Carbon monoxide (CO) is an endogenous signaling molecule with known pharmacological activities in a range of animal model studies, including systemic inflammation, ischemia-reperfusion injury of organs, and chemically induced organ injury. For improved delivery of CO as a potential therapeutic agent, we are interested in its targeted delivery. Along this line, we have reported an enrichment-triggered release (ETR) approach for the activation of prodrug payloads for delivery to mitochondria. This approach exploits the concentration-dependent nature of bimolecular reactions and increased concentrations of prodrug components after enrichment for a “one stone, two birds” approach for drug targeting. As an expansion of the ETR strategy, we examine the feasibility of targeted delivery to lysosomes. For this, we tether a prodrug pair, each with a morpholine moiety for enrichment in lysosomes for their bio-orthogonal activation and subsequent release of the payload in a kinetically controlled fashion. We use the delivery of carbon monoxide as an example. In this regard, our LC-MS experiments showed morpholine-facilitated enrichment of CO prodrug pair in lysosomes resulting in a 13-fold increase in CO release compared to the non-targeted controls. Furthermore, LysoTracker Red co-localization experiments confirmed the presence of the fluorescent product after CO release in lysosomes (Pearson’s correlation coefficient of 0.94). This presentation will discuss the experimental details, key findings, and their implications.

Morpholine-facilitated enrichment-triggered delivery of carbon monoxide in lysosomes

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