New polymeric anticancer conjugates of agents derived from natural sources

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Project objective

This project will design new polymeric-natural product anticancer agents. Instituto Biomar has identified pyridoacridine alkaloids and 1 ,5-diazaanthraquinones as promising novel anticancer compounds of high potency, but both display problems in vivo; in particular poor solubility and high toxicity . N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer conjugates will be synthesized to improve tumor targeting and increase water solubility. Prof. Duncan's group has experience in the design of polymer therapeutics for tumour specific delivery, and an HPMA copolymer conjugate (PK1) arising from her work is in Phase II of clinical trials. This project wilI have several phases:i) synthesis of pyridoacridine and 1,5-diazaanthraquinone derivatives containing an aliphatic amine group for polymer conjugation (collaboration with Biomar - some derivatives are already available)ii) synthesis and characterization of a library of polymer-drug conjugates (using HPMA copolymers) with tri- and tetrapeptide spacersiii) evaluation of the rate of drug liberation during incubation with isolated lysosomal enzymes in vitro iv) in vitro cytotoxicity v) in vivo pharmacokinetics and pharmacology. The initial biological results will lead to conjugate optimization and further testing. Most important features are appropriate rate of drug release from the conjugate in vitro by the activating lysosomal enzymes and optimal tumour targeting in vivo (the polymer conjugate must have minimal access to potential sites of toxicity). As a conjugate(s) with optimal therapeutic index emerge more detailed studies will be conducted to determine preclinical toxicity and verify mechanism of action at the cellular level.

Original text from CORDIS.

Participants

• UNIVERSITY OF WALES CARDIFF · CARDIFFCoordinatorUnited Kingdom

Links

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