Intracellular fate of bioresponsive poly(amidoamine)s in vitro and in vivo

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, b...

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Bibliographic Details
Published in:Journal of controlled release 2010-02, Vol.142 (1), p.78-88
Main Authors: RICHARDSON, Simon C. W, PATTRICK, Nicola G, LAVIGNAC, Nathalie, FERRUTI, Paolo, DUNCAN, Ruth
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Line
Cell Membrane Permeability - drug effects
Controlled release
Endocytosis
General pharmacology
Hepatocytes
Hepatocytes - cytology
Hepatocytes - drug effects
Hepatocytes - metabolism
Intravenous administration
Male
Medical sciences
Molecular Structure
pH effects
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Polyamines - administration & dosage
Polyamines - chemistry
Polyamines - pharmacokinetics
Radioactivity
Rats
Rats, Wistar
Toxicity
Toxins
Vesicles
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Summary: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.
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2009.09.025