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

Richardson, Simon C. W., Pattrick, Nicola G., Lavignac, Nathalie, Ferruti, Paolo, 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. E-ISSN 1873-4995. (doi:10.1016/j.jconrel.2009.09.025)

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 (0.5-3 h) and ISA1 dose (0.04-100 mg/kg) on trafficking, and vesicle permeabilisation (N-acetyl-b-D-glucosaminidase (NAG) release from an isolated vesicular fraction) were also studied. ISA1-OG displayed similar to 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 10 mg/kg to 100 mg/kg increased both radioactivity and NAG levels in the cytosolic fraction (5-10 fold) at 1 h. Moreover, internalised ISA1 provoked NAG release from an isolated vesicular fraction in a close-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. (C) 2009 Elsevier B.V. All rights reserved.

Item Type: Article
DOI/Identification number: 10.1016/j.jconrel.2009.09.025
Uncontrolled keywords: Endosomolytic polymer; Poly(amidoamine); Subcellular fractionation
Subjects: Q Science
Q Science > QD Chemistry
R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Nathalie Lavignac
Date Deposited: 15 Dec 2014 12:35 UTC
Last Modified: 29 May 2019 13:55 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/46117 (The current URI for this page, for reference purposes)
Lavignac, Nathalie: https://orcid.org/0000-0002-9259-7603
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