurNP) is suksesvol gesintetiseer en gekarakteriseer deur dinamiese ligverstrooiing, skandeerelektronmikroskopie en gevind dat dit nie giftig is nie. Aangesien die steariensuur CurNP's onreëlmatig gevorm was en 'n veranderlike grootteverspreiding gehad het, is hierdie NP's uitgesluit van verdere eksperimente. Geneesmiddel laai studies het aan die lig gebring dat die PCL NP's 'n aansienlike hoër curcumin laaikapasiteit (8.3%) het in vergelyking met PCL-Lecithin NPs (4.6%). Beide NPs het 'n volgehoue vrystelling profiel gehad, maar die PCL-Lecithin NPs het 'n stadiger vrystelling profiel gehad. Daarbenewens het fluoresserende mikroskopie bewys dat beide CurNP's deur SH-SY5Y-selle opgeneem is. Die effek van die CurNPs op BBB integriteit sowel as hul BBB deurlaatbaarheid is geëvalueer in 'n transwell in vitro model van die BBB. Die transendoteliale elektriese weerstand oor die bEnd.5-selmonolae is geassesseer om te bevestig dat die monolaag inderdaad gevorm is en of die behandelings die integriteit van die monolaag beïnvloed het. Verder is die hoeveelheid kurkumien wat die bEnd.5-monolaag oorgesteek het, gekwantifiseer deur vloeistofchromatografie/massaspektrometrie.Vrye curcumin, PCL en PCL-Lecithin CurNPs het nie die BBB-integriteit beïnvloed nie en daar is gevind dat almal die BBB kruis. Geen betekenisvolle verskille is egter waargeneem in die BBB deurlaatbaarheid tussen die vrye curcumin (0.13%), en die CurNPs (PCL: 0.14% en PCLLecithin: 0.17%). Die vermoë van die CurNPs om α-sinuklein-samevoeging te verminder, is ondersoek in pasiënt-afgeleide primêre dermale fibroblaste wat 'n SNCA triplisering huisves. Fibroblaste is vooraf behandel met CurNPs gevolg deur α-sinokleien-voorgevormde fibrille. Kolvlek-analise het bewys dat voorbehandeling met die CurNPs, die totale α-sinokleienvlakke (albei 1.8-voudig) aansienlik verlaag het in vergelyking met Epigallokatechien-3-gallaat (EGCG) (1.6-voudig), 'n bekende α-sinuklein-samevoeging-inhibeerder. Verder het voorbehandeling met EGCG, PCL en PCL-Lecithin CurNPs die aantal α-synuclein puncta (2.8-, 1.8- en 4.9-voudig, onderskeidelik) verminder wat deur immunositochemie geassesseer is. Die beskermende effekte van vrye curcumin en CurNP voorbehandeling teen parakwat-geïnduseerde mitochondriale disfunksie in SH-SY5Y selle is vergelyk met behulp van die Seahorse XF Mito Stress Toetsop die XF96e ontleder. PCL-lecithin CurNPs het maksimum asemhaling gered, terwyl PCL CurNPs ekstra respiratoriese kapasiteit verbeter het, alhoewel nie een van die effek beduidend verskil van vry curcumin nie. Ten slotte, PCL en PCL-lecithin CurNPs is suksesvol gesintetiseer met aanvaarbare eienskappe, het die BBB gekruis, die vlakke van toksiese α-sinuklein-samevoeging verminder en selle beskerm teen aspekte van parakwat-geïnduseerde mitochondriale respiratoriese disfunksie. Hierdie bevindinge onderstreep die potensiaal van NP-gebaseerde geneesmiddelafleweringstelsels om curcumin se farmakokinetiese beperkings te oorkom. Alhoewel addisionele ondersoek nodig is om die grootte en zeta-potensiaal van die NP's te verbeter, en om hul farmakokinetiese eienskappe en geneesmiddel-middel interaksies in in vivo modelle te evalueer, bied hierdie studie 'n stewige platform vir toekomstige studies in hierdie veld. Die implikasies van hierdie studie strek verder as PD na ander α-sinukleinopatieë en afwykings waar mitochondriale disfunksie geïmpliseer word. Boonop verskaf hierdie studie 'n basis vir toekomstige werk deur hierdie NP-formulerings te gebruik om ander fitomediisyne vir die behandeling van breinafwykings in te kap. Doctoral 2025-12-12T11:30:03Z 2025-12-12T11:30:03Z 2025-12 Thesis https://scholar.sun.ac.za/handle/10019.1/134555 en Stellenbosch University xvi, 123 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Parkinson’s disease -- Treatment Curcumin -- Therapeutic use Parkinson’s disease -- Pathophysiology Nanoparticles -- Therapeutic use Burns, Jessica An investigation of curcumin-loaded nanoparticles to treat pathological hallmarks of Parkinson's disease |
| title | An investigation of curcumin-loaded nanoparticles to treat pathological hallmarks of Parkinson's disease |
| title_full | An investigation of curcumin-loaded nanoparticles to treat pathological hallmarks of Parkinson's disease |
| title_fullStr | An investigation of curcumin-loaded nanoparticles to treat pathological hallmarks of Parkinson's disease |
| title_full_unstemmed | An investigation of curcumin-loaded nanoparticles to treat pathological hallmarks of Parkinson's disease |
| title_short | An investigation of curcumin-loaded nanoparticles to treat pathological hallmarks of Parkinson's disease |
| title_sort | investigation of curcumin loaded nanoparticles to treat pathological hallmarks of parkinson s disease |
| topic | Parkinson’s disease -- Treatment Curcumin -- Therapeutic use Parkinson’s disease -- Pathophysiology Nanoparticles -- Therapeutic use |
| url | https://scholar.sun.ac.za/handle/10019.1/134555 |
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