Doctor of Philosophy / Department of Chemistry / Viktor Chikan / This thesis focuses on exploring fast and controlled drug release from several liposomal drug delivery systems including its underlying mechanics. In addition, the construction of a pulsed high-voltage rotating electromagnet is demonstrated based on a nested Helmholtz coil design. Although lots of different drug delivery mechanisms can be used, fast drug delivery is very important to utilize drug molecules that are short-lived under physiological conditions. Techniques that can release model molecules under physiological conditions could play an important role to discover the pharmacokinetics of short-lived substances in the body. In this thesis, an experimental method is developed for the fast release of the liposomes’ payload without a significant increase in (local) temperatures. This goal is achieved by using short magnetic pulses to disrupt the lipid bilayer of liposomes loaded with magnetic nanoparticles. This thesis also demonstrates that pulsed magnetic fields can generate ultrasound from colloidal superparamagnetic nanoparticles. Generating ultrasound remotely by means of magnetic fields is an important technological development to circumvent some of the drawbacks of the traditional means of ultrasound generation techniques. In this thesis, it is demonstrated that ultrasound is generated from colloidal superparamagnetic nanoparticles when exposed to pulsed and alternating magnetic fields. Furthermore, a comparison between inhomogeneous and homogeneous magnetic fields indicates that both homogeneous and inhomogeneous magnetic fields could be important for efficient ultrasound generation; however, the latter is more important for dilute colloidal dispersion of magnetic nanoparticles. In strong magnetic fields, the ultrasound generated from the colloidal magnetic nanoparticles shows reasonable agreement with the magnetostriction effect commonly observed for bulk ferromagnetic materials. At low magnetic fields, the colloidal magnetic nanoparticle dispersion produces considerable amount of ultrasound when exposed to a.c. magnetic fields in the 20−5000 kHz frequency range. It is expected that the ultrasound generated from magnetic nanoparticles will have applications toward the acoustic induction of bioeffects in cells and manipulating the permeability of biological membranes

Application of neural prostheses in today's medicine successfully helps patients to increase their activities of daily life and participate in social activities again. These implantable microsystems provide an interface to the nervous system, giving cellular resolution to physiological processes unattainable today with non-invasive methods. The latest developments in genetic engineering, nanotechnologies and materials science have paved the way for these complex systems to interface the human nervous system. The ideal system for neural signal recording would be a fully implantable device which is capable of amplifying the neural signals and transmitting them to the outside world while sustaining a long-term and accurate performance, therefore different sciences from neurosciences, biology, electrical engineering and computer science have to interact and discuss the synergies to develop a practical system which can be used in daily medicine practice. This work investigates the main building blocks necessary to improve the quality of acquired signal from the micro-electronics and MEMS perspectives. While all of these components will be ultimately embedded in a fully implantable recording probe, each of them addresses and deals with a specific obstacle in the neural signal recording path. Specifically we present a low-voltage low-noise low-power CMOS amplifier particularly designed for neural recording applications. This is done by surveying a number of designs and evaluating each design against the requirements for a neural recording system such as power dissipation and noise, and then choosing the most suitable topology for design and implementation of a fully implantable system. In addition a surface modification method is investigated to improve the sacrificial properties and biocompatibility of probe in order to extend the implant life and enhance the signal quality. / Applied Science, Faculty of / Electrical and Computer Engineering, Department of / Graduate

No description available.

Liposomes are promising drug delivery vesicles due to their biodegradibility, large volume and biocompatibility towards both hydrophilic and hydrophobic drugs. They suffer, however, from poor stability which limits their use in controlled delivery applications. Herein, a novel method was devised for modification of liposomes with small molecules, polymers or nanoparticles to afford stimuli responsive systems that release on demand and stay relatively stable in the absence of the trigger.. This dissertation discusses thermosensitive, pH sensitive, light sensitive and magnetically triggered liposomes that have been prepared for controlled drug delivery application. RAFT polymerization was utilized for the preparation of thermosensitive liposomes (Cholesterol-PNIPAm) and acid-labile liposomes (DOPE-PAA). With low Mw Cholesterol-PNIPAm, the thermosensitive liposomes proved to be effective for controlled release and decreased the cytotoxicity of PNIPAm by eliciting the polymer doses. By crosslinking the DOPE-PAA on liposome surface with acid-labile diamine linkers, DOPE-PAA liposomes were verified to be sensitive at low pH. The effects of polymer structures (linear or hyperbranched) have also been studied for the stability and release properties of liposomes. Finally, a dual-responsive Au@SPIO embedded liposome hybrid (ALHs) was prepared with light-induced “on-and-off” function by photo-thermal process (visible light) and instant release properties triggered by alternating magnetic field, respectively. The ALH system would be further applied into the cellular imaging field as MRI contrast agent.

This work was performed as a preliminary transdermal drug delivery (TDD) study to investigate the diffusion characteristics and effects of skin surfactants in vitro of four active ingredients on a poly(dimethyl siloxane) polycarbonate copolymer membrane. A Franz-type diffusion cell and various receptor solutions were used. The adhesive used was comprised of a polyisobutylene-based pressure sensitive adhesive manufactured by Adhesives Research Inc. High performance liquid chromatography was used to analyze the diffusion characteristics of these systems. In addition, the effects of two skin surfactants (sodium lauryl sulfate and dimethyl sulfoxide) on the adhesive were also investigated. Results from peel testing and thermal analysis showed that the peel strength, glass transition, and softening temperature of the adhesive was greatly reduced with the addition of the surfactants. / Master of Engineering

Magister Pharmaceuticae - MPharm / Background/Introduction: Atopic dermatitis (AD) is one of the most prevalent diseases worldwide. It is a rapidly growing field of study with several research avenues to explore its pathophysiology and to find innovative treatment and management regimens. Clinically, it is classified as a non-contagious, intensely pruritic, inflammatory, chronic skin disorder mediated by abnormalities associated with atopy. Symptoms include inflammation, redness, pain and a negative impact on the patient‘s overall quality of life. Chronic itching often leads to the formation of lichenified skin, which may increase the thickness of the epidermis and exacerbate the barrier function of the skin. AD is treated with topical corticosteroids which help to decrease inflammation. However, lichification of the skin may decrease the efficacy of topical dosage forms. Nanomedicine is a rapidly developing field where advances have been made using ethosomes for topical delivery. As such, corticosteroid loaded ethosomal formulations containing hydrocortiosone acetate (HCA) and betamethasone valerate (BMV) were developed and characterised to develop novel tools for topical drug delivery. Aim: This study aimed at developing corticosteroid loaded ethosomes as a pre-formulation component for inclusion in a topical dosage form. To date, no ethosmal formulation with HCA and BMV has been investigated for topical drug delivery. Method: Ethosomes were synthesised using the hot method and the cold method, a modified version of a double emulsion (o/w/o), solvent evaporation technique, as developed by Touitou et al, 2007.1 Ethosomes were prepared using fixed concentrations of either BMV or HCA (10 mg/ml), ethanol (30% v/v) and purified water (70% v/v) and were comminuted using bath sonication or mini-extrusion. Centrifugation and centrifugal drying were used to purify and isolate the ethosomes for solid state characterisation. The morphology was determined using Scanning electron microscopy (SEM). Ethosomes were characterised using: dynamic light scattering (DLS), Fourier-transform infrared spectroscopy (FTIR), hot stage microscopy (HSM), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The encapsulation efficiency (EE) and drug loading (DL) were determined using validated HPLC methods. Finally, the drug release was determined using Franz diffusion cells and mathematical models were fitted to the % cumulative release data to determine the release kinetics. Results: Ethosomes were assessed according to the following criteria for topical drug delivery which were determined using dynamic light scattering (DLS): Hydrodynamic diameter (HdD), ~ 200 nm, polydispersity index (PdI) < 0.5 and zeta potential (ζp) ± 30 mV. The optimum formulations contained phosphatidylcholine (PC) 50 mg/ml. Extrusion was found to be the best method for particle reduction based on the reproducibility of the results. The HdD was 163.8±31.99 and 147.7±19.91 for BMV loaded ethosomes and HCA loaded ethosomes respectively and both formulations had an acceptable PdI of 0.049 and 0.111, respectively. SEM analyses indicated that the ethosomes had a spherical shape. Encapsulation of the APIs was verified by the thermoanalyses and possible intermolecular interactions were identified using FTIR. BMV loaded and HCA loaded ethosomes had a respective EE of 74.57 % and 37.30 %, and a DL of 14.91 % and 7.46 %, respectively. The release kinetics best fit the Peppas-Sahlin model indicative of an anomalous non-Fickian diffusion coupled with polymer relaxation and zero order release. Conclusions: BMV and HCA loaded ethosomes for topical drug delivery were successfully synthesised and characterised. These novel nanoparticles have provided an array of avenues for further investigation and application in the topical delivery of corticosteroids

This thesis describes the preparation and characterization of core-shell noble metal-magnetite hybrid hollow nanocomposites utilizing hierarchical architecture. The hollow magnetite (hFe3O4) nanoparticles were prepared by hydrothermal method, forming the cavity via Oswald ripening. Further surface modifications involved both inorganic and organic coatings, conferring the intracellular drug delivery ability and the catalytic enhancement. In the first part, a series of hierarchical core-shell nanostructures flower-like hFe3O4@AlOOH was synthesized through solvothermal method and sol-gel process. The formation of cavity accessible hFe3O4@γ-AlOOH was achieved using silica-templated solvothermal treatment where the Kirkendall effect was observed. The morphologies of the as-prepared nanocomposites were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), dynamic light scattering (DLS), thermogravimetric analysis (TGA) and Fourier-transform infrared spectroscopy (FTIR). Then, the nano-encapsulation of platinum drug using hollow magnetite and its derivatives, has been developed with improved loading efficiency via co-solvent system. A dimethylformamide/water co-solvent system was found to be the most efficient system to encapsulate water-insoluble cisplatin. The platinum content was further quantitatively and qualitatively analyzed by inductively coupled plasma mass spectrometry (ICP-MS) and FTIR spectroscopy. The enhancement of loading efficiency could be driven by emulsification due to the diffusion of hydrophobic cisplatin into the hollow cavity of iron oxide nanoparticles. By incorporating water, the loading efficiency of hFe3O4 and hFe3O4@γ-AlOOH increased from 1-2% to 27% and from 6% to 54%, respectively. The grafting of cisplatin on AlOOH nanoflakes might account for the high loading efficiency of flower-like hFe3O4@AlOOH. As a complement to naked hFe3O4, a cell-penetrating poly(disulfide)s (CPD)-decorated hollow iron oxide nanoparticle was synthesized by immobilizing both cysteine and MPTMS as an initiator, followed by in situ polymerization to form hFe3O4-Cys-CPD-CONH2 and hFe3O4-MPS-CPD-CONH2. The morphologies were characterized by TEM/energy-dispersive X-ray spectroscopy (TEM/EDX) and the compositions of the as-prepared iron oxide nanocomposites were characterized by TGA, FTIR and X-ray photoelectron spectroscopy (XPS) and ICP-MS. The CPD coating not only serve as a protective layer, but also prevent the encapsulated cisplatin from a premature release. The hFe3O4-MPS-CPD-CONH2 exhibit promising features for the intracellular delivery of cisplatin, demonstrating a glutathione (GSH)-responsive drug release. Comparing with other hFe3O4 nanoparticles, an enhancement of cellular uptake of hFe3O4-MPS-CPD-CONH2 could be observed by optical microscope, showing rapid accumulation of the hFe3O4-MPS-CPD-CONH2 nanocomposites in the primary human renal proximal tubular epithelial cells (HRPTEpiCs) cell in 2 h. At 24 h, hFe3O4 (F), hFe3O4-MPS (FS) and hFe3O4-MPS-CPD-CONH2 (FSC) together with cisplatin treatment did not cause any significant cytotoxicity to the cells when the particle concentration is less than 10 µg/mL. Interestingly, FSCC showed a certain extent of toxicity with increasing Fe and Pt concentration along with the treated time. It may suggest that the hFe3O4-MPS-CPD-CONH2 nanoparticle, as a cisplatin carrier, could enhance the drug efficiency by increasing cellular uptake of the nanoparticles in HRPTEpiCs together with the boosted cytotoxicity. Based on these data, cisplatin- hFe3O4-MPS-CPD-CONH2 (FSCC) treatments with the concentration less than 20 µg/mL and duration no more than 24 h could maintain around 70% of the cell viability of the HRPTEpiCs. The hypothesis, at which CPD serves as an efficient carrier for intracellular cisplatin delivery, could be confirmed by both microscopic images and the cell viability test. In the second part, a series of Au/Fe3O4 hybrid nanocomposites was prepared to investigate their catalytic efficiencies using 4-nitrophenol reduction as a model system. The flower-like hFe3O4@γ-AlOOH@SiO2-NH2@Au was prepared by using protonated ammonium on hFe3O4@γ-AlOOH@SiO2-NH2 to entangle gold nanoparticles (AuNPs) via electrostatic attraction. In comparison to numerous of catalytic studies, the turnover frequency (TOF) of hFe3O4@γ-AlOOH@SiO2-NH2@Au shows a superior conversion rate up to 7.57 min-1 (4-nitrophenol per Au per min) for the 4-nitrophenol using sodium borohydride as a reductant. A rapid conversion of 4-nitrohpenol was observed using flower like composites that converted the 4-nitrophenol within 2 min. Our result suggests that silica residue hinders the reduction rate of the 4-nitrophenol. A significant deviation from pseudo first order was observed for densely AuNPs-functionalized nanoflower system, hFe3O4@γ-AlOOH@SiO2-NH2@Au2X, which is different from most of the 4-nitrophenol reductions reported in literature. The hFe3O4@γ-AlOOH@SiO2-NH2@Au also demonstrates catalytic activity when heated up to 800 °C before reduction. The recyclability was examined using magnetically recycled hFe3O4@γ-AlOOH@SiO2-NH2@Au, which showed insignificant decrease in the catalytic efficiency. To prove the concept, platinum nanoparticles (PtNPs) immobilized hFe3O4@γ-AlOOH@SiO2-NH2@Pt and hFe3O4@γ-AlOOH@SiO2-NH2@Pt/Au were also prepared via electrostatic attraction to verify the feasibility of endowing modular functionality via post modification.

Delivery of macromolecules into the cytosolic space of eukaryotic cells is a pressing challenge in biopharmaceutics. Macromolecules are often encapsulated into liposomes for protection and improved distribution, but the their size often induces endocytosis of the vehicle at the target site, leading to degradation of the cargo. Listeriolysin O is a key virulence factor of Listeria monocytogenes that forms pores in the endosomal membrane, ultimately allowing the bacterium to escape into the cytosol. This function of LLO has been used to improve cytosolic delivery of liposomally encapsulated macromolecules in a number of instances, but its innate toxicity and immunogenicity have prevented it from achieving widespread acceptance. Through site-directed mutagenesis, this study establishes a mutant of LLO (C484S) with enhanced activity, allowing for a reduction in the amount of LLO used for future applications in liposomal drug delivery.

Delivery of macromolecules into the cytosolic space of eukaryotic cells is a pressing challenge in biopharmaceutics. Macromolecules are often encapsulated into liposomes for protection and improved distribution, but the their size often induces endocytosis of the vehicle at the target site, leading to degradation of the cargo. Listeriolysin O is a key virulence factor of Listeria monocytogenes that forms pores in the endosomal membrane, ultimately allowing the bacterium to escape into the cytosol. This function of LLO has been used to improve cytosolic delivery of liposomally encapsulated macromolecules in a number of instances, but its innate toxicity and immunogenicity have prevented it from achieving widespread acceptance. Through site-directed mutagenesis, this study establishes a mutant of LLO (C484S) with enhanced activity, allowing for a reduction in the amount of LLO used for future applications in liposomal drug delivery.

MS, Pharmaceutical Affairs, Faculty of Health Sciences, University of the Witwatersrand / PEO (Polyethylene Oxide) is one of the most important biodegradable polymers used in pharmaceutical formulations, mainly because of its non-toxicity, high water-solubility and swellability, insensitivity to the pH of the biological medium and flexibility during dosage form production (Kim, 1995; Picker-Freyer, 2006; Kiss et al., 2008). The lack of studies attempting to achieve controlled drug delivery of hydrophilic drugs has provided us with motivation to use a drug of this nature but we have combined it with a PEO-electrolyte combination in order to control drug delivery. This study was aimed at modifying the physicochemical and physicomechanical properties of PEO in order to influence the hydrodynamic diffusion of its three-dimensional network. Hence, through such alteration, it was envisaged that if drug is loaded into its PEO matrix, its solubility and dissolution can be regulated in order to achieve zero-order influx of dissolution medium. The interaction between PEO and electrolytes may allow for precipitation of ions on the polymer backbone. This would lead to the attraction of water molecules to the ions. As a result, this would cause dehydration of the polymer matrix, hence minimising its mobility and relaxation. In this study, 36 PEO-electrolyte combinations were prepared by combining a high molecular weight PEO with different statistically planned combinations of electrolytes. The 36 formulations were microscopically analyzed and subjected to textural analysis. The salted-out PEO-electrolyte combinations were then further selected and analyzed. Assessment of the molecular structural transition and thermal compatibility analysis indicated minimal interaction between the electrolytes and PEO indicating that the polymer-electrolyte combination was stable enough to be employed as a medium for controlled drug release. The polymer-electrolyte combination was combined with a model drug, diphenhydramine HCl to form a tablet matrix and then subjected to dissolution. In vitro drug release varied depending on the different electrolytes and their combinations. The type of polymer, molecular weight of the polymer, concentration of the polymer, different electrolyte combinations and solubility of the drug played a significant role in controlling drug release. After optimization of the fracture force, resilience and work performed values, results have established that equal concentrations of Na2CO3 and K2HPO4 are desirable for achieving controlled release of drug from the salted-out PEO combination in a zero-order manner. Furthermore, Na2CO3 and K2HPO4 had a significant influence on controlling the release of drug from the salted-out PEO combination due to crosslinking between PEO and the electrolytes ultimately leading to zero-order release kinetics. The salting-out of PEO notably modified the physicochemical and micromechanical properties of basic PEO, which demonstrably enhanced the ability of the sample to achieve controlled drug release. The formulation strategy employed in this study where in our sample drug, diphenhydramine HCl was combined with a PEO-electrolyte combination has shown promising results in regulating drug release.