Daou, Anis (2020) Formulation of smart nanocapsules for targeted drug delivery. (PhD thesis), Kingston University, .
Abstract
Drug delivery through the Blood Brain Barrier (BBB) represent a significant challenge in transporting active pharmaceutical ingredients into the brain. Nanotechnology offers unprecedented opportunities to not only circumvent the BBB, but also have the ability to selective deliver drugs to target site. Polymeric nano-carriers allow for a more efficacious drug targeting strategy at cellular and sub-cellular level, they can also be used for sustained release of drug, henceforth prolonging effect of drug leading to fewer side effects. Boron Neutron Capture therapy (BNCT) is a targeted chemo-radiotherapeutic technique that allows the selective depletion of cancer cells by means of selective tagging of cancer cells with boron, followed by irradiation with low-energy neutrons. This results is the selective destruction of cancer cells. Consequently, the combination of a polymer based nano-delivery system enclosing an effective BNCT pharmacophore can potentially lead to the selective delivery of the load to cancer cells beyond the BBB. In this work, novel boronated agents, based on carboranyl-functionalised Delocalized Lipophilic Cations (DLCs), which selectively target the mitochondria of tumour cells, were synthesised. Literature suggests that the treatment of tumour and cancer stem cells using these types of agents induce selective and permanent cancer cell growth arrest through activation of the p53/p21 axis. The drugs were then encapsulated in nano-carriers constituted by chitosan, modified with moieties that are expected to promote permeability through the BBB. Also, the same functionalised chitosan was used in combination with poly-pyrrole to form a smart composite nano-shell of reduced size, which are expected to release their drug load with variations in pH. Results indicate achievement of more selective boron delivery to cells via carboranyl DLCs. Carboranyl DLCs have shown a 10 fold increase in boron uptake into CaCo2 cells as opposed to non-synthesised boron, we hypothesise this is due to the selective tagging of boron enforced via the DLCs. Furthermore, alkyl-glycerol functionalised chitosan has shown great potential in improving the nano-vehicles physical characteristics, modified chitosan, when compared to pristine chitosan, decreased size of nanoparticles by an average of 200mm, resulting in nano-vehicles in the range of between 50-300mm. Furthermore the charge profile of the nano-vehicles decreased, with values between 15-30mV, forming a less toxic, more favourable delivery vehicle towards cancer drug delivery. The addition of poly-pyrrole to chitosan to form a composite nano-vehicle enhanced the release profile in more acidic environments. This is due, in part to the pyrrole protonating in more acidic environments, in addition to protecting the chitosan from degradation occurring, henceforth preventing early degradation of the nano-vehicle. Finally, preliminary cell studies indicate that no toxicity was detected in alkyl-glycerol functionalised chitosan nanocapules, in addition, alkyl-glycerol functionalised chitosan improved permeation of delivery vehicle across a cellular monolayer, this was due to two factor, the decreased size and increased hydrophobicity of the nano-vehicle. Therefore we conclude that poly-pyrrole in combination with alkyl-glycerol functionalised chitosan as part of a nano-vehicle has the potential to not only enhance its potential of surpassing the BBB but also be a suitable delivery vehicle in the BNCT of brain tumours.
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