One of the main problems of current cancer chemotherapy is the lack of selectivity of anti-cancer drugs to tumor cells which leads to systemic toxicity and adverse side effects. In order to overcome these limitations, researches on controlled drug delivery systems have gained much attention. Nanoscale based drug delivery systems provide tumor targeting. Among many types of nanocarriers, superparamagnetic nanoparticles with their biocompatible polymer coatings can be targeted to an intented site by an external magnetic field. Thus, the drug can be carried to the targeted site safely. The aim of this study is to prepare poly(dl-lactic-co-glycolic acid) (PLGA) coated magnetic nanoparticles and load anti-cancer drug, doxorubicin to them. For this purpose, magnetite (Fe3O4) iron oxide nanoparticles were synthesized as a magnetic core material (MNP) and then coated with oleic acid. Oleic acid coated MNP (OA-MNP) was encapsulated into PLGA. Effects of different OA-MNP/PLGA ratios on magnetite entrapment efficiency were investigated. Doxorubicin loaded magnetic polymeric nanoparticles (DOX-PLGA-MNP) were prepared. After the characterization of prepared nanoparticles, their cytotoxic effects on MCF-7 cell line were studied. PLGA coated magnetic nanoparticles (PLGA-MNP) had a proper size and superparamagnetic character. The highest magnetite entrapment efficiency of PLGA-MNP was estimated as 63 % at 1:8 ratio. Cytotoxicity studies of PLGA-MNP did not indicate any notable cell death between the concentration ranges of 2 and 250 &mu / g ml-1. It was observed that DOX-PLGA-MNP showed significant cytotoxicity on MCF-7 cells compared to PLGA-MNP. The results showed that prepared nanoparticles have desired size and superparamagnetic characteristics without serious toxic effects on cells. These nanoparticles may be suitable for targeted drug delivery applications. The findings obtained from drug studies may contribute to further work.

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Growth plate is a highly organized cartilaginous tissue found at the end of long bones and is responsible for longitudinal growth of the bones. Growth plate fracture leads to retarded growth and unequal limb length, which might have a lifelong effect on a person’s physical stature. This research is a tissue engineering approach for the treatment of growth plate injury. Insulin-like growth factor I (IGF-I), which can stimulate cartilage formation, was encapsulated within PLGA microspheres that were then used to form porous scaffolds. The release profile of the IGF-I from the PLGA scaffold showed a biphasic release pattern. In vitro studies were done by seeding rat bone marrow cells (BMCs) on the top of IGF-I encapsulated PLGA scaffolds, and the results showed an increase in cell multiplication and glycosaminoglycan content. The final in vivo studies were conducted by creating growth plate injury and implanting scaffolds in the tibiae of the New-Zealand white rabbits. Histological analysis of tissue sections showed regeneration of cartilage, albeit with disorganized structure, at the site of implantation of IGF-I encapsulated scaffolds. This work will be a significant step towards tissue engineering of growth plate cartilage.

Nanoparticles have received special attention over past few years as potential drug carriers for proteins/peptides and genes. Biodegradable polymeric poly (lactic-co-glycolic acid) (PLGA) nanoparticles are being employed as non-viral gene delivery systems for DNA. This work demonstrates a scalable technology for synthesis of nanoparticles capable of gene delivery. Cationic PLGA nanoparticles are produced by emulsiondiffusion- evaporation technique employing polyvinyl alcohol (PVA) as stabilizer and chitosan chloride for surface modification. A sonicator is used for the emulsion step and a static mixer is used for dilution in the diffusion step of the synthesis. A static mixer is considered ideal for the synthesis of PLGA nanoparticles as it is easily scalable to industrial production. The resulting nanoparticles are spherical in shape with size in the range of 100–250 nm and posses a zeta potential above +30 mV, indicating good stability of the colloid with a positive charge to bind to anionic DNA. The mechanism of nanoparticle formation was analyzed using multimodal size distributions (MSD), zeta potential data, and transmission electron microscopy (TEM) images. Several emulsion techniques and dilution effect were analyzed in this work. PVA acts as a compatibilizer for chitosan chloride and dilution of primary emulsion has little effect over the particle size of the PLGA nanoparticles.

Spinal fusion is used to treat diseases or disorders of the spine by fusing together two or more vertebrae. Two associated risks with spinal fusion are infection and blood loss. Administration of tranexamic acid is used to prevent blood loss, and transfusions are given following blood loss. Surgical site infections are prevented with vancomycin powder spread into the surgical wound, while established infections are treated by debridement and delivery of antibiotics for 4 to 6 weeks. The present research explored an alternate method to prevent and treat blood loss or infection in spinal fusion. Poly(lactic-co-glycolic acid) (PLGA) microspheres was used to encapsulate vancomycin for 42 days to treat infection. Vancomycin encapsulated in gelatin microspheres had a controlled release of 7 days to prevent infection. Tranexamic acid was dissolved into phosphate-buffered saline or carboxymethylcellulose to provide a release of 6 hours to prevent blood loss after surgery. The microspheres and tranexamic acid were delivered to a target region using a water based spray system. The spray system demonstrated the delivery and distribution of drugs to a target region. The microsphere spray system is capable of spraying drugs onto a target region to prevent or treat blood loss and infection over time.

Tuberculosis (TB) is an infectious, deadly disease, caused by Mycobacterium tuberculosis (M.tb). In 2010, there were 8,8 million incident cases of TB globally. South Africa currently has the third highest TB incident cases worldwide. In an attempt to address the challenges facing TB chemotherapy, among which frequent dosing and long duration of therapy resulting in poor patient compliance, a novel poly(DL-lactic-co-glycolic) acid (PLGA) nanoparticulate drug delivery system (DDS) encapsulating anti-TB drugs was developed. It is hypothesised that this nanoparticulate DDS will address the challenges mentioned by enabling decreased dosing frequency, shortening duration of therapy and minimising adverse side effects. Therefore, favourable modification of pharmacodynamic (PD) and pharmacokinetic (PK) properties of the conventional anti-TB drugs was demonstrated. Furthermore, the nanoparticles will provide a platform for drug delivery to macrophages that serve as hosts for M.tb. The study design was based on determining specific physicochemical properties of the nanoparticulate DDS to elucidate the hypothesis. Spray-dried PLGA nanoparticles were prepared using the double emulsion solvent evaporation technique. In vivo analysis of macrophage uptake and possible immunological response in mice were evaluated. In vitro protein-binding assays of PLGA nanoparticles encapsulating anti-TB drugs isoniazid (INH) and rifampicin (RIF) were performed with subsequent in vivo tissue distribution assays to support protein-binding data generated. Finally, PK/PD analyses were conducted to evaluate the effect of nanoencapsulation on the anti-TB drugs. These involved in vitro assays to determine if sufficient drug was released from the nanoparticles to exhibit minimum inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC). Furthermore, in vivo drug distribution and drug release kinetics assays of encapsulated RIF, INH, pyrazinamide (PZA) and ethambutol (ETB) in a mouse model were performed. The results confirmed that the PLGA nanoparticles (<250 nm, low positive zeta potential) were taken up by macrophages in vivo with no significant immunological effect. Furthermore the nanoparticles were present in the brain, heart, kidneys, lungs, liver and spleen for up to 7 days following once-off oral dosing at 13.23± 0.11%, 16.81± 0.11%, 54.89± 0.95%, 15.61± 1.15%, 48.48± 2.28% and 5.73± 0.21%, respectively. This was further confirmed by drug analysis demonstrating the presence of INH, RIF and ETB at different time points up to 7 days in the lungs, kidneys, liver and spleen. However, PZA was not detected. Nanoencapsulated RIF and INH exhibited MICs and MBCs in vitro over 14 days and these drugs were also observed in plasma for up to 7 days post once-off oral dosing. ETB and PZA were observed up to 3 days. From the results generated, it can be concluded that the nanoparticles were taken up by macrophages without eliciting an immune response. This provides a platform for drug delivery to specific sites. Furthermore, the nanoparticulate DDS exhibited sustained drug release in vitro and in vivo over a number of days above the MIC for the drugs analysed. Sustained drug distribution was also observed. It can therefore be concluded that the hypothesised reduction in dose frequency and duration of therapy for this DDS is a possibility / Thesis (PhD (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

Tuberculosis (TB) is an infectious, deadly disease, caused by Mycobacterium tuberculosis (M.tb). In 2010, there were 8,8 million incident cases of TB globally. South Africa currently has the third highest TB incident cases worldwide. In an attempt to address the challenges facing TB chemotherapy, among which frequent dosing and long duration of therapy resulting in poor patient compliance, a novel poly(DL-lactic-co-glycolic) acid (PLGA) nanoparticulate drug delivery system (DDS) encapsulating anti-TB drugs was developed. It is hypothesised that this nanoparticulate DDS will address the challenges mentioned by enabling decreased dosing frequency, shortening duration of therapy and minimising adverse side effects. Therefore, favourable modification of pharmacodynamic (PD) and pharmacokinetic (PK) properties of the conventional anti-TB drugs was demonstrated. Furthermore, the nanoparticles will provide a platform for drug delivery to macrophages that serve as hosts for M.tb. The study design was based on determining specific physicochemical properties of the nanoparticulate DDS to elucidate the hypothesis. Spray-dried PLGA nanoparticles were prepared using the double emulsion solvent evaporation technique. In vivo analysis of macrophage uptake and possible immunological response in mice were evaluated. In vitro protein-binding assays of PLGA nanoparticles encapsulating anti-TB drugs isoniazid (INH) and rifampicin (RIF) were performed with subsequent in vivo tissue distribution assays to support protein-binding data generated. Finally, PK/PD analyses were conducted to evaluate the effect of nanoencapsulation on the anti-TB drugs. These involved in vitro assays to determine if sufficient drug was released from the nanoparticles to exhibit minimum inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC). Furthermore, in vivo drug distribution and drug release kinetics assays of encapsulated RIF, INH, pyrazinamide (PZA) and ethambutol (ETB) in a mouse model were performed. The results confirmed that the PLGA nanoparticles (<250 nm, low positive zeta potential) were taken up by macrophages in vivo with no significant immunological effect. Furthermore the nanoparticles were present in the brain, heart, kidneys, lungs, liver and spleen for up to 7 days following once-off oral dosing at 13.23± 0.11%, 16.81± 0.11%, 54.89± 0.95%, 15.61± 1.15%, 48.48± 2.28% and 5.73± 0.21%, respectively. This was further confirmed by drug analysis demonstrating the presence of INH, RIF and ETB at different time points up to 7 days in the lungs, kidneys, liver and spleen. However, PZA was not detected. Nanoencapsulated RIF and INH exhibited MICs and MBCs in vitro over 14 days and these drugs were also observed in plasma for up to 7 days post once-off oral dosing. ETB and PZA were observed up to 3 days. From the results generated, it can be concluded that the nanoparticles were taken up by macrophages without eliciting an immune response. This provides a platform for drug delivery to specific sites. Furthermore, the nanoparticulate DDS exhibited sustained drug release in vitro and in vivo over a number of days above the MIC for the drugs analysed. Sustained drug distribution was also observed. It can therefore be concluded that the hypothesised reduction in dose frequency and duration of therapy for this DDS is a possibility / Thesis (PhD (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

Antibiotic use is a vital method for the treatment of most diseases involving bacterial infections. Unfortunately, in certain cases these agents are not effective in treatments against diseases for either some limitation in antibiotic usage because of the side effects or some distribution problems caused by physiological or pathological barriers in the body. Such problems are thought to be minimized by development of controlled release systems which involve implantation of antibiotic loaded polymeric systems directly to the site of infection. Present study involves Vancomycin, a very strong antibiotic with a wide spectrum of activity, and two biocompatible and biodegradable polymers, poly(3-hydroxybutyrate-co-3-valerate) PHBV and poly(L-lactide-co-glycolide) PLGA, in the construction of rod shaped controlled release systems designed for the aim of local treatment of osteomyelitis. Vancomycin carrying rods of either PHBV 8 or PLGA (50:50) polymers were prepared by the use of cold paste and hot extrusion methods in two different loading ratios (2:1 and 1:1 P:V). In situ release kinetics of each type of rod was determined by spectrophotometric measurement of vancomycin concentration. For determination of drug content of the controlled release rods initially and at the end of the release experiments, extraction and IR (infrared) studies were carried out. The efficacy of the system was measured in vitro on the bacterial strain, B. subtilis. Characterization of the rods was made by the use of stereomicroscopy and SEM (scanning electron microscopy). In situ release results of the controlled Vancomycin release formulations revealed that for both polymer types, hot extrusion process enabled the formation of a more compact system that provided slower release of the agent compared to the cold paste method. With the combined effect of variable loading proportion and polymer type the most prolonged release was obtained by PHBV rods having 2:1, P:V, ratio (prepared by hot extrusion method). In general, the release kinetics from the rods obeyed the Fickian diffusion kinetics except for PLGA rods prepared by cold paste method with 1:1 and 2:1 (P:V) loading ratios, which had a first order rate of drug release. According to in vitro bioactivity assays, all the groups effectively inhibited bacterial growth with the first day release samples. On the seventh day, however, only two cold paste samples, PHBV:Vancomycin 1:1 and PLGA:Vancomycin 1:1 had drug content barely sufficient for MEC while the others were in the ineffective range. The IR and grinding-extraction studies proved that Vancomycin was still present within the rods after a ten day release period. The PHBV rods with 2:1 (P:V) ratio prepared by hot extrusion method seem to be the most promising drug delivery system in terms of providing prolonged release as an implantable drug delivery system for the treatment of bacterial infections of the bone, namely osteomyelitis.

A conformação de dispositivos médicos implantáveis a partir de uma blenda exige o desenvolvimento de um produto com propriedades próximas do comportamento ideal, combinando propriedades térmicas e mecânicas e boa resposta tecidual. O Poli (ácido láctico-co-glicólico) (PLGA) e o Poli (isopreno) (IR) foram escolhidos como componentes da blenda com finalidade de promover boa biocompatibilidade e características mecânicas especificas. As blendas foram obtidas por dissolução dos polímeros em solvente orgânico, seguida de secagem. Para determinar a influência do teor de IR sobre as propriedades da blenda, foram realizados ensaios de espectroscopia na região de infravermelho por transformada de Fourier (FTIR), calorimetria diferencial de varredura (DSC), análise dinâmico-mecânica (DMA), microscopia óptica por luz polarizada (POM), análise de dureza, ensaio de tração e análise de viabilidade celular. A presença de IR na blenda provocou alteração na estrutura molecular semi-cristalina do PLGA, bem como influenciou o comportamento mecânico analisado a partir da curva tensão-deformação do material. A blenda se mostrou biocompativel em ambiente celular e em ensaios preliminares em animais, apresentando potencial para aplicação como biomaterial. / The conformation of an implantable medical device from a polymeric blend requires the development of a product with properties as close as possible of ideal behavior with the combination between thermal and mechanical properties and good tissue response. The poly (lactic-co-glycolic acid) (PLGA) and the poly (isoprene) (IR) were chosen as the blend components to promote good biocompatibility and specific mechanical characteristics. The blends were obtained by dissolution of polymers in organic solvent, followed by drying. In order to determine the IR content influence over the blend properties, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), polarized light optical microscopy (POM), hardness analysis, tensile test and cell viability test were carried out. The IR presence caused changes in semi-crystalline molecular structure of PLGA, as well as actuated over the mechanical response analyzed on material’s stress-strain curve. The blend showed itself biocompatible at cellular environment and at preliminary animal tests, presenting potential for application as biomaterial.

A conformação de dispositivos médicos implantáveis a partir de uma blenda exige o desenvolvimento de um produto com propriedades próximas do comportamento ideal, combinando propriedades térmicas e mecânicas e boa resposta tecidual. O Poli (ácido láctico-co-glicólico) (PLGA) e o Poli (isopreno) (IR) foram escolhidos como componentes da blenda com finalidade de promover boa biocompatibilidade e características mecânicas especificas. As blendas foram obtidas por dissolução dos polímeros em solvente orgânico, seguida de secagem. Para determinar a influência do teor de IR sobre as propriedades da blenda, foram realizados ensaios de espectroscopia na região de infravermelho por transformada de Fourier (FTIR), calorimetria diferencial de varredura (DSC), análise dinâmico-mecânica (DMA), microscopia óptica por luz polarizada (POM), análise de dureza, ensaio de tração e análise de viabilidade celular. A presença de IR na blenda provocou alteração na estrutura molecular semi-cristalina do PLGA, bem como influenciou o comportamento mecânico analisado a partir da curva tensão-deformação do material. A blenda se mostrou biocompativel em ambiente celular e em ensaios preliminares em animais, apresentando potencial para aplicação como biomaterial. / The conformation of an implantable medical device from a polymeric blend requires the development of a product with properties as close as possible of ideal behavior with the combination between thermal and mechanical properties and good tissue response. The poly (lactic-co-glycolic acid) (PLGA) and the poly (isoprene) (IR) were chosen as the blend components to promote good biocompatibility and specific mechanical characteristics. The blends were obtained by dissolution of polymers in organic solvent, followed by drying. In order to determine the IR content influence over the blend properties, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), polarized light optical microscopy (POM), hardness analysis, tensile test and cell viability test were carried out. The IR presence caused changes in semi-crystalline molecular structure of PLGA, as well as actuated over the mechanical response analyzed on material’s stress-strain curve. The blend showed itself biocompatible at cellular environment and at preliminary animal tests, presenting potential for application as biomaterial.