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• W121382810 abstract "Surgical techniques to remove blockages in diseased (atherosclerotic) arteries frequently damage the artery wall. Aggregation of clotting factors and inflammatory cells on the newly exposed surface, and subsequent release of inflammatory mediators, promotes vascular smooth muscle cell (SMC) proliferation, migration and matrix production, and ultimately re-blockage (restenosis) of the artery. Despite the identification of a number of anti-restenotic drugs, most have had limited success clinically, due to problems with delivery. Hence there is wide interest in developing new strategies to prevent or treat restenosis. One emerging strategy uses functional nanoparticles to effectively deliver the active drugs, and shows a number of advantages over other drug delivery systems. The platforms for nanoparticle-based approaches include polymers, liposomes and inorganic nanoparticles. This thesis investigates the feasibility of using inorganic layered double hydroxide (LDH) nanoparticles as an anti-restenotic drug delivery system. The anti-restenotic drug low molecular weight heparin (LMWH) was intercalated into magnesiumaluminium- chloride-layered double hydroxide (MgAl-Cl-LDH) interlayers by the co-precipitation method to form the nanohybrid LMWH-LDH. The intercalation was confirmed by the expansion of interlayer spacing. In vitro release tests (in pH 7.4 PBS at 37 oC) showed a biphasic and sustained profile of LMWH release, with ~20% in the first 12 h and another ~20% over the following 108 h. The mechanism of LMWH release from MgAl-LMWH-LDH nanohybrids was studied by fitting dissolution-diffusion kinetic models, and the results suggested that the release was due to surface diffusion and bulk diffusion via anionic exchange of LMWH anions on the surface or in the interlayer of LDH with anions in the PBS solution. Low cytotoxicity of LDH was evidenced by cell culture showing that SMCs were able to tolerate LDH at concentrations below 50 μg/ml. With the aid of the LDH carrier, the ability of LMWH to inhibit SMC proliferation and migration was significantly enhanced. The enhancement was attributed largely to the increased internalisation of LMWH when conjugated to LDH and the sustained release of LMWH from these LDH-LMWH nanohybrids. Subsequently, the intracellular pathway of LMWH-LDH was investigated. On the basis of the confocal microscopic and transmission electron microscopic observations, we proposed a unique ‘modified endocytic’ pathway, whereby the nanohybrids were internalised by early endosomes within SMC, sorted in late endosomes, then rapidly released from late endosomes/lysosomes, thus avoiding degradation. Further, LMWH released from LDH-LMWH nanohybrids was shown to suppress mitogen-activated protein kinase (MAPK) signal transduction by inhibiting ERK1/2 phosphorylation in a sustained manner, thus indicating a mechanism for the sustained antiproliferative effects. LMWH-LDH was then intercalated with antibody (1D2)-conjugated LMWH to produce 1D2- LMWH-LDH conjugates for targeted delivery of LMWH-LDH to injured arteries in a rat model of balloon angioplasty. The conjugation was successfully performed using (4-[4-Nmaleimidophenyl] butyric acid hydrazide hydrochloride) (MPBH) as a linker. 1D2 is an antibody to cross-linked fibrin (anti-XLF) that recognises the site of arterial injury. 1D2-LMWH-LDH was then administered to carotid arteries of rats immediately following balloon catheter injury. The targeting capability of 1D2 for LMWH-LDH delivery was confirmed with the aid of quantum dots labelling. Although the number of rats analysed to date was too low to obtain statistical significance, the data showed that lesion size (the intima to media ratio) in carotid arteries treated with 1D2-LMWH-LDH was reduced in comparison with that in control groups treated with LMWH, LMWH-LDH, and irrelevant mouse immunoglobulin conjugated LMWH-LDH. In summary, this thesis demonstrates, both in vitro and in vivo, the potential of an inorganic LDH nanoparticle-based drug delivery system for anti-restenotic therapies." @default.
• W121382810 created "2016-06-24" @default.
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• W121382810 date "2011-03-01" @default.
• W121382810 modified "2023-09-27" @default.
• W121382810 title "Inorganic Layered Double Hydroxide Nanoparticle-based Anti-restenotic Drug Delivery System" @default.
• W121382810 hasPublicationYear "2011" @default.
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