Synthesis and preliminary evaluation of poly(amidoamine)-melittin conjugates as endosomolytic polymers and/or potential anticancer therapeutics

Lavignac, N. and Lazenby, M. and Franchini, J. and Ferruti, P. and Duncan, R. (2005) Synthesis and preliminary evaluation of poly(amidoamine)-melittin conjugates as endosomolytic polymers and/or potential anticancer therapeutics. International Journal of Pharmaceutics, 300 (1-2). pp. 102-112. ISSN 0378-5173. (The full text of this publication is not available from this repository)

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Official URL
http://dx.doi.org/10.1016/j.ijpharm.2005.06.001

Abstract

The pH-responsive poly(amidoamine)s (PAAs) have been previously described. Whereas ISA23 enhances transfection in vitro and ISA1 promotes the cytosolic delivery of the non-permeant toxins this process shows poor efficiency. The aim of this study was to prepare and evaluate PAA conjugates containing the membrane disrupting peptide melittin (MLT). It was hypothesised that PAA conjugation would reduce the haemolytic activity of MLT at pH 7.4, however, upon delivery to tumours by the EPR effect, the polymer would uncoil in an acidic environment exposing MLT and allowing it to interact with membranes. PAA-MLT conjugates were prepared using MLT as a comonomer together with bis-acryloylpiperazine, 2-methylpiperazine and bis-hydroxyethylethylenediamine (ISA1-like), or bis-acrylamidoacetic acid and 2-methylpiperazine (ISA23-like). The melittin content of the conjugates was 6-19% (w/w). Although ISA1-MLT improved gelonin delivery compared to the parent polymer ISA1 (alpha 13-fold increase) and showed pH-dependent haemolytic activity at a polymer concentration of 0.05 mg/ml, this conjugate also displayed high haemolytic activity at pH 7.4. In contrast, ISA23-MLT like the parent compound ISA23 did not deliver gelonin. However, this conjugate could have potential as a novel polymeric anticancer conjugate due to its lack of haemolytic activity at pH 7.4 and retention of cytotoxicity. (c) 2005 Elsevier B.V. All rights reserved.

Item Type: Article
Additional information: Times Cited: 8
Uncontrolled keywords: endosomotropic delivery; pH-sensitive polymers; poly(amidoamine)s; melittin
Subjects: Q Science > QD Chemistry
R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Science Technology and Medical Studies > Medway School of Pharmacy
Depositing User: Nathalie Lavignac
Date Deposited: 31 May 2009 08:06
Last Modified: 31 May 2009 08:06
Resource URI: http://kar.kent.ac.uk/id/eprint/18606 (The current URI for this page, for reference purposes)
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