The delivery method of a math course may affect the math scores of nursing students, which relates to rates of medication errors that could be fatal. The purpose of this study was to discover the relative effectiveness of a delivery method of a math course. Benner's novice-to-expert theory guided the study. A sequential explanatory, mixed-methods, nonexperimental pre-/posttest alternative treatment design was used. Phase 1 answered which delivery methods-online self-directed, face-to-face, or a mix of online self-directed with instructor lead-were associated with the best Medication Administration Competency exam results. Phase 2 included students' assessment of each learning method. The sample size was 148 students who were admitted to 1 nursing school between 2011 and 2013. The data were collected from 4 sources: (a) archival standardized entrance exam math scores, (b) archival standardized exit exam math scores, (c) a qualitative survey regarding student perceptions of the delivery method, and (d) a qualitative section of the same survey with math questions. The ANCOVA analysis showed no statistically significant difference in the delivery method used. Students with lower pretest exam scores took the posttest exam more times and also had lower posttest grades. The content analysis showed that students from all 3 groups did not see an advantage in the delivery method, but in certain teaching strategies that support learning. Therefore, the nursing school should continue to allow students to select their preferred delivery method, or offer fewer methods as they were equivalent. Positive change could come from using teaching strategies that students valued, improving their ability to provide correct dosages and increasing patient safety in the healthcare environment.

Dendrimers are a class of polymers with a highly branched, three-dimensional architecture comprised of an initiator core, several interior layers of repeating units, and multiple active surface terminal groups. Dendrimers have been recognized as the most versatile compositionally and structurally controlled nanoscale building blocks for drug and gene delivery. Polyamidoamine (PAMAM) dendrimers have been most investigated because of their unique structures and properties. Polycationic PAMAM dendrimers form compacted polyplexes with nucleic acids at physiological pH, holding great potential for gene delivery. Folate receptor (FRα) is expressed at very low levels in normal tissues but expressed at high levels in cancers in order to meet the folate demand of rapidly dividing cells under low folate conditions. Our primary aim was to investigate folic acid (FA)-conjugated PAMAM dendrimer generation 4 (G4) conjugates (G4-FA) for targeted gene delivery. The in vitro cellular uptake and transfection efficiency of G4-FA conjugates and G4-FA/DNA polyplexes were investigated in Chapter 4. It was found the cellular uptake of G4-FA conjugates and G4-FA/DNA polyplexes was in a FR-dependent manner. Free FA competitively inhibited the cellular uptake of G4-FA conjugates and G4-FA/DNA polyplexes. G4-FA/DNA polyplexes were preferentially taken up by FR-positive HN12 cells but not FR-negative U87 cells. In contrast, the cellular uptake of G4 dendrimers and G4/DNA polyplexes was non-selective via absorptive endocytosis. G4-FA conjugates significantly enhanced cytocompatibility and transfection efficiency compared to G4 dendrimers. This work demonstrates that G4-FA conjugates allow FR-targeted gene delivery, reduce cytotoxicity, and enhance gene transfection efficiency. The in vivo biodistribution of G4-FA conjugates and anticancer efficacy of G4-FA/siRNA polyplexes were investigated in Chapter 5. Vascular endothelial growth factor A (VEGFA) is one of the major regulators of angiogenesis, essential for the tumor development. It was found G4-FA/siVEGFA polyplexes significantly knocked down VEGFA mRNA expression and protein release in HN12 cells. In the HN12 tumor-bearing nude mice, G4-FA conjugates were preferentially taken up by the tumor and retained in the tumor for at least 21 days following intratumoral (i.t.) administration. Two-dose i.t. administration of G4-FA/siVEGFA polyplexes significantly inhibited tumor growth by lowering tumor angiogenesis. In contrast, two-dose i.t. administration of G4/siVEGFA polyplexes caused severe skin lesion, presumably as a result of local toxicity. Taken together, this work shows great potential for the use of G4-FA conjugates in targeted gene delivery and cancer gene therapy. We also explored polyanionic PAMAM dendrimer G4.5 as the underlying carrier to carry camptothecin (CPT) for glioblastoma multiforme therapyin Chapter 6. "Click" chemistry was applied to improve polymer-drug coupling reaction efficiency. The CPT-conjugate displayed a dose-dependent toxicity with an IC50 of 5 μM, a 185-fold increase relative to free CPT, presumably as a result of slow release. The conjugated CPT resulted in G2/M arrest and cell death while the dendrimer itself had little to no toxicity. This work indicates highly efficient "click" chemistry allows for the synthesis of multifunctional dendrimers for sustained drug delivery. Immobilizing PAMAM dendrimers to the cell surface may represent an innovative method of enhancing cell surface loading capacity to deliver therapeutic and imaging agents. In Chapter 7, macrophage RAW264.7 (RAW) was hybridized with PAMAM dendrimer G4.0 (DEN) on the basis of bioorthogonal chemistry. Efficient and selective cell surface immobilization of dendrimers was confirmed by confocal microscopy. It was found the viability and motility of RAW-DEN hybrids remained the same as untreated RAW cells. Furthermore, azido sugar and dendrimer treatment showed no effect on intracellular AKT, p38, and NFκB (p65) signaling, indicating that the hybridization process neither induced cell stress response nor altered normal signaling. This work shows the feasibility of applying bioorthogonal chemistry to create cell-nanoparticle hybrids and demonstrates the noninvasiveness of this cell surface engineering approach. In summary, these studies indicate surface-modification of PAMAM dendrimer G4 with FA can effectively target at FR-positive cells and subsequently enhance in vitro transfection efficiency and in vivo gene delivery. G4-FA conjugates may serve as a versatile targeted gene delivery carrier potentially for cancer gene therapy. PAMAM dendrimers G4.5 may serve as a drug delivery carrier for the controlled release of chemotherapeutics. The immune cell-dendrimer hybrids via bioorthogonal chemistry may serve as an innovative drug and gene delivery carrier potentially for cancer chemotherapy. Taken together, engineering of PAMAM dendrimers may advance anticancer drug and gene delivery.

Historically, Zimbabwe’s urban population enjoyed high water supply and sanitation service levels and standards, having one of the highest coverage levels in Africa. However, over the last two decades, the quality of Zimbabwe’s urban water supply and sanitation services has slowly been eroded. The poor, displaced and disenfranchised Zimbabweans that occupy Harare’s informal urban settlements are vulnerable to challenges posed by unavailability of basic water and sanitation services. This qualitative research project, carried out between January and June 2013 in Harare’s Hopley and Retreat informal settlements, investigates factors that have been preventing delivery of basic sanitation services to residents in these two settlements. Presenting evidence from the two informal settlements of Hopley and Retreat, this research establishes that there is a complex relationship at play between policy processes, the prevailing political environment and the way in which institutions have responded to the problem of sanitation in these settlements. The study was undertaken towards the end of an era of a negotiated Government of National Unity between ZANU-PF and the Movement for Democratic Change, highlights the dominance of power and political contestation between the two parties that has spilled into policy decisions on basic service provision in the informal settlements. The deep rooted culture of political violence which characterised the political environment from 2000 onwards, with very little commitment to democratic processes, was instrumental in the development of Hopley settlement after the 2005 elections. At face value, ZANU-PF was providing displaced people with alternative accommodation. However, as Muzondidya notes, this along with other ZANU-PF strategies is ‘(c)onsistent with its hegemonic political culture… to engage in cosmetic political and economic reforms that will not result in further democracy or result in a loss of its historic monopoly over power…’ (Muzondidya in Raftopolous, 2013, p.50). Informal settlements are a relatively new phenomenon in Zimbabwe. However, since their inception, they have continued to grow, fuelled by ZANU-PF’s strategy to allocate unserviced residential stands in exchange for residents’ allegiance to the party, with the most recent illegal residential stand allocations taking place in Chitungwiza town in 2013. A close examination of Hopley and Retreat revealed that water and sanitation services provided in Zimbabwe’s informal settlements are typically inadequate or non-existent – a situation that has the potential for severe public health impacts. The emergency actions taken by Non-Governmental Organisations during the height of the 2008 cholera outbreak only provided short-term sanitation solutions. The research concludes that water and sanitation services in Zimbabwe’s informal urban settlements have come to this point, mainly due to the interacting forces of politics. These have influenced policy processes on decision-making, formulation and implementation of sanitation policies for informal settlements. Despite the political origins of several informal settlements, there is a notable absence of practical policies to tackle the issues posed by this development and a lack of institutions capable of instigating the plans needed for change.

Polymer brushes generated via "grafting-from" approach emerged as an attractive surface modification tool offering chemical stability, synthetic flexibility and unprecedented control over the polymer grafting density, thickness, chemical composition and functionality. They display interesting features to many applications in regenerative medicine including cell culture, tissue engineering and as delivery systems due to exquisite control of physicochemical and biological properties. Cationic polymer brushes are particularly attractive in the field of designing effective vectors for gene delivery as polymer brush allows the design and coating of a variety of particles with well-defined core-shell architecture and chemistry to efficiently condense and deliver nucleic acids. This thesis concentrates on designing safe and efficient gene delivery vectors based on 'graft from' cationic polymer brush and understanding the interaction of nucleic acids with polymer brush. Chapter one presented fundamental knowledge of polymer brush and its biomedical application. The first part of this chapter describes the definition of polymer brush, the preparation strategies, mechanism of atom transfer radical polymerisation and the responsiveness of polymer brush including solvent, pH and ionic strength. The second part discusses the state-of-art applications of polymer brush in regenerative medicine including protein resistant polymer brush for tissue engineering and as drug/gene delivery systems.

A major challenge in drug development is ensuring that each new candidate drug is delivered to the appropriate location, in a timely manner and at an optimal concentration. Low drug solubility, drug instability, drug degradation, drug toxicity, or rapid clearance from the body can reduce the effectiveness of an otherwise promising drug candidate. Formulations such as nano/microparticles and melt extruded pellets made with synthetic and natural polymers are effective solutions for the advancement of drug delivery technology. These polymeric formulations can provide controlled release of therapeutic agents by delivering constant doses over long periods, cyclic dosages, and tunable release of both hydrophilic and hydrophobic drugs in order to improve the bioavailability and bioactivity of a drug. PLGA-based nanoparticles formed by emulsion or nanoprecipitation techniques can be designed to have a range of degradation times. Particle degradation and drug release kinetics can be controlled by the physiochemical properties of the polymer, such as molecular weight, hydrophobicity, and polydispersity. This study is focused on developing polymeric-based delivery systems for small and large molecules as treatment strategies for arthrofibrosis and bone tissue engineering. In developing arthrofibrotic treatments, several mechanosignaling and biochemical pathways were targeted using small molecule therapeutics such as blebbistatin (a myosin II ATPase inhibitor), paclitaxel (a microtubule stabilizer), sulfasalazine (a kappa B suppressor), beta-aminopropionitrile (a lysyl oxidase inhibitor) and cis-hydroxyproline (inhibits the formation of stable triple helix structure of collagen). The aforementioned drugs were delivered either via PLGA micro/nanoparticles or via pellets formed by melt extrusion. From the studies performed, it was found that blebbistatin delivered by PLGA nanoparticles could reversibly inhibit fibroblast contractile activity and could significantly inhibit collagen synthesis. These findings lay the foundations for further optimization of drug dosing and potentially enabling a new drug delivery technology for treating arthrofibrosis. Sulfasalazine delivered by melt extruded PLGA pellets significantly inhibited myofibroblast numbers as deduced from α-SMA expression and col1A1 gene expression results and thus can be considered a potential treatment for arthrofibrosis. For bone tissue engineering, plasmids encoding differentiation promoting factors or growth factors such as BMP-2 (pBMP-2), FGF-2 (pFGF-2), PDGF (pPDGF) and VEGF (pVEGF) were delivered via polyethylenimine (PEI), a cationic carrier that interacts electrostatically with negatively charged DNA. The formed nanoplexes were either tested directly or by coating them onto biocompatible titanium metal implants and cultured with human bone marrow derived mesenchymal stem cells (hBMSCs). We found that the combinatorial delivery of pBMP-2 and pFGF-2 significantly enhanced bone regeneration as deduced from Runx-2, alkaline phosphatase and osteocalcin gene expression results as well as from data yielded from alizarin red staining assays and atomic absorption spectroscopy where calcium ion levels were measured. It was also found that pBMP-2 nanoplex-coated titanium discs could significantly enhance bone regenerative gene expression for osteocalcin, Runx-2, and alkaline phosphatase as well as enhance calcium ion expression in human adipose derived mesenchymal stem cells (hADMSCs). Thus, it can be concluded that pFGF-2 and pBMP-2 nanoplexes have osteogenic potential and our studies demonstrate a new methodology with the potential to modify titanium disc implant surfaces for the purposes of enhancing osseointegration.

Thesis (Ph.D. (Pharmacy))--North-West University, Potchefstroom Campus, 2008.

A class of mitochondria-penetrating peptides (MPPs) was studied in an effort to optimize their applications in the delivery of bioactive cargo to this therapeutically important organelle. The sequence requirements for mitochondrial entry were monitored, and it was discovered that while an alternating cationic/hydrophobic residue motif is not required, the inclusion of a stretch of adjacent cationic amino acids can impede access to the organelle. In addition, a variety of C-terminal cargos were tested to determine if there are limitations to the lipophilicity, charge, or polarity of compounds that can be transported to mitochondria by MPPs. Furthermore, these systematic studies aided the design and synthesis of a copper-binding MPP for the delivery of copper ions to mitochondria for the potential rescue of disorders associated with copper-deficiency. The results reported demonstrate that MPPs are versatile transporters that may have a wide range of biological applications.

Spinal cord injury and stroke are two devastating neurological events that lack effective clinical treatments. Recent neuroregenerative approaches involving the delivery of cells or drugs to the injured tissue have shown promise, but face critical challenges to clinical translation. Herein, hyaluronan-methylcellulose (HAMC) hydrogels were investigated as a versatile means of overcoming the challenges facing central nervous system cell and drug delivery. HAMC was shown to support the viability of encapsulated human umbilical tissue-derived cells, demonstrating utility as a scaffold for therapeutic cell delivery to the injured spinal cord. In a drug delivery context, release of the neuroregenerative drug cyclosporin A from the hydrogel was tunable over 2-28 days and the drug diffused to the stem cell niche in the brain and persisted for up to 24 days at a stable concentration when the HAMC-based system was implanted epi-cortically. HAMC is thus a promising tool for emerging neuroregenerative therapies.

A class of mitochondria-penetrating peptides (MPPs) was studied in an effort to optimize their applications in the delivery of bioactive cargo to this therapeutically important organelle. The sequence requirements for mitochondrial entry were monitored, and it was discovered that while an alternating cationic/hydrophobic residue motif is not required, the inclusion of a stretch of adjacent cationic amino acids can impede access to the organelle. In addition, a variety of C-terminal cargos were tested to determine if there are limitations to the lipophilicity, charge, or polarity of compounds that can be transported to mitochondria by MPPs. Furthermore, these systematic studies aided the design and synthesis of a copper-binding MPP for the delivery of copper ions to mitochondria for the potential rescue of disorders associated with copper-deficiency. The results reported demonstrate that MPPs are versatile transporters that may have a wide range of biological applications.

Spinal cord injury and stroke are two devastating neurological events that lack effective clinical treatments. Recent neuroregenerative approaches involving the delivery of cells or drugs to the injured tissue have shown promise, but face critical challenges to clinical translation. Herein, hyaluronan-methylcellulose (HAMC) hydrogels were investigated as a versatile means of overcoming the challenges facing central nervous system cell and drug delivery. HAMC was shown to support the viability of encapsulated human umbilical tissue-derived cells, demonstrating utility as a scaffold for therapeutic cell delivery to the injured spinal cord. In a drug delivery context, release of the neuroregenerative drug cyclosporin A from the hydrogel was tunable over 2-28 days and the drug diffused to the stem cell niche in the brain and persisted for up to 24 days at a stable concentration when the HAMC-based system was implanted epi-cortically. HAMC is thus a promising tool for emerging neuroregenerative therapies.