Morphing low-affinity ligands into high-avidity nanoparticles by thermally triggered self-assembly of a genetically encoded polymer.
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Multivalency is the increase in avidity resulting from the simultaneous interaction of multiple ligands with multiple receptors. This phenomenon, seen in antibody-antigen and virus-cell membrane interactions, is useful in designing bioinspired materials for targeted delivery of drugs or imaging agents. While increased avidity offered by multivalent targeting is attractive, it can also promote nonspecific receptor interaction in nontarget tissues, reducing the effectiveness of multivalent targeting. Here, we present a thermal targeting strategy--dynamic affinity modulation (DAM)--using elastin-like polypeptide diblock copolymers (ELP(BC)s) that self-assemble from a low-affinity to high-avidity state by a tunable thermal "switch", thereby restricting activity to the desired site of action. We used an in vitro cell binding assay to investigate the effect of the thermally triggered self-assembly of these ELP(BC)s on their receptor-mediated binding and cellular uptake. The data presented herein show that (1) ligand presentation does not disrupt ELP(BC) self-assembly; (2) both multivalent ligand presentation and upregulated receptor expression are needed for receptor-mediated interaction; (3) increased size of the hydrophobic segment of the block copolymer promotes multivalent interaction with membrane receptors, potentially due to changes in the nanoscale architecture of the micelle; and (4) nanoscale presentation of the ligand is important, as presentation of the ligand by micrometer-sized aggregates of an ELP showed a low level of binding/uptake by receptor-positive cells compared to its presentation on the corona of a micelle. These data validate the concept of thermally triggered DAM and provide rational design parameters for future applications of this technology for targeted drug delivery.
Published Version (Please cite this version)
Simnick, Andrew J, C Alexander Valencia, Rihe Liu and Ashutosh Chilkoti (2010). Morphing low-affinity ligands into high-avidity nanoparticles by thermally triggered self-assembly of a genetically encoded polymer. ACS Nano, 4(4). pp. 2217–2227. 10.1021/nn901732h Retrieved from https://hdl.handle.net/10161/4103.
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Ashutosh Chilkoti is the Alan L. Kaganov Professor of Biomedical Engineering and Chair of the Department of Biomedical Engineering at Duke University.
My research in biomolecular engineering and biointerface science focuses on the development of new molecular tools and technologies that borrow from molecular biology, protein engineering, polymer chemistry and surface science that we then exploit for the development of applications that span the range from bioseparations, plasmonic biosensors, low-cost clinical diagnostics, and drug delivery.
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