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Title: HPMA copolymer-aminoellipticine conjugates : mechanism of action
Author: Keane, Richard
ISNI:       0000 0001 3596 0210
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2002
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Over the past two decades cancer chemotherapy has resulted in a small number of previously fatal cancers becoming curable. Many cancers, particularly the so-called solid tumours, do not respond well to conventional chemotherapy. To maximise tumour targeting and minimize host tissue toxicity a large number of drug delivery systems have been proposed. Polymer anticancer conjugates based on N-(2- hydroxypropyl) methacrylamide (HPMA) have recently entered early clinical trial. It has been shown that HPMA copolymer conjugates preferentially extravasate into solid tumours and are retained there by a process known as the 'enhanced permeability and retention' (EPR) effect. A natural anticancer agent, derived from ellipticine, namely 6-(3-aminopropyl) ellipticine (APE) was selected for conjugation to HPMA copolymers. In this study a series of HPMA copolymer-APE conjugates were synthesised, containing a variety of drug loadings (1.07-6.10%w/w) conjugated via the tetrapeptide linker (Gly-Phe-Leu- Gly). These conjugates were designed to be localised in tumours following injection and to be taken up by tumour cells via the process of endocytosis before liberating APE, mediated by cathepsin B present in the lysosome. These conjugates were shown to form complex intramolecular micelles in solution which resulted in the conjugates of a high drug loading showing reduced APE release in vitro (20%/5h) compared to the medium and low drug loading conjugates (55%/5h), suggesting hindered enzyme access. All conjugates showed a marked reduction in haemolysis, a common problem with ellipticines, compared to APE alone. Anti-tumour activity was observed in the s.c. B16F10 murine melanoma model and also in the CORL-23 human non small cell lung carcinoma xenograft in mice, particularly for the conjugate of medium APE loading. This thesis also examined the extravasation and intratumoural distribution of HPMA copolymer-anticancer conjugates using HPMA copolymer doxorubicin (PK1) as a model conjugate in the rat dorsal window chamber model.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacology & pharmacy & pharmaceutical chemistry