The incorporation of E09 into albumin microspheres and their evaluation as a potential anticancer therapy

Gardiner, Jill (2000) The incorporation of E09 into albumin microspheres and their evaluation as a potential anticancer therapy. MD thesis, University of Glasgow.

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E09 is one of a series of fully synthetic indoloquinones developed for their ability to act as potential bioreductive anticancer agents. Pre-clinical studies suggested that E09 was an active drug which demonstrated preferential activity against solid tumour cell lines. However, disappointing results were seen in subsequent Phase II trials which failed to detect any significant antitumour activity. This was thought to be due, in part, to dose limiting renal toxicity combined with E09's short half-life and instability. For these reasons E09 was felt to be a suitable drug to consider for encapsulation into albumin microspheres for use in locoregional therapy. This would have the benefit of delivering a high concentration of the drug to the tumour site whilst at the same time minimising systemic exposure and therefore toxicity. In addition, the possible induction of hypoxia by the microspheres might enhance the drugs bioreductive activity. A new technique was developed allowing the successful encapsulation of E09 into human albumin microspheres. This was an emulsification process which took place at room temperature using 6.25% gluteraldehyde as the chemical cross-linking agent. The E09-loaded microspheres produced by this method had a median size of 19.9mum with 70% of the microspheres being greater than 12mum in diameter. This would enable them to lodge in the first capillary bed they encounter and makes them suitable for use in locoregional therapy. The drug payload of the microspheres, determined by HPLC analysis, was 1.24 +/- 0.2mg/100mg of microspheres, which represented the actual amount of chemically intact drug released from the microspheres. This appeared to be rapidly released following resuspension in comparison to other microsphere systems, but would be acceptable for a drug such as E09, whose mode of action is related to peak drug concentration rather than prolonged drug exposure. The antitumour activity of the E09-loaded microspheres was compared to free drug when given by direct intratumoural injection in four tumour models. These were the subcutaneously grown human colonic xenografts; HT29 and BE and the murine adenocarcinomas of colon; MAC 16 and MAC 26. In the HT29 tumour no significant difference m antitumour activity was detected between the free drug (250?g) and the equivalent dose of drug-loaded microspheres. In the MAC 16 tumour twice the dose of E09-loaded microspheres (500mug) was required to produce equivalent antitumour activity to the free drug. In the MAC 26 and BE tumours, antitumour activity was detected with the free drug, but no antitumour activity was seen with the E09-loaded microspheres. In an attempt to explain the differences which were seen in the antitumour studies between the free drug and the microspheres, pharmacokinetic analyses were performed in each of the tumour types. No significant differences were seen in the tumour pharmacokinetic profiles. Similarly, HPLC analysis failed to detect any obvious metabolites which might be indicators of drug activity. However, analysis was limited due to the lack of available data on E09 metabolites in terms of standard curves and extraction efficiencies. Direct intratumoural injection of the E09-loaded microspheres is not the best way of assessing the potential of a drug delivery system. Therefore, a more clinically relevant model to assess the microspheres was developed. Preliminary in vitro and in vivo studies have established the sensitivity of the HSN rat sarcoma cell line to E09. The liver of the Lister Hooded rat has subsequently been implanted with HSN cells and treated by the administration of free drug or microspheres via the hepatic artery. Further work is required to improve on both the consistency of tumour growth within the liver, as well as the technique of hepatic arterial injection, before definite conclusions can be made about whether encapsulating E09 into microspheres improves drug delivery to the tumour following intra-arterial administration.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Pharmacology.
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Jodrell, Dr. Duncan
Date of Award: 2000
Depositing User: Enlighten Team
Unique ID: glathesis:2000-72007
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 24 May 2019 15:11
Last Modified: 03 Sep 2021 15:48

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