During their life time one from three people will suffer from cancer and due to inadequate treatment one from four will die. The main objective of this proposal is to prepare a new generation of tumour targeting polymer conjugates of anticancer drugs with improved therapeutic performance, based on soluble, biodegradable high molecular weight polymers, and to bring at least one of them up to the level of clinical evaluation.
Rationale: Polymer conjugates of anticancer drug containing bound active moieties are used to improve pharmacokinetics, prolonging antitumour activity and decreasing protein immunogenicity. This technique allows concentrating the drug in solid tumour tissue by enhanced capillary permeability and retention (EPR) effect. This effect is strictly dependent on the molecular weight of the conjugates, the higher the molecular weight the higher the selectivity achievable. The first generation of polymer conjugates, N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymer conjugates with doxorubicin and poly(ethyleneglycol) (PEG)-L-asparaginase (Oncaspar) although promising, cannot be considered optimised since their polymer chain lacks biodegradability.
This restricts use to low molecular weight compounds that can be excreted, but do not for that reason exploit the full potentiality of the technique. The new polymer conjugates object of the proposal: The proposed polymeric systems will be based on high molecular weight water-soluble functionalised polyesters of novel structure.
In particular, they will show the following features: a) high molecular weight; b) biodegradable backbone; c) water solubility, achieved by the presence of poly (ethyleneglycol) or other hydrophilic segments; d) novel peptide and pH sensitive spacers which are stable in blood but selectively cleaved within the tumour; d) peptide (eg. Vapreotide or LHRHanalogues or aminosugar moieties) as targeting side substituents.
The outcome of the project will be significantly improved polymer conjugates of the following anticancer drugs: doxorubicin (as a model), Ara C, mitomycinC, neocarcinostatin or taxol.
Structure of the Consortium: The consortium is composed of 3 industrial and 4 academic partners of internationally confirmed expertise in biology, medicine, polymer and organic chemistry, materials science and pharmaceutics. BE97-4133
Funding SchemeCSC - Cost-sharing contracts
WC1N 1AX London
AB25 2ZD Aberdeen
CF10 3XF Cardiff