Carbon monoxide (CO),
an endogenous signaling molecule, is known
to exert a range of pharmacological effects, including anti-inflammation,
organ protection, and antimetastasis in various animal models. We
have previously shown the ability of organic prodrugs to deliver CO
systemically through oral administration. As part of our efforts for
the further development of these prodrugs, we are interested in minimizing
the potential negative impact of the “carrier” portion
of the prodrug. Along this line, we have previously published our
work on using benign “carriers” and physically trapping
the “carrier” portion in the gastrointestinal (GI) tract.
We herein report our feasibility studies on using immobilized organic
CO prodrugs for oral CO delivery while minimizing systemic exposure
to the prodrug and the “carrier portion.” In doing so,
we immobilize a CO prodrug to silica microparticles, which are generally
recognized as safe by the US FDA and known to provide large surface
areas for loading and water accessibility. The latter point is essential
for the hydrophobicity-driven activation of the CO prodrug. Amidation-based
conjugation with silica is shown to provide 0.2 mmol/g loading degree,
effective prodrug activation in buffer with comparable kinetics as
the parent prodrug, and stable tethering to prevent detachment. One
representative silica conjugate, SICO-101, is shown to
exhibit anti-inflammation activity in LPS-challenged RAW264.7 cells
and to deliver CO systemically in mice through oral administration
and GI CO release. We envision this strategy as a general approach
for oral CO delivery to treat systemic and GI-specific inflammatory
conditions.