Richardson, Simon C.W. ORCID: 0000-0002-7927-0649, Pattrick, Nicola G., Lavignac, Nathalie, Ferruti, Paolo and Duncan, Ruth (2009) Intracellular fate of bioresponsive poly(amidoamine)s in vitro and in vivo. Journal of Controlled Release, 142 (1). pp. 78-88. ISSN 0168-3659 (doi:https://doi.org/10.1016/j.jconrel.2009.09.025)

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Abstract

Linear poly(amidoamine)s (PAAs) have been designed to exhibit minimal non-specific toxicity, display pH-dependent membrane lysis and deliver genes and toxins in vitro. The aim of this study was to measure PAA cellular uptake using ISA1-OG (and as a reference ISA23-OG) in B16F10 cells in vitro and, by subcellular fractionation, quantitate intracellular trafficking of (125)I-labelled ISA1-tyr in liver cells after intravenous (i.v.) administration to rats. The effect of time after administration (0.5-3h) and ISA1 dose (0.04-100mg/kg) on trafficking, and vesicle permeabilisation (N-acetyl-b-D-glucosaminidase (NAG) release from an isolated vesicular fraction) were also studied. ISA1-OG displayed approximately 60-fold greater B16F10 cell uptake than ISA23-OG. Passage of ISA1 along the liver cell endocytic pathway caused a transient decrease in vesicle buoyant density (also visible by TEM). Increasing ISA1 dose from 10mg/kg to 100mg/kg increased both radioactivity and NAG levels in the cytosolic fraction (5-10 fold) at 1h. Moreover, internalised ISA1 provoked NAG release from an isolated vesicular fraction in a dose-dependent manner. These results provide direct evidence, for the first time, of PAA permeabilisation of endocytic vesicular membranes in vivo, and they have important implications for potential efficacy/toxicity of such polymeric vectors.

Item Type:	Article
Additional Information:	[1] Available online 12 October 2009. Published in Journal of Controlled Release, Volume 142, Issue 1, 25 February 2010.
Uncontrolled Keywords:	endosomolytic polymer, poly(amidoamine), subcellular fractionation
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science > School of Science (SCI)
Related URLs:	Publisher Organisation
Last Modified:	06 Nov 2020 11:23
URI:	http://gala.gre.ac.uk/id/eprint/2095

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