Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.647303
Title: Development of novel pyrrolobenzodiazepines for treatment of skin cancer and actinic keratosis
Author: Haque, T.
ISNI:       0000 0004 5366 2294
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Abstract:
The pyrrolobenzodiazepines (PBDs) are members of a family of DNA minor-groove binding anticancer agents. Some PBD compounds have very potent in vitro cytotoxicity and in vivo antitumour activities. Topical dosage forms in some cases offer more advantages than oral or parenteral dosage forms as more localised delivery of drug is possible with comparatively lower side effects. However, there are only a few anticancer topical formulations currently available for the treatment of skin cancer. Therefore, the main objective of this project was to develop topical formulations using PBD compounds for the palliative treatment of late stage melanoma patients, and for the treatment of non-melanoma skin cancers and potentially actinic keratosis. In order to develop suitable topical formulations for PBD compounds, a number of formulations were initially evaluated using anthramycin, a model PBD compound. In addition, the permeation and retention of the penetration enhancers (solvents) in human skin were also evaluated. Single solvent analysis results showed that Transcutol® and propylene glycol (PG) were the most highly permeable solvents. For all formulations, anthramycin absorption was comparatively higher in PG:PGML (propylene glycol monolaurate) (90:10). A focussed library of PBD C8-conjugates and a PBD-dimer (SJG-136) were also evaluated using dimethyl sulphoxide as a solvent. Potential topical efficacy was confirmed for a number of the compounds based on skin flux values and in vitro potency data. KMR-04-175 and KMR-28-24 were ranked as the most topically effective PBD conjugates. SJG-136 which has reached Phase II clinical trials, also showed higher skin absorption values compared with the other PBD compounds (except for KMR-28-24). This is the first report describing the preparation and evaluation of topical formulations of PBD compounds. The results are encouraging and suggest that topical formulations of PBD compounds could be efficacious for the topical treatment of skin cancers and potentially actinic keratosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.647303  DOI: Not available
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