4. Electronic Theses and Dissertations (ETDs) - Faculties submissions

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    The effect of cholesterol depletion on TGF-ß-induced epithelial-mesenchymal transition in pancreatic cancer cells
    (University of the Witwatersrand, Johannesburg, 2024-06) Breytenbach, Andrea; Kaur, Mandeep
    Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic cancer that relies on the epithelial to mesenchymal transition (EMT) program for its spread. EMT is a cell plasticity program that involves the reorganization of cell structure as cells transition from an epithelial to a mesenchymal phenotype. The dysregulated cholesterol metabolism resulting from metabolic reprogramming in PDAC is thought to play a role in EMT by affecting EMT-related signalling pathways. However, no publication has yet investigated the impact of EMT on cholesterol content in PDAC. To shed light on these dynamics, EMT was induced in PANC-1 cells using TGF-β1, thereafter the effect of cholesterol-depleting agents (KS-01 and methyl-β-cyclodextrin) alone or in combination with chemotherapeutic agents (Gemcitabine (GEM) and 5-Fluorouracil (5-FU)) on cholesterol content, EMT state, drug resistance, and invasion were investigated. Our results showed that mesenchymal cells rely on reduced membrane cholesterol levels, synthesis, and uptake, while storing more cholesterol and promoting efflux. EMT also promoted drug resistance via upregulation of ABCB1 expression and reduced hENT1 expression. Targeting cholesterol using cyclodextrins promoted a cholesterol compensatory mechanism, leading to a hybrid EMT state, drug resistance, and metastatic potential. Treating mesenchymal PANC-1 cells with GEM or 5-FU monotherapies were seen to promote EMT-transcription factors, as well as promote cholesterol efflux, synthesis, and import, an unexpected result as these chemotherapeutic agents are not known to affect cholesterol. When GEM was combined with KS-01, drug resistance, invasion, EMT-transcription factors, vimentin, and E-cadherin was promoted indicating the promotion of a hybrid EMT state. Interestingly however, combining KS-01 with 5-FU resulted in an interplay that was seen to mitigate the EMT-promoting effects typically associated with cholesterol depletion alone. The exact mechanism linking the cholesterol compensatory mechanism to EMT remains complex and unknown. Based on work presented in this dissertation, it is proposed that targeting cellular cholesterol should be continued to be investigated, particularly in understanding the repercussions of the use of cholesterol depleting agents for the treatment of other disorders in patients with PDAC.
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    Modelling and analysis of COVID-19 outspread at micro-levels using spatial autocorrelation: Case of eThekwini
    (University of the Witwatersrand, Johannesburg, 2024-09) Ngubane, Samukelisiwe; Chimhamhiwa, Dorman; Adam, Elhadi
    The alarming effects of the COVID-19 pandemic on different socio-economic spheres have been felt across the globe. These destructive effects have prompted plenty of research to understand and control the coronavirus pandemic. Notably, one strategic method of mitigating the effects of the coronavirus epidemic has been the utilisation of spatial and geostatistical models to gain insights into the potential predictors of the prevalence of the coronavirus. Considering the above, it was the aim of this study to explore the use of advanced geospatial modelling and analysis techniques, including Moran’s I, spatial error models, spatial lag models, MGWR, and GWR for analysing and modelling the settlement level determining factors of COVID-19 incidence within the eThekwini Metro to inform effectual micro-level planning. Notably, the lack of micro-level modelling of COVID-19 prevalence predictors also motivated the undertaking of this study. To the above aim, the objectives of the research were to utilise spatial autocorrelation to map the granular level COVID-19 spatial distribution over the 3rd wave in the eThekwini Metro, compare the applicability of global and local models in analysing and modelling micro-level COVID-19 incidence, analyse the spatial dependence of the occurrence of COVID-19 on local level variables through Moran’s I and to spatially model the effects of significant local-level determinants on COVID-19. The incidence of COVID-19 cases for the 3rd wave, which was from the 2nd of May 2021 to the 11th of September 2021, was analysed and modelled. The Moran’s I result illustrated that COVID-19 incidence within the eThekwini settlement places had a positive spatial autocorrelation, with a Moran’s I value of 0.14 and a p-value of 0.00. Also, the MGWR model's local R2 value was greater (72.5%) as compared to the other models. Moreover, economic wellness score, the sum of TB cases and population density came out as the significant determining factors of settlement level incidence of COVID-19. This research report offers a great foundation for gaining insights into the applicability of advanced geospatial models in guiding targeted COVID-19 interventions at lower levels.
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    Investigating the DNA methylation status of the PXDN and PXDNL promoter regions in OSCC cell lines
    (University of the Witwatersrand, Johannesburg, 2024-06) Sebastian, Mistral; Mavri-Damelin, Demetra
    Background: Oesophageal squamous cell carcinoma (OSCC) is the most prevalent form of oesophageal cancer in South Africa. Aberrant DNA methylation is a well-established epigenetic mechanism involved in various cancers, including OSCC. This study focuses on the DNA methylation status of the peroxidasin (PXDN) and perodixasin like (PXDNL) promoter regions and the expression of PXDN and PXDNL in OSCC cell lines. PXDN consolidates the basement membrane through collagen IV unit oligomerization, influences epithelial-mesenchymal transition and correlates with poor prognosis in various cancers. PXDNL modulates the extracellular matrix (ECM) by antagonising PXDN. Since PXDNL shares domains with PXDN, that allow PXDN to interact with the ECM, it is speculated that PXDNL may possess other ECM modulation roles that require further elucidation. Dysregulated PXDNL expression also correlates with poor cancer prognosis. To date, within the context of South African derived OSCC cell lines, no studies pertaining to the DNA methylation status of the PXDN and PXDNL promoter regions and the expression of PXDN and PXDNL have been carried out. Aim: The aim of this project was to investigate the DNA methylation status of the PXDN and PXDNL promoter regions and observe PXDN and PXDNL expression in the SNO and WHCO5 OSCC cell lines. Methods: PXDN and PXDNL localisation was observed using immunofluorescence microscopy; expression of PXDN and PXDNL was quantified using western blotting and the DNA methylation status of the PXDN and PXDNL promoters was assessed using methylation specific PCR and bisulfite sequencing, respectively. Results: Immunofluorescence microscopy results indicated that both cell lines show varying degrees of PXDN and PXDNL expression. In addition, these results also showed that PXDN and PXDNL localise in the ECM. The western blotting results established that these cell lines express the canonical version of PXDN and possibly a PXDNL isoform (146kDa). Methylation specific PCR has shown that the promoter region of PXDN is differentially methylated across both cell lines. The sequencing results of the bisulfite converted PXDNL promoter region were unsuccessful. Hence, bisulfite sequencing requires further optimisation before the DNA methylation status of the PXDNL promoter region can be determined. Conclusion: This study is the first to show the novel finding that PXDN and PXDNL are expressed in South African derived OSCC cell lines. Within the context of OSCC, further investigation is warranted in order to elucidate the underlying mechanisms that these proteins play a role in. In addition, further study may determine whether a correlation exists between PXDN and PXDNL promoter methylation, protein expression as well as prognosis and whether these aspects should serve as novel markers for diagnosis and therapy. This may subsequently lead to increased OSCC patient survival rates by contributing to early diagnosis of OSCC and efficacious targeted therapeutic intervention.
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    Identifying Markers of Differentiation in Monocyte-Derived-Macrophages
    (University of the Witwatersrand, Johannesburg, 2024-08) Gibson, Matthew Leo; Cronjé, Marianne; Gentle, Nikki
    The importance of monocytes and monocyte-derived macrophages (MDMs) in both adaptive and innate immunity makes their study a topic of interest. Monocytes differentiate into macrophages through transcriptomic alterations, resulting in extensive changes in gene expression. Macrophage colony stimulating factor (M-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) are the two primary cytokines that stimulate this differentiation, and are known to cause partial polarisation towards the M2 and M1 macrophage subtypes, respectively. However, the degree to which this polarisation takes place is not well-characterised. Therefore, this study aimed to use a computational approach to identify the differences and similarities in gene expression changes in macrophages induced with M-CSF and GM-CSF. RNA sequencing data for three human donors was obtained through EBI and used to quantify gene expression changes associated with M-CSF or GM-CSF treatment. Differential gene expression analysis was performed to identify the genes that were differentially expressed as a result of either treatment relative to the untreated monocytes. Over-representation analysis was used to determine the biological processes in which the differentially expressed genes (DEGs) were involved. Finally, transcription factors were identified within the lists of DEGs, as well as the genes encoding their known protein-protein interacting partners. Treatment with M-CSF and GM-CSF induced 4 072 and 4 399 DEGs, respectively, 2 734 of which were common. An examination of these DEGs revealed that the resultant macrophages lacked changes in expression of genes commonly associated with the M1 and M2 polarisation states. An investigation of the DEGs involved in myeloid cell differentiation and the regulation of inflammatory response revealed CCR2, IGF1 and INHBA to be inversely regulated by the two treatments. Furthermore, nine uniquely differentially expressed transcription factors involved in these biological processes were identified, each of which may be contributing to the lack of complete polarisation following differentiation. These results revealed that M-CSF and GM-CSF-induced macrophages, in the absence of activation, experience highly similar gene expression changes and lack changes in the expression of key polarisation marker genes.
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    Unveiling the biochemical pathway between Type 2 Diabetes Mellitus and early Alzheimer’s disease
    (University of the Witwatersrand, Johannesburg, 2024-08) Tooray, Shweta; van der Merwe, Eloise
    Research related to Alzheimer's Disease (AD) remains a focal point in neurodegeneration studies. This is due to the severity of AD and the clear necessity for non-palliative treatment approaches, as underscored by the high prevalence of the disease. The combined formation of extracellular senile plaques and neurofibrillary tangles (NFTs) plays a crucial role in the development of the cognitive and behavioural symptoms observed in individuals with AD. Despite extensive research efforts, discovering a definitive cure for the disease remains a challenge. Therefore, it is imperative to explore new perspectives and identify the upstream molecular mechanisms that contribute to the onset of the disease. Metabolic disorders are widely recognized as a significant risk factor for AD. Specifically, the metabolic syndrome, Type 2 Diabetes Mellitus (T2DM), is connected to neurodegeneration by promoting the accumulation of neurotoxins, inducing neuronal stress, affecting synaptic communication, and leading to brain atrophy. Individuals with T2DM have an increased risk of developing dementia, with hyperglycaemia exacerbating the impact of AD by causing mitochondrial dysfunction and oxidative stress through reactive oxygen species (ROS) formation, which are also present in AD. Additionally, patients with T2DM exhibit shorter telomeres linked to cell death, which is an associated risk factor for developing AD. These key pathways involved in connecting T2DM and AD were explored in the current study to enhance the understanding of the early events that precede AD. Glucose uptake was measured and observed to decrease over time as a potentially protective response of the cell. Subsequently, mitochondrial activity, assessed using the Alamar blue assay, was found to be heightened as an initial protective mechanism of Aβ42. This was later overwhelmed by the elevated ROS detected through a Total ROS assay kit, induced by the hyperglycaemic state of T2DM. In turn causing the amount of Aβ42 to become toxic and leading to a decline in mitochondrial DNA (mtDNA) over time as measured through qPCR. Additionally, the increases in ROS induced by hyperglycaemia resulted in oxidative damage to telomeres. Simultaneously, Aβ42 physically hinders telomere-telomerase binding, leading to reduced telomerase activity and consequently, shorter telomeres. Furthermore, this study reveals, for the first time, that the novel glucose-lowering drug (GLD) caused an increase in Aβ42 production in the T2DM cell model, whilst effectively decreasing ROS production over a 24-hour period compared to the untreated cell model. The rise in Aβ42 levels caused by GLD could potentially be working to prevent the increase in hyperglycaemia-induced ROS through its metal chelating antioxidant properties by scavenging ROS, in the presence of oxidative stress associated with T2DM. These findings are indicative of an appealing function of GLD by reducing ROS and thereby impeding the progression towards AD. Hence making GLD an attractive therapeutic option for the treatment and/or prevention of AD.
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    The effect of parental education on child and adult health in Zambia: A regression discontinuity analysis
    (University of the Witwatersrand, Johannesburg, 2024) Daka, Lincoln; Booysen, Frederik
    This thesis expands upon and enhances existing research in the field of health economics. The thesis consists of three separate yet interrelated chapters that examine the effect of education on key demographic variables: child health, fertility and HIV/AIDS in Zambia, three key factors affecting the progress of development in Africa. The endogeneity problem is present in all of the three empirical papers examined. To circumvent this endogeneity problem and establish a credible causal effect, we explore the impact of Zambia’s 2002 Universal Free Primary Education (UFPE) policy which created an exogenous source of variation in education as a quasi – experiment. The three substantial empirical studies, employ the same econometric methodology, a Regression Discontinuity Design (RDD), whose appealing feature is local randomisation. This characteristic has distinguished the method from other evaluation methods in terms of estimating unbiased treatment effects. Another advantage of the fuzzy Regression Discontinuity design is that it can account for the endogeneity of the treatment variable. The utilisation of the fuzzy Regression Discontinuity design is a valuable contribution in all of the research. Furthermore, every chapter makes a unique contribution within its respective sector. We outline Zambia’s Universal Free Primary Education (UFPE) Policy and also present the Regression Discontinuity Design methodology framework. We find significant causal impacts of maternal education on child health measured by height-for-age, weight-for-height and Weight-for- age. The findings also indicate that maternal education is associated with a reduction in the prevalence of stunting and underweight and no effect wasting contrary to other research. We present evidence of the several mechanisms by which maternal education impacts child health. The results of our study indicate that a greater level of maternal education exerts a beneficial influence on child health through the postponement of marriage, the reduction in total fertility, and the delay in the age of first childbirth and sexual debut. Additionally, we have discovered indications of positive assortative mating. Furthermore, education empowers moms by facilitating their access to information via television and newspapers, equipping them with knowledge about the ovulation time, and helping them to make well-informed decisions regarding contraceptive techniques. Conventional wisdom posits that decreased fertility may indicate the presence of “superior quality” children and increased rates of survival for both mother and child. Can education serve as a catalyst for decreasing fertility rates in developing nations? We find that female education reduces iv | P a g e the number of children ever born. We present evidence of the reduction in total fertility as a result of female education. We also show that female schooling reduces the preferred number of children and increases the age at first birth. We find that female schooling affects fertility through age at first sex and marriage, literacy, assortative mating and the knowledge effect. There is no evidence to suggest that female schooling has a major impact labour market participation. We present evidence of the heterogeneous impacts of a mother’s education based on “poor versus wealthy” criterion, whether rural/urban status, region and religion. We also present evidence of the effect of female education on the HIV seroprevalence status, number of sexual partners and knowledge of HIV transmission mechanisms. We show that female education lowers HIV seroprevalence status, decreases the number of sexual partners and increases HIV knowledge. Our research suggests that educated women are more likely to have a deep and detailed understanding of HIV. Lastly, we present evidence of the heterogeneous effects of female education by household status on HIV related outcomes.
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    Immunomodulation of the innate immune system: The role of vitamin D in the context of monocytes and macrophages
    (University of the Witwatersrand, Johannesburg, 2024-07) Mol, Bronwyn Ashleigh; Gentle, Nikki; Meyer, Vanessa
    Macrophages are widely distributed cells of the innate immune system with essential roles in homeostasis and disease. Despite concerted efforts, several aspects of macrophage origin, biology, and functionality remain poorly understood. To gain a deeper understanding of these cells, a physiologically relevant, but practical model is required. In vitro, macrophages are principally generated from primary monocytes and monocyte-like cell lines through a natural process referred to as monocyte-to-macrophage differentiation. Monocyte-like cell lines have several practical advantages over the use of primary monocytes with the most commonly employed monocyte-like cell lines being THP-1 and U937 cells. Despite their frequent use, no standardised protocol is employed in the differentiation of monocyte-like cell lines to macrophages. Naturally, this results in large discrepancies and a lack of comparability between studies. Furthermore, many of these protocols are not physiologically relevant and produce macrophages that are not responsive to downstream stimuli. 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active form of vitamin D3, is a recognised immunomodulator that shows pronounced genomic and non-genomic effects in immune cells. It is also reported as an inducer of monocyte-to-macrophage differentiation, though heavily debated, and a potential macrophage polarisation agent. Despite this, there is relatively little information concerning the role of 1,25(OH)2D3 in monocyte-to-macrophage differentiation and macrophage biology. This study aimed to develop a more physiologically relevant differentiation protocol for the monocyte-like THP-1 and U937 cell lines. This model was then used to investigate the role of 1,25(OH)2D3 in monocyte-to-macrophage differentiation and macrophage biology. Assessment of morphological features and the macrophage markers, CD11b and CD14, indicated that in both THP-1 and U937 cells, differentiation induced using a combination of 5 nM of phorbol 12-myristate 13-acetate (PMA) and 10 nM 1,25(OH)2D3 over 96 hours produced the most mature macrophages. It was observed that 1,25(OH)2D3 alone was not capable of inducing differentiation, yet when combined with PMA, greatly enhanced macrophage features. THP-1 cells are the most widely employed monocyte-like cell line, and are proposed to be the most reflective of primary monocytes. In this study these cells were shown to be more responsive to the effects of 1,25(OH)2D3 than their U937 counterparts. As such, RNA-sequencing was used to explore the efficacy of the proposed differentiation protocols and the influence of 1,25(OH)2D3 on macrophage biology in THP-1 cells. Differential gene expression analysis confirmed that the most effective differentiation protocol was the combination of 5 nM PMA with 10 nM 1,25(OH)2D3 when considering macrophage associated features including transcription factor usage, adhesion, phagocytosis, and cytokine and cytokine receptor expression. This protocol also produced THP-1-derived macrophages that showed increased expression of genes considered to be primary macrophage markers. These results also suggested that THP-1 cells differentiated with neither PMA nor PMA with 1,25(OH)2D3 were likely to represent fully polarised macrophages. 1,25(OH)2D3 treatment of THP-1 monocytes and THP-1-derived macrophages produced distinct gene expression profiles with considerably less overlap than expected. Though 1,25(OH)2D3 treatment often affected similar biological processes in both cell types, the genes within these processes found to be differentially expressed in each cell line were often distinct. For example, in THP-1- derived macrophages, but not THP-1 monocytes, 1,25(OH)2D3 treatment resulted in the increased expression of genes encoding numerous antibacterial peptides, several small GTPases and their regulators. Additionally, several type I interferon response related proteins showed decreased expression, while expression of cytokines and cytokine receptors was variable. This, taken together with the morphological work, indicates two potential roles for 1,25(OH)2D3 in macrophages. Firstly, a protective role as it suggests the potential to prime an antibacterial response, while still balancing inflammatory responses and protecting against autoinflammation induced by aberrant type I interferon response. Secondly, a potential role in determining the morphological features, clearly demonstrated through microscopy, and further suggested by the differential expression of a variety of small GTPases and their regulators.
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    Detecting Disease in Citrus Trees using Multispectral UAV Data and Deep Learning Algorithm
    (University of the Witwatersrand, Johannesburg, 2024-06) Woolfson, Logan Stefan; Adam, Elhadi
    There is a high prevalence, in South Africa, of fruit tree related diseases infesting lemon trees, subsequently affecting overall crop yield and quality. Ultimately, the income for the farmers is significantly diminished and limits the supply of nutritional food crops for the South African population, who already suffer from a high incidence of malnutrition. Currently, there are various methods utilized to detect diseases in fruit trees, however they pose limitations in terms of efficiency and accuracy. By employing the use of drones and machine learning methods, fruit tree diseases could be detected at an earlier stage of development and with a much higher level of accuracy. Consequently, the chances of remedying the trees before the disease spreads is greatly improved, and the supply of nutritious fruit within South Africa is increased. This research report’s aim is to investigate the effectiveness of a deep learning algorithm for detecting and classifying diseases in lemon orchards using multispectral drone imagery. This entails assessing the performance of a pretrained ResNet-101 model, fine-tuned with additional sample images, in accurately identifying and classifying diseased lemon trees, specifically those affected by Phytophthora root rot. The methodology involves the utilization of a pretrained ResNet-101 model, a deep learning architecture, and the retraining of its layers with an augmented dataset from multispectral aerial drone images of a lemon orchard. The model is fine-tuned to enhance its ability to discern subtle spectral variations indicative of disease presence. The selection of ResNet-101 is grounded in its proven success in image recognition tasks and transfer learning capabilities. The results obtained demonstrated an impressive accuracy of 80%. The deep learning algorithm exhibited notable performance in distinguishing root rot-affected lemon trees from their healthy counterparts. The findings indicate the promise of utilizing advanced deep learning methods for timely and effective disease detection in agricultural farmlands, facilitating orchard management.
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    Knockdown of long non-coding RNA PANDA improves the cytotoxic effects of cisplatin in oesophageal squamous cell carcinoma cell lines
    (University of the Witwatersrand, Johannesburg, 2024-11) Moonsamy, Sasha Sarasvathee Keshnee; Mavri-Damelin, Demetra; Jivan, Rupal
    Oesophageal cancer is one of the leading causes of cancer death worldwide, of which oesophageal squamous cell carcinoma (OSCC) is the major subtype in southern and eastern Africa. Cisplatin is a well-established drug used to treat multiple cancers, including OSCC. Drug resistance is a major impediment to continued cisplatin therapy in numerous cancers. LncRNA P21-associated non-coding RNA DNA damaged activated RNA (PANDA) is known to function in cell cycle regulation in response to DNA damage and is upregulated in OSCC. We aim to determine lncRNA PANDA expression in South African-derived OSCC cells and establish whether down-regulation of this lncRNA can be used to supplement cisplatin therapy. In this study, MTT assays were performed to determine the EC50 concentrations of cisplatin in OSCC (WHCO1, WHCO5, and SNO) cells and HEK293 cells as a non-cancer control. The cytotoxic effects of cisplatin were exerted in all cell lines, with WHCO5 and SNO appearing more responsive to cisplatin than WHCO1 and HEK293. RT-PCR was used to detect if lncRNA PANDA is expressed in untreated and cisplatin-treated cells and was detected in all cell lines. Knockdown of lncRNA PANDA by siRNA was assessed with RT-PCR. Phase contrast microscopy was used to assess whether siRNA reagents altered cell morphology at 5, 24, and 48 hours post treatment. No significant alterations in cell morphology were observed in WHCO1, WHCO5, SNO, and HEK293 cells. MTT assay evaluation after 48 hours of cisplatin exposure, with or without siRNA for lncRNA PANDA, showed a significant reduction in EC50 concentrations in WHCO5, SNO, and HEK293 cell lines, suggesting that knockdown of lncRNA PANDA may improve cisplatin cytotoxicity in some cell lines. However, the EC50 values were higher with lncRNA PANDA knockdown in the WHCO1 cell line, suggesting that not all OSCC cell types may be responsive to this approach. In conclusion, lncRNA PANDA is expressed in response to cisplatin-induced DNA damage, and the down regulation of lncRNA PANDA improves the cytotoxic effects of cisplatin; however, further investigations are warranted in OSCC.
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    Novel antiangiogenic peptide targeted therapeutic nanosystem for non-small-cell lung carcinoma
    (University of the Witwatersrand, Johannesburg, 2023) Ngema, Lindokuhle Malibongwe; Choonara, Yahya Essop; Marimuthu, Thashree; Adeyemi, Adebawole
    Lung cancer is the leading cause of cancer deaths globally, with nearly 1.8 million deaths and 2.2 million incidences recorded annually. Primarily, non-small-cell lung carcinoma (NSCLC) is the most commonly diagnosed type of lung cancer, which makes up approximately 85% of all reported lung cancer cases. Currently, the management of NSCLC is a global challenge, and although, various treatment protocols are available, such as surgery, radiotherapy, and chemotherapy, the survival outcomes remain poor. Combination chemotherapy is the current first-line treatment for NSCLC, however, it presents with a myriad of drawbacks, including non-specificity, high dosage, and detrimental side effects, resulting in patients intolerability to the regimen. Consequently, a new therapeutic approach is greatly needed and warrants the design of biocompatible targeted drug delivery nanosystems that can halt tumor proliferation and metastasis by targeting key molecules and deliver drugs directly to tumors, with limited side effects and toxicity to healthy cells. Tumor targeted drug delivery nanosystems such as magnetic nanoparticles (MNPs) modified with biomolecules and functionalized with homing peptides are of great interest for potential application as a potent nanomedicine in NSCLC management. Accordingly, the present study set to develop novel targeted paclitaxel (PTX) delivery nanosystems from the amenable superparamagnetic iron oxide nanoparticles (SPIONs) coated with trans-10,cis-12 conjugated linoleic acid (10E, 12Z) and functionalized with either a vascular endothelial growth factor receptor (VEGFR) binding or a matrix metalloproteinase 2 (MMP-2) binding peptide, for specific delivery of PTX to VEGFR and MMP-2 expressing NSCLC tumors. A preceding nanosystem without the peptides (CLA-coated PTX-SPIONs) was originally fabricated as proof of concept for the application of 10E, 12Z CLA as a surface coating and drug partitioning biomolecule. CLA-coated PTX-SPIONs exhibited a spherical shape, with an average particle size and zeta potential of 96.5 ± 0.6 nm and −27.3 ± 1.9 mV, respectively. The nanosystem had a drug loading efficiency of 98.5% and demonstrated a sustained site-specific in vitro release of PTX over 24 h (i.e., 94% at pH 6.8 mimicking the tumor microenvironment). Enhanced anti-proliferative activity was also observed with the CLA-coated PTX-SPIONs against a lung adenocarcinoma (A549) cell line after 72 h, with a recorded cell viability of 17.1%. Thereafter, the fabricated nanosystem was optimised for direct tumor-targeting by functionalization with HRH or CTT peptides, to give CLA-coated PTX-SPIONs@HRH and CLA-coated PTX-SPIONs@CTT. A new design methodology was established for the tandem surface functionalization of CLA-coated PTX-SPIONs with the antiangiogenic peptides, via coupling reactions. A series of robust nanotechnological techniques were employed for pertinent physicochemical characterization, in vitro evaluation of drug release, anti-proliferative activity, and quantification of VEGF-A and MMP-2 levels. Meanwhile, in vivo testing was carried out on a lung tumor xenograft mouse model. Both nanosystems exhibited a marked cellular uptake and internalization by A549 cells, and CLA-coated PTX-SPIONs@HRH significantly reduced secretion levels of VEGF-A in human dermal microvascular endothelial cells (HMEC-1) from 46.9 pg/mL to 35.6 pg/mL, meanwhile CLA-coated PTX-SPIONs@CTT significantly inhibited MMP-2 secretion by almost 70% , indicating specific anti-MMP-2 activity. A 76.6% and 69.7 % tumor regression was observed in a lung tumor xenograft mouse model treated with CLA-coated PTX SPIONS@HRH and CLA-coated PTX-SPIONs@CTT, respectively, demonstrating tumor targetability and angiogenesis inhibition. Lastly, the pharmacokinetics (PK) evaluation revealed that both nanosystems prolonged the half-life of PTX and circulation time in vivo. In essence, potent antiangiogenic tumor-targeted PTX delivery nanosystems were successfully fabricated, and the obtained results suggest potential application of CLA-coated PTX SPIONs@HRH and CLA-coated PTX-SPIONs@CTT for effective management of NSCLC.