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The design and synthesis of polymers for eukaryotic membrane disruption

Murthy, Niren and Robichaud, John R. and Tirrell, David A. and Stayton, Patrick S. and Hoffman, Allan S. (1999) The design and synthesis of polymers for eukaryotic membrane disruption. Journal of Controlled Release, 61 (1-2). pp. 137-143. ISSN 0168-3659. doi:10.1016/S0168-3659(99)00114-5.

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The intracellular trafficking of drugs is critical to the efficacy of drugs that are susceptible to attack by lysosomal enzymes. It is therefore an important goal to design and synthesize molecules which can enhance the transport of endocytosed drugs from the endosomal compartments to the cytoplasm. The pH of an endosome is lower than that of the cytosol by one to two pH units, depending on the stage of endosomal development. This pH gradient is a key factor in the design of membrane-disruptive polymers which could enhance the endosomal release of drugs. Such polymers should disrupt lipid bilayer membranes at pH 6.5 and below, but should be non-lytic at pH 7.4. We have designed and synthesized pH-sensitive synthetic polymers which efficiently disrupt red blood cells within a sharply defined pH range. One of these polymers, poly(ethyl acrylic acid) (PEAAc) has been previously shown to disrupt synthetic vesicles in a pH-dependent fashion. PEAAc hemolyzes red blood cells with an activity of 10^7 molecules per red blood cell, which is as efficient on a molar basis as the peptide melittin. The mechanism of RBC hemolysis by PEAAc is consistent with the colloid osmotic mechanism. PEAAc’s hemolytic activity rises rapidly as the pH decreases from 6.3 to 5.0, and there is no hemolytic activity at pH 7.4. A related polymer, poly(propyl acrylic acid) (PPAAc), was synthesized to test whether making the pendant alkyl group more hydrophobic by adding one methylene group would increase the hemolytic activity. PPAAc was found to disrupt red blood cells 15 times more efficiently than PEAAc at pH 6.1. PPAAc was also not active at pH 7.4 and displayed a pH-dependent hemolysis that was shifted toward higher pH’s. Random 1:1 copolymers of ethyl acrylate (EA) and acrylic acid (AAc) (which contain random –COOH and –C_2H_5 groups that are present and regularly repeat in PEAAc) also displayed significant hemolytic activity, with an efficiency close to PEAAc. These results demonstrate that pH-sensitive synthetic polymers can be molecularly engineered to efficiently disrupt eukaryotic membranes within defined and narrow pH ranges. Thus, these polymers might serve as endosomal disruptive agents with specificities for early or late endosomes.

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Tirrell, David A.0000-0003-3175-4596
Additional Information:© 1999 Elsevier. Received 19 December 1998; received in revised form 3 May 1999; accepted 3 May 1999. This work was mainly supported by the NIH (NIGMS Grant No. R01-GM53771-02). We are also grateful for support from the UW Center for Nanotechnology (graduate fellowship to N.M.), the UW Office of Technology Transfer, the Washington Technology Center at UW, and the Washington Research Foundation.
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University of WashingtonUNSPECIFIED
Washington Technology CenterUNSPECIFIED
Washington Research FoundationUNSPECIFIED
Subject Keywords:Gene therapy; Drug delivery; Endosomal release; Hemolysis; pH-sensitive polymers
Issue or Number:1-2
Record Number:CaltechAUTHORS:MURjcr1999
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Official Citation:Niren Murthy, John R Robichaud, David A Tirrell, Patrick S Stayton, Allan S Hoffman, The design and synthesis of polymers for eukaryotic membrane disruption, Journal of Controlled Release, Volume 61, Issues 1–2, 27 August 1999, Pages 137-143, ISSN 0168-3659, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:53384
Deposited By: Anne Hormann
Deposited On:06 Feb 2015 06:09
Last Modified:10 Nov 2021 20:01

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