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Zawartość zarchiwizowana w dniu 2024-05-21

New polymeric anticancer conjugates of agents derived from natural sources

Cel

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 spacers
iii) 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.

Dziedzina nauki (EuroSciVoc)

Program(-y)

Temat(-y)

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Zaproszenie do składania wniosków

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System finansowania

RGI - Research grants (individual fellowships)

Koordynator

UNIVERSITY OF WALES CARDIFF
Wkład UE
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Adres
King Edward VII Avenue, Redwood Building
CF10 3XF CARDIFF
Zjednoczone Królestwo
Koszt całkowity
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