Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 134, Issue 14, Pages 6491-6497Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja301491h
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Funding
- National Science Foundation [1011796]
- NIH [GM083658]
- Skaggs Institute for Chemical Biology
- Eli Lilly
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1011796] Funding Source: National Science Foundation
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Oxanorbornadienedicarboxylate (OND) reagents were explored for purposes of binding and releasing drugs from serum albumins as representative macromolecular carriers. Being highly reactive Michael acceptors, ONDs form adducts with thiols and amines, which then undergo retro-Diels-Alder fragmentation. A study of more than 30 model adducts revealed a number of modifications that can be used to influence adduct stability. For the most reactive OND linkers, the labeling of the single available bovine serum albumin (BSA) cysteine residue was complete within minutes at a mid-micromolar concentration of reactants. While a selectivity of greater than 1000-fold for thiol over amine was observed with model amino acids, the labeling of protein amines with ONDs is fast enough to be practical, as demonstrated by the reaction with thiol-depleted BSA. The OND amine adducts were found to be up to 15 times more stable than OND thiol adducts, and to be sensitive to acid by virtue of a stereochemically dependent acceleration of cycloreversion. The release rate of fluorescent cargo from serum albumins was tuned by selecting the coupling partners: the available half-lives ranged from 40 min to 7 days at 37 degrees C. Such versatility of release profiles from protein carriers, controlled by the nature of the OND linkage, is a useful addition to the drug delivery toolbox.
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