Abd Kadir, E;
(2017)
Nano-enabled disulfiram for cancer therapy.
Doctoral thesis , UCL (University College London).
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Abstract
The hypothesis was that encapsulation of labile disulfiram (DS) in a high capacity nanoemulsion stabilized by quaternary ammonium palmitoyl glycol chitosan (GCPQ) could protect DS from degradation in the blood and increase its delivery to tumours. GCPQ was synthesized from glycol chitosan and characterized. GCP20Q11 polymer was chosen to be incorporated with DS in soybean oil into homogenous DS-GCP20Q11-E nanoemulsion. The nanoemulsions showed capability of oil-loading up to 50% v/v for a stable entrapment of high drug content. With increasing oil content (5 to 50%) the mean particle size increased, as did overall polydispersity (190 to 359 nm and 0.14 to 0.21, respectively). Transmission electron microscope (TEM) images showed existence of heterogeneous particles with a size below 100 nm. The drug load and colloidal stability were seen improved in lower oil-content formulations stored at low temperature. Formulations showed highly positive particle surface charge (51 mV at pH 4.50), proving the ionic stability of the individual particles. DS-GCP20Q11-E showed marked cytotoxicity effect against human pancreatic cancer cell line (MIAPaCa-2) with enhanced activity seen in the presence of copper (IC50 of 0.37 µM compared to 34.17 µM with the nanoemulsion treatment without copper). In vivo oral pharmacokinetic (PK) study of DS-GCP20Q11-E showed low DS level (low area under curve (AUC)) in the mouse plasma compared to control group whereas the intravenous (IV) PK showed an improved AUC value with DS half-life of 17 minutes. DS-GCP20Q11-E anticancer activity against development of human pancreatic cancer xenograft tumour in mice revealed significant prolonged survival in animals treated with IV DS-GCP20Q11-E or oral DS in soybean oil compared to control (no treatment). No toxicity or side effects were seen from the multiple administration of the nanoemulsion. In conclusion, DS-GCP20Q11-E nanoemulsion has the potential to be used or developed further for cancer therapeutic purposes.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Nano-enabled disulfiram for cancer therapy |
| Event: | UCL (UNIVERSITY COLLEGE LONDON) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1541547 |
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