Thesis

Novel methods to deliver platinum(II) chemotherapeutics to the nose

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Awarding institution
  • University of Strathclyde
Date of award
  • 2013
Thesis identifier
  • T13588
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Abstract
  • Efforts to reduce side effects and improve efficacy of platinum-based drugs have seen the focus shift away from developing new drugs, towards improving the delivery of existing ones. This thesis presents an investigation into improving the delivery of platinum(II) drugs using lyophilised hydroxypropyl methylcellulose (HPMC) nasal insert formulations, designed to resist rapid mucociliary clearance in vivo and extend drug absorption. Cisplatin was conjugated to carbon nanotubes (CNTs), which was expected to improve tumour targeting through the enhanced permeability and retention effect; however this project was halted due to safety concerns. Cucurbiturils (CB[n]s) were investigated as an alternative drug delivery vehicle, as they have been shown to improve platinum(II) drug stability. The high cost of the most soluble homologue, CB[7] prompted an investigation into whether or not more readily available CB[6] could be used as reliable a model for CB[7] in nasal insert formulations. A series of investigations revealed that CB[6] had a similar effect on HPMC nasal inserts as CB[7]. A theory for the observed behaviour has been proposed, whereby the CB[n]s act as points of pseudo-cross-linking in the HPMC matrix by forming hydrogen bonds with adjacent polymer chains. CB[6] and CB[7] have been shown to increase the thermal stability of the di-nuclear platinum(II) drug di-Pt, and the fluorescent dye, K6. Additionally, the encapsulated forms have shown improved distribution throughout a lyophilised nasal insert. This work may represent the formulation of a pH-responsive supramolecular delivery system for di-Pt. Cucurbit[n]urils have, therefore, been shown to warrant further investigation as pharmaceutical excipients for controlled release. Finally, cisplatin protected in CB[7] was included in lyophilised nasal inserts. The encapsulation was shown to improve the thermal stability of cisplatin, but not significantly affect the hardness, spreadability or mucoadhesion of the nasal insert formulation. Additionally, the release of cisplatin@CB[7] was more repeatable than its cisplatin counterpart.
Resource Type
DOI
Date Created
  • 2013
Former identifier
  • 1001861

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