Cobalamin has shown promise as a
light-sensitive drug delivery
platform owing to its ease of modification and the high quantum yields
for drug photorelease. However, studies to date on the general photochemistry
of alkyl cobalamins have primarily focused on methyl and adenosyl-substituted
derivatives, the natural cofactors present in various enzymatic species.
We describe the synthesis and photolytic behavior of cobalamin conjugates
comprised of different combinations of fluorophores and β-axial
ligands. In general, cobalamin conjugates containing β-axial
alkyl substituents undergo efficient photolysis under aqueous conditions,
with quantum yields up to >40%. However, substituents that are
large
and hydrophobic, or unable to readily support the presumed radical
intermediate, suffer less efficient photolysis (<15%) than smaller,
water-soluble, analogs. By contrast, quantum yields improve by 2-fold
in DMF for cobalamins containing large hydrophobic β-axial substituents.
This suggests that drug release from carriers comprised of membranous
compartments, such as liposomes, may be significantly more efficient
than the corresponding photorelease in an aqueous environment. Finally,
we explored the impact of fluorophores on the photolysis of alkyl
cobalamins under tissue-mimetic conditions. Cobalamins substituted
with efficient photon-capturing fluorophores display up to 4-fold
enhancements in photolysis relative to unsubstituted derivatives.
In summary, we have shown that the photosensitivity of alkyl cobalamin
conjugates can be tuned by altering the Co-appended alkyl moiety,
modulating the polarity of the environment (solvent), and installing
photon-capturing fluorophores onto the cobalamin framework.