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Title: An implantable hydrogel for the delivery of cisplatin and the ex vivo neurotoxic, neuromyopathic and cardiotoxic activity of platinum-based anticancer drugs and macrocyclic drug delivery systems
Author: Oun, Rabbab Hadi
ISNI:       0000 0004 5367 6602
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2015
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Abstract:
Cisplatin iscurrently aleading anticancer drug used in the treatment of various cancers. Its clinical use, however, is limited by its poor bioavailability, its undesirable toxic side effects profile and by the ability of certain tumours to develop cisplatin resistance. A method that may overcome these problems is the reversible encapsulation of cisplatin within the cavity of a macro cyclic container such as cucurbit[7]uril; a macrocycle formed by the acid condensation of glycoluril and formaldehyde, which has been shown to overcome acquired resistance in an in vivo human tumour xenograft model via a pharmacokinetic effect. In the first section of this thesis an implantable hydrogel based system was developed for the delivery of cisplatin and cisplatin@CB[7]. First, cisplatin was encapsulated within cucucrbit[7]uril (CB[7]) to form the host-guest complex: cisplatin@CB[7]. This was then incorporated into gelatin and 0-4% w/v polyvinyl alcohol (PVA)-based hydrogels as slow release drug delivery systems. In vitro studies of the hydrogels demonstrated predictable yet not significant swelling and disintegration dependent on their PVA concentration. The hydrogel with the highest PVA content was slower to swell and release drug compared with hydrogels containing lower concentrations of PVA. The effect of the hydrogel's PVA concentration on in vitro cytotoxicity was examined using A2780/CP70 ovarian cancer cells with results showing a significant reduction in cytotoxicity as the hydrogel's PVA concentration increased which indicated that a slow release system was achieved. Over the 24 hours of drug exposure time used, hydrogels containing 4% PVA loaded with 1mM of cisplatin@CB[7] showed a 19 ± 0.01% (p = 0.004) decrease in viable cells compared to the control, whereas hydrogels containing 0% and 2% PVA induced an 81.2 ± 0.003% (p = 0.0005) and 42 ± 0.02% (p = 0.0002) inhibition of cell growth, respectively. Finally, the in vivo efficacy of a 2% PVA hydrogel implanted under the skin of nude mice bearing A2780/CP70 xenografts showed that low dose hydrogels containing cisplatin@CB[7] (30 μg equivalent of drug) was just as effective as an intraperitoneal high dose administration of free cisplatin (150 μg) at inhibiting tumour growth. Overall, the results suggest an ability of implantable hydrogels to treat cancers with much lower doses of drug, thereby reducing the severity of the toxic side effects induced. In the second section of this thesis, cisplatin, CB[7] and cisplatin@CB[7] were tested and compared for their ex vivo neurotoxic, neuromyopathic and cardiotoxic activity amongst other platinum-based drugs (K₂PtCl₄, 56MESS and PHENEN) and macrocyclic drug delivery systems (CB[6], β-cyclodextrin, Motor2 and pentamer) using electrophysiological methods. The neurotoxic activity of the drugs was studied using mouse desheathed sciatic nerve preparations. Both cisplatin and CB[7] administered at a concentration of 300 μM decreased the amplitude of the nerve compound action potential (nCAP) by 13 ± 4.7% ( p = 0.3) and 4 ± 0.2% ( p = 0.8), respectively over an 80 minute period. Neuromyopathic activity was studied using the chick biventer cervicis nerve muscle preparation. Results showed that incubation of the nerve-muscle tissue with 300 μM of cisplatin caused statistically significant muscle paralysis to occur by decreasing the electrically stimulated muscle twitch response by 96 ± 4% (p = 0.001), through interference in the presynaptic neuron. Whereas, CB[7] caused a statistically significant muscle paralysis by decreasing the electrically stimulated muscle twitch response by 84 ± 9% (p = 0.001) through interference with the postsynaptic muscle membrane. Cardiotoxic activity was examined using the rat right and left heart atria. Results show that incubation of the atria tissue with 300 μM of cisplatin reduced the contraction rate of the right atria by 68.8 ± 1% (p = 0.001) and in the left atria by 1 ± 1% (p = 0.4) by the end of the two hour period study. When incubated with 300 μM of CB[7], the contraction rate in the right atria increased by 31 ± 13.6% (p = 0.3) and decreased in the left atria by 10 ± 3.5% (p = 0.3) Finally, the effect of the encapsulation of cisplatin by CB[7] on its neurotoxic, neuromyopathic and cardiotoxic activity was investigated. Results show that while the encapsulation had no effect on the neurotoxic activity of cisplatin, the encapsulated complex reduced the extent of cisplatin's neuromyopathic activity by reducing the muscle paralysis induced by cisplatin by 60%. When encapsulated by CB[7], the cardiotoxicity of cisplatin on the contraction rate of the right atria was also significantly decreased from 65.8% to 11%. In conclusion, these results suggest that CB[7] could exhibit neuromyopathy and cardio protective properties as it reduced the neuromyopathic and cardiotoxic activity of the encapsulated cisplatin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.668876  DOI: Not available
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