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Alkylated derivatives of poly(ethylacrylic acid) can be inserted into preformed liposomes and trigger pH-dependent intracellular delivery of liposomal contents

Chen, Tao and McIntosh, Deirdre and He, Yuehua and Kim, Jungsoo and Tirrell, David A. and Scherrer, Peter and Fenske, David B. and Sandhu, Ammen P. and Cullis, Pieter R. (2004) Alkylated derivatives of poly(ethylacrylic acid) can be inserted into preformed liposomes and trigger pH-dependent intracellular delivery of liposomal contents. Molecular Membrane Biology, 21 (6). pp. 385-393. ISSN 0968-7688. doi:10.1080/09687860400010516.

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Poly(ethylacrylic acid) (PEAA) is a pH-sensitive polymer that undergoes a transition from a hydrophilic to a hydrophobic form as the pH is lowered from neutral to acidic values. In this work we show that pH sensitive liposomes capable of intracellular delivery can be constructed by inserting a lipid derivative of PEAA into preformed large unilamellar vesicles (LUV) using a simple one step incubation procedure. The lipid derivatives of PEAA were synthesized by reacting a small proportion (3%) of the carboxylic groups of PEAA with C_(10) alkylamines to produce C_(10)-PEAA. Incubation of C_(10)-PEAA with preformed LUV resulted in the association of up to 8% by weight of derivatized polymer with the LUV without inducing aggregation. The resulting C_(10)-PEAA-LUV exhibited pH-dependent fusion and leakage of LUV contents on reduction of the external pH below pH 6.0 as demonstrated by lipid mixing and release of calcein encapsulated in the LUV. In addition, C_(10)-PEAA-LUV exhibited pH dependent intracellular delivery properties following uptake into COS-7 cells with appreciable delivery to the cell cytoplasm as evidenced by the appearance of diffuse intracellular calcein fluorescence. It is demonstrated that the cytoplasmic delivery of calcein by C_(10)-PEAA-LUV could be inhibited by agents (bafilomycin or chloroquine) that inhibit acidification of endosomal compartments, indicating that this intracellular delivery resulted from the pH-dependent destabilization of LUV and endosomal membranes by the PEAA component of the Clo-PEAA-LUV. It is concluded that C_(10)-PEAA-LUV represents a promising intracellular delivery system for in vitro and in vivo applications.

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Tirrell, David A.0000-0003-3175-4596
Additional Information:© 2004 Taylor & Francis Ltd Received 11 June 2004; and in revised form 23 August 2004.
Subject Keywords:Liposomes, intracellular delivery, pH-sensitive polymers, poly(ethylacrylic acid), pH-dependent membrane fusion
Issue or Number:6
Record Number:CaltechAUTHORS:20150130-161321146
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:53305
Deposited By: Donna Wrublewski
Deposited On:26 Feb 2015 04:12
Last Modified:10 Nov 2021 20:00

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