Intracellular fate of bioresponsive poly(amidoamine)s in vitro and in vivo
Richardson, Simon C.W., Pattrick, Nicola G., Lavignac, Nathalie, Ferruti, Paolo and Duncan, Ruth (2010) 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:10.1016/j.jconrel.2009.09.025)Full text not available from this repository.
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.
|Additional Information:|| 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|
|School / Department / Research Groups:||School of Science|
School of Science > Department of Pharmaceutical, Chemical & Environmental Sciences
|Last Modified:||16 May 2013 18:02|
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