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Download fileVault Nanoparticles: Chemical Modifications for Imaging and Enhanced Delivery
journal contribution
posted on 2016-12-28, 00:00 authored by Nancy
L. Benner, Xiaoyu Zang, Daniel C. Buehler, Valerie A. Kickhoefer, Michael E. Rome, Leonard H. Rome, Paul A. WenderVault
nanoparticles represent promising vehicles for drug and probe
delivery. Innately found within human cells, vaults are stable, biocompatible
nanocapsules possessing an internal volume that can encapsulate hundreds
to thousands of molecules. They can also be targeted. Unlike most
nanoparticles, vaults are nonimmunogenic and monodispersed and can
be rapidly produced in insect cells. Efforts to create vaults with
modified properties have been, to date, almost entirely limited to
recombinant bioengineering approaches. Here we report a systematic
chemical study of covalent vault modifications, directed at tuning
vault properties for research and clinical applications, such as imaging,
targeted delivery, and enhanced cellular uptake. As supra-macromolecular
structures, vaults contain thousands of derivatizable amino acid side
chains. This study is focused on establishing the comparative selectivity
and efficiency of chemically modifying vault lysine and cysteine residues,
using Michael additions, nucleophilic substitutions, and disulfide
exchange reactions. We also report a strategy that converts the more
abundant vault lysine residues to readily functionalizable thiol terminated
side chains through treatment with 2-iminothiolane (Traut’s
reagent). These studies provide a method to doubly modify vaults with
cell penetrating peptides and imaging agents, allowing for in vitro studies on their enhanced uptake into cells.
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Keywords
vault lysine residuesfunctionalizable thiolEnhanced Delivery Vault nanoparticlesacid side chains2- iminothiolaneMichael additionsdisulfide exchange reactionsprobe deliverybiocompatible nanocapsulesnucleophilic substitutionsvault propertiescovalent vault modificationsvault lysineinsect cellssupra-macromolecular structuresbioengineering approachesChemical Modificationsvault Nanoparticlesside chainsimaging agentscysteine residueschemical study