Lavignac, N. and Lazenby, M. and Foka, P. and Malgesini, B. and Verpilio, I. and Ferruti, P. and Duncan, R. (2004) Synthesis and endosomolytic properties of poly(amidoamine) block copolymers. Macromolecular Bioscience, 4 (10). pp. 922-929. ISSN 1616-5187.
|The full text of this publication is not available from this repository. (Contact us about this Publication)|
The poly(amidoamine)s (PAAs) ISA 1 and ISA 23 display pH-dependent conformational change and pH-dependent membrane perturbation. These properties confer potential for use as endosomolytic polymers for intracytoplasmic delivery of toxins and genes. Both polymers are relatively non-toxic, and moreover ISA 23 has the beneficial property in vivo, of being non hepatotropic when administered intravenously. Although ISA 23 and ISA 1 demonstrate ability to transfect cells, ISA 1 is also able to promote intracellular delivery of non-permeant toxins. The aim of this study was to synthesise random and block copolymers of ISA 1 and ISA 23 and investigate whether these second generation hybrids would allow optimisation of PAA biological characteristics. Random and block copolymers of ISA 1 and ISA 23 were synthesised by hydrogen transfer polyaddition to generate a library of PAAs with an ISA 23:ISA 1 molar ratios of 2:1 to 4: 1. The resultant polymers have a pI slightly below 7.4 and a (M) over bar (w) of 19900-49000 g/mol and a (M) over bar (n) of 13100-24100 g/mol. Whereas none of the random or block copolymers were haemolytic at pH 7.4 all demonstrated pH-dependent membrane activity. At pH 5.5 they caused 50-60% haemoglobin (Hb) release over 1 h. This was slightly less than that seen for ISA 23 (80% Hb release). None of the copolymers were cytotoxic against B16F10 cells during a 72 h incubation (IC50 > 2 mg/ml; MTT assay). The ability of the random and block copolymer PAAs to deliver the toxin gelonin was also examined, but only ISA 1 and the block copolymer B2 (ISA 23:ISA 1 at a 2:1 molar ratio) were able to promote intracellular delivery, as measured by cytotoxic activity. It would be interesting to study the body distribution of B2 and determine whether this toxin-delivering PAA is able to escape liver capture.
|Additional information:||Times Cited: 9|
|Uncontrolled keywords:||block copolymers • endosomotropic delivery • pH-sensitive polymers • poly(amidoamine)s • random copolymers|
|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:||29 May 2009 15:02|
|Last Modified:||29 May 2009 15:02|
|Resource URI:||http://kar.kent.ac.uk/id/eprint/18605 (The current URI for this page, for reference purposes)|
- Depositors only (login required):