Keane, Richard; (2002) HPMA copolymer - aminoellipticine conjugates: mechanism of action. Doctoral thesis (Ph.D.), University College London.

Text HPMA_copolymer_-_aminoelliptic.pdf Download (9MB)

Abstract

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.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as JSONXMLCSV

Downloads by country - last 12 months

Export as JSONCSVXML

Archive Staff Only

View Item