New targetable conjugates of anticancer drugs with soluble biodegradable polymeric carriers

• Research unit: EU RFP
• Project number: 97.0273

Key words (English)

Drug delivery; biopolymer; cancer; drug targeting; polymer conjugate; polymer therapeutics

Alternative project number (English)

EU project number: BRPR-CT97-0493

Research programs (English)

EU-programme: 4. Frame Research Programme - 2.1 Industrial and materials technologies

Short description (English)

See abstract

Partners and International Organizations (English)

INSTM (I), Universitá degli Studi di Padova (I), The School of Pharmacy of the University of London (UK), University of Aberdeen (UK), Polymer Laboratories Ltd (UK), Polypeptide Laboratories (DK), Debio R.P. (CH)

Abstract (English)

The main objective of the Project is to prepare a new generation of tumour targeting polymer conjugates of anticancer drugs with improved therapeutic performance, based on new soluble, biodegradable high molecular weight polymers, and to bring one of them up to the level of clinical evaluation.
Polymer drugs, e.g. polymer-doxorubicin conjugates, are showing considerable promise in early clinical development. Those new chemical entities have the ability to improve tumour targeting and enhance therapeutic index with diminished toxicity of the free drug. Two polymer-anticancer conjugates are already present on clinical trial, but their main chain is not degradable on the body. As a consequence, their molecular weight must be kept relatively low, in order to obtain the elimination of the polymer residues through the kidneys. However, in this way the molecular-weight dependant 'Enhanced Permeation and Retention Effect' (EPR effect), responsible for passive tumour targeting of the polymer conjugates, is not fully exploited.
The novelty of the polymer conjugates that are the objective of this Project consists in having a biodegradable backbone. This will permit the easy elimination of polymer metabolites from the body after liberation of the drug. So the molecular weight of the conjugates must not be necessarily limited.
The molecular architecture of the polymer drug conjugates designed for the Project is quite complex and their preparation has involved several steps:
1. the preparation of high molecular weight, water soluble and biodegradable carriers;
2. the preparation of drug oligomeric side arms containing an anticancer drug attached via a peptide spacer (selectively cleavable inside cells) to one end of a heterobifunctional hydrophilic spacer;
3. the biological assessment of each component;
4. the assembling of the polymer carrier and the drug-containing oligomeric arm, leading the final polymer anticancer drug conjugate;
5. the biological assessment of the final conjugate.
Chemical technologies amenable to industrial up-scaling for the preparation of soluble, biocompatible, biodegradable and functionalised polyester have been established.
More than two anticancer conjugates of the above polyester have been prepared and characterized.

References in databases (English)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
Tel. [phone]
Swiss Project-Number: 97.0273