Morphing low-affinity ligands into high-avidity nanoparticles by thermally triggered self-assembly of a genetically encoded polymer.
Abstract
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.
Type
Journal articleSubject
ElastinHumans
Hydrophobic and Hydrophilic Interactions
Integrin alphaVbeta3
K562 Cells
Ligands
Micelles
Nanoparticles
Peptides
Temperature
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https://hdl.handle.net/10161/4103Published Version (Please cite this version)
10.1021/nn901732hPublication Info
Simnick, Andrew J; Valencia, C Alexander; Liu, Rihe; & Chilkoti, Ashutosh (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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Ashutosh Chilkoti
Alan L. Kaganov Distinguished Professor of Biomedical Engineering
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 bio

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