No description available.

Liposomes are small phospholipid vesicles that have been widely investigated as drug carriers for the delivery of therapeutic agents. A variety of liposome formulations are presently under clinical trial exploration, while others have already been approved for clinical use. The aim of this study was to optimize liposome uptake into bacterial cells. Both gram-positive and gram-negative bacteria were used in the study as well as Candida albicans.Response surface methodology (RSM) using a central composite design (CCD) model was used to optimize liposomal formulations of carboxyfluorescien (CF) for each of the three microbes, and also the three microbes in combination namely; Staphylococcus aureus (Sa), Escherichia coli (Ec) and Candida albicans (Ca). Percentage of CF encapsulated and CF increase in Uptake were investigated with respect to two independent variables that were, cholesterol (CHOL) and stearylamine (SA) content. Design Expert 8 was used for the purpose of finding the combination of independent variables that would yield an optimal formulation for each microbe and the three microbes in combination. The model selected by the software managed to reasonably correlate the predicted models to the experimental data. Encapsulation of carboxyfluorescien (CF) into a liposome formulation enhanced its uptake by Staphylococcus aureus and Escherichia coli as well as Candida albicans. This was evident in the increase in CF uptake when the uptake rate of free CF was compared with that of liposomal CF.

No description available.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfillment of the requirements for the degree of Doctor of Philosophy / Alzheimer’s disease (AD) is the most prevalent and progressive neurodegenerative disorder (ND). It is characterized by a progressive decline of cognitive function, complete loss of memory, deterioration of visual capacity and the inability to function independently. According to the World Health Organization (WHO) it is estimated that about 26 million people suffer with AD worldwide. Although the etiology of AD is not fully understood, the aggregation of β-amyloidal (A) peptides that are associated with the formation of extracellular neurotoxin senile plaques and neurofibrillary tangles comprising hyperphosphorylated tau proteins have been recognized as the primary constituents that play a crucial role in AD. Several potential neurotherapeutic agents that can improve the management of AD such as metal chelators and alkaloid drugs have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Metal chelators [e.g. histidine, Ethylenediaminetetraacetic acid (EDTA) and zinc acetate (ZnAc)] are the main therapy used for modulating Aβ peptide aggregation with biological metals (such as zinc and copper ions) which is associated with promoting neurotoxicity in AD. While alkaloid drugs, such as donepezil, galantamine and rivastigmine, are used to inhibit the enzyme acetylcholinesterase (AChE); memantine is used to block the N-methyl-D-aspartate (NMDA) receptors associated with pathological activation. Despite the availability of these indispensable drugs, the clinical utility of these drugs is hampered by their poor retention and difficulty in bypassing the highly restrictive Blood Brain Barrier (BBB). Therefore this study aimed at developing novel nanoliposomes (NLPs) surface-engineered with chelating and synthetic peptides that are capable of crossing the BBB thus improving delivery efficacy and modulating the extracellular neurotoxicity associated with β-Amyloid aggregates of AD. Furthermore, since this system was designed for a chronic condition, a temporary depot-based polymeric system was integrated for further enhancement of the liposomal half-life, storage and prolonged drug delivery over a period of 50 days. The surface-engineered NLPs produced were spherical in shape, 100-149±28nm ~ size, with a zeta potential range of -9.59 to -37.3mV and a polydispersity index (PdI) of 0.02-0.2. A Box-Behnken experimental design was employed for maximizing the ligand coupling efficiency (40-78%) and drug entrapment efficiency (DEE) that ranged from 42-79%. The optimized peptide-based ligand NLP formulation showed sustained drug release (30% of drug released within 48 hours). Chelating ligands on the surface of NLPs showed 50-68% modulation of neurotoxicity on PC12 neuronal cells induced by ZnAβ (1-42) or CuAβ (1-42) aggregates. When drug-loaded functionalized NLPs were embedded within the temporal hydrophilic hydrogel network/scaffold as an implantable nano-enabled bio-robotic intracranial device (BICD), the physicomechanical and physicochemical dynamics showed improvement of liposomal structure such as the stability, and homogeneity in distribution of the liposomes within the internal core of the hydrogel networks and post-lyophilized scaffold. In vitro studies in simulated cerebrospinal fluid (CSF) showed prolonged release behavior of the drug-loaded functionalized NLPs from the BICD with 50-70% released over 50 days. Scanning Electron Microscopy (SEM) and confocal microscopy confirmed intact liposomal structures within the temporal polymeric scaffold/depot post-fixation and post-lyophilization. Ex vivo studies confirmed cell proliferation and a low level of lactate dehydrogenase (LDH), which is associated with cell membrane damage/injury, after PC12 neuronal cells were exposed to the BICD. In addition, when PC12 neuronal cells were exposed to the BICD high accumulation of galantamine (GAL) into these PC12 neuronal cells was observed post-cultivation. This outcome indicated that the released drug-loaded functionalized NLPs from the BICD were still in their intact form and capable of serving as bio-robotic markers for the delivery of GAL into the neuronal cells in response to AD. Furthermore, intracellular activity validated that the synthetic peptide has the potency for targeted delivery of the drug-loaded NLPs post-release of the BICD in ex vivo studies. Overall, results from this study revealed that the BICD device had superior cytocompatibility and may be suitable for application as a prolonged and targeted delivery system for GAL into neuronal cells to treat AD.

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No description available.

Thesis (M.S.)--University of Toledo, 2010. / Typescript. "Submitted to the Graduate Faculty as partial fulfillment of the requirements of the Master of Science degree in Pharmaceutical Sciences with Industrial Pharmacy Option." "A thesis entitled"--at head of title. Title from title page of PDF document. Bibliography: p. 87-102.

No description available.

Delivery of complex molecules such as peptides, proteins, oligonucleotides and plasmids is an intensively studied subject, which has attracted considerable medical and pharmaceutical interest. Encapsulation of these molecules with biodegradable polymers represents one way of overcoming various problems associated with the conventional delivery of macromolecules, for example instability and short biological half-life. The use of carriers made of hydrophilic polysaccharides such as chitosan, has been pursued as a promising alternative for improving the transport of biologically active macromolecules across biological surfaces. The development of nanoparticles as a delivery system also has major advantages of achieving possible drug protection, controlled release and drug targeting by either a passive or an active means. The aim of this study was to develop a simple and effective method to formulate biodegradable nanoparticles for the delivery of a model protein-bovine serum albumin (BSA) and an angiogenesis inhibitor, arginine-rich hexapeptide (ARE peptide). Major factors which determine nanoparticle formation and loading of the protein and the peptide as well as the underlying mechanisms controlling their incorporation and release characteristics were investigated. The preparation technique, based on the complex coacervation process, is extremely mild and involves the mixture of two aqueous solutions (chitosan and dextran sulfate) at room temperature. The formation of nanoparticles is dependent on the concentrations of chitosan (CS) and dextran sulfate (DS); particles with size, of 257 to 494nm can be obtained with 0.1%w/v solutions of CS and DS. Zeta potential of nanoparicles can be modulated conveniently from -34.3mV to +52.7mV by varying the composition of the two ionic polymers. / Both bovine BSA and the ARH peptide were successfully incorporated into CS-based nanoparticles, mainly via an electrostatic interaction, with entrapment efficiency up to 100% and 75.9% for the protein and peptide respectively. Incorporation of both the protein and peptide into nanoparticles resulted in an increase in size suggesting their close association with the nanoparticle matrix material. The difference in sign and magnitude of zeta potential of empty and macromolecules-loaded nanoparticles supports the hypothesis that protein and peptide association with nanoparticles can be modulated by their ionic interaction with the oppositely charged ionic polymer (DS) in the nanoparticles. The release of BSA from the nanoparticles was very slow in water compared to that in l0mM phosphate buffer pH 7.4; whereas, ARH peptide showed extremely low level of release in water at the low ratio of DS but at the high ratio of DS, its release was in biphasic fashion, with an initial burst effect followed by an almost constant but very slow release up to 7 days in both water and 1 OmM phosphate buffer (pH 7.4). It was found that, unlike ARH peptide, the percentage of BSA released was relatively slower for the nanoparticles with a high ratio of DS. It is speculated that this difference in the release behaviour of BSA and ARH peptide, could be due to the effect of molecular size of the compounds and their interaction with the polymer matrix of the nanoparticle. The results of this study suggest that these novel CS/DS nanoparticulate system, prepared by a very mild ionic crosslinking technique, have potential to be a suitable carrier for the entrapment and controlled release of peptides and proteins.

Thesis (Ph. D.)--Ohio State University, 2006. / Full text release at OhioLINK's ETD Center delayed at author's request