Effective treatment of ocular diseases presents a formidable task, dually attributed to their nature, and the presence of the ocular barriers. This was exemplified in the presented review of developments in ocular drug delivery systems. Conceptualization of novel polymeric systems with intelligent (e.g. stimulus-responsive) mechanisms and advances in nanotechnology are at the forefront of achieving directed and controlled delivery for treating vision-threatening diseases. It was thus the pertinent goal of this investigation to assimilate these observations in the design of an intelligent ocular drug delivery system. The design of an autofeedback polymeric platform, employing biodegradable polymers is exemplified through the implementation of two-way communication systems between our bodies and the delivery platform to create innovative drug delivery systems that recognize a biochemical process that is characteristic of a disease, and then responding via drug release. To achieve this intelligence in design, the delivery platform was based on novel stimulus-responsive polymeric materials. The concept of an autofeedback polymeric platform was intrinsically implemented in the design of an intelligent intraocular implant - called the I3 - employing inflammation-responsive polymers, having application as a smart release system capable of delivering controlled therapeutic levels of anti-inflammatory and/or antibiotic drug/s for posterior segment disorders of the eye in response to inflammation and infection. Inner and outer bioresponsive polymeric matrices (BPMs) were designed that released the incorporated anti-inflammatory and antibiotic in a fashion responsive to a stimulus, such as the highly reactive intermediates including hydroxyl radicals (OH.) that are released from activated leukocytes both in vitro and during acute and chronic intraocular inflammatory reactions in vivo (Hawkins and Davies, 1996).
The first step in developing the intelligent device implicated design of an anti-inflammatory nanosystem (NS) with satisfactory size and surface properties, adequate permeation potential, uptake by inflamed cells, low cellular toxicity, and enhanced anti-inflammatory effect availed to the incorporated drug. A composite lipoidal-polymeric NS was developed (Lipo-Chit-PCL NS) and compared to a purely polymeric NS. The NS was ultimately enclatherated as a NS-polymer superlattice, forming the inner BPM of the I3. The designed composite lipoidal-polymeric NS attested its significant potential for selective drug delivery to inflamed tissues, demonstrating significantly enhanced tissue permeation, cell uptake, and anti-inflammatory activity compared to an indomethacin suspension. Subsequent molecular modeling revealed that the composite NS displayed an enhanced lipophilicity and superior cellular internalization efficiency. The preferred NS was subsequently selected for optimization via a Plackett-Burman Statistical Design Method.
Design of the NS was proceeded by development and optimization of the inner and outer BPMs, being the stimulus-responsive component of the device, via implementation of a novel methodology for simultaneous design of the two intimately crosslinked matrices. Inflammation-responsive polymers such as hyaluronic acid, alginate, poly(acrylic) acid, and chitosan, were ultimately selected for design of the I3drug delivery system. Intensive device optimization was then undertaken, first employing a Response Surface Methodology, embodied by the Box-Behnken Design, ensued by Artificial Neural Networks. Characterization of the drug release kinetics from the optimized I3 is pivotally provided, as well as molecular modeling. The reagent (N-hydroxysuccimide, NHS) and catalyst employed (aluminium chloride, AlCl3) had a significant or notable effect on the mean dissolution time of indomethacin under normal and pathological conditions, respectively (p=0.048; p=0.058). The interaction between the inflammation-responsive hyaluronic acid and carbodiimide crosslinker emanated in a significant effect on the change in mean dissolution time of indomethacin from normal to inflammatory conditions (p=0.050). Subsequent execution of ANN with further training of the data confirmed the adequacy of the design. Analysis of the drug release kinetics from the optimum I3 under both normal and pathological conditions was in coherence with the anticipated behavior of an inherently bioresponsive device. Molecular simulations generated provided clear evidence for the catalytic effect of the hydroxyl radicals, specifically in hyaluronic acid hydrolysis.
It was imperative to elucidate the intricate modus operandi of the optimized I3. The intricately crosslinked polymeric system comprising the I3 responds at an innate level predicted by its molecular make-up to inflammatory conditions as indicated by the results of the rheological analysis, MRI and SEM imaging. FTIR explicated the formation of pivotal intra- and intermolecular bonds within and between the inflammation-responsive polymers of the I3, while TMDSC confirmed the extent to which the composite polymeric system had altered from its native consituents to form a device of the desired functionality. Tensile analysis provided an indication of the overall mechanical performance of the implant. The porosity ascertained for both the inner and outer BPMs was a predictor of the overall internal architecture and potential drug release characteristics of the BPMs comprising the I3, as were critical morphological changes, visualized via SEM and interpreted via image analysis displayed during device erosion. Furthermore, molecular mechanics simulations were carried out to model the interaction between the polymeric components of the inner and outer BPM and confirmed the formation of a ‘secure-fit’ dual polymeric matrix system by highlighting the anticipated interconnectivity between the inner and outer BPM of the I3.
The in vivo performance of the device was assessed to further provide a convincing argument as to the ocular suitability and overall contrasting performance under normal and inflammatory conditions. Histological assessment was key to predicting significant inflammatory changes, as well as reductions in inflammation initiated by the I3. Analysis of ocular drug levels under normal and inflammatory conditions was undertaken for correlation with in vitro results, for ultimate establishment of an in-vitro-in-vivo correlation (IVIVC). The device was well-tolerated following implantation in the rabbit eye. Investigations of drug concentrations attained and device erosion were a good indication that the I3 expresses bioresponsive capabilities in vivo. There was enhanced release of both drugs in the inflamed rabbit eye even after 7 days (the maximum period in which the induced inflammation was permitted to ensue), with indomethacin levels of 0.749±0.126μg/mL and 1.168±0.186μg/mL, and ciprofloxacin levels of 1.181±0.150μg/mL and 6.653±0.605μg/mL being attained in the normal and inflamed eye, respectively. At 28 days in the normal eye, concentrations of indomethacin detected were only 0.564±0.111μg/mL and those of ciprofloxacin were 1.226±0.209μg/mL. Furthermore, the enhanced erosion of the I3 in the inflamed eye is also exemplified, with the I3 eroding 1.504±0.505% in the normal eye and 22.609±2.421% in the inflamed eye after 7 days; and only reaching 13.830±1.010% erosion after 28 days in the normal rabbit eye. Elaboration of the IVIVC undertaken for both indomethacin and ciprofloxacin approached or attained a Level A correlation, respectively, and provided further evidence for the feasibility of the I3 and for advancement of this concept toward application in a clinical setting. Establishment of such a correlation for the inflamed rabbit eye would be the main consideration in prospective investigations.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/14573 |
| Date | 23 April 2014 |
| Creators | Du Toit, Lisa Claire |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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