Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide

Abstract

Controlled activation is a critical component in prodrug development. Herein we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two “click and release” systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of this approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix upon the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo, as compared to controls that did not result in enrichment. This method is thus a platform for targeted drug delivery amenable to conjugation with a variety of molecules and not limited to cell-surface delivery. Taken together, these two click and release pairs clearly demonstrate the concept of enrichment-triggered drug release and critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer.

Dissociative Bioorthogonal Reactions

“…Cyclooctyne : Zheng et al. combined the reaction of strained alkynes and tetrazines with a release step . After cycloaddition between a cyclooctyne with a nucleophilic hydroxy at the propargylic position and a tetrazine bearing an amide‐connected leaving group, a lactonization occurs and releases the amine (Scheme ).…”

“…Other delivery strategies will certainly be developed in the coming years. For example, a recent report has shown how the enrichment of prodrugs and activator molecules in subcellular organelles can trigger the release of bioactive molecules . Moreover, although these strategies have been confined to demonstrations on tumor models, they might be applicable to other ailments.…”

Tracking CO Release in Cells via the Luminescence of Donor Molecules and/or their By‐Products

“…Wang and co‐workers have explored the development of organic prodrugs that undergo cheletropic reaction under physiologically relevant conditions to spontaneously release CO ,. These generally non‐toxic molecules (up to 100 μM) are designed to undergo inter‐ or intra‐molecular inverse electron demand Diels‐Alder (DA inv ) reactions with tunable CO release rates.…”

“…The Wang group has also ingeniously applied the ability to visualize CO delivery in a bimolecular approach in targeting complementary reaction components to mitochondria in vitro and in vivo ( 24 and 25 , Figure ) . The subcellular co‐localization of both molecules was used to enhance the concentration and probability of collision between the two reactive species leading to CO release.…”

A Phosphinate‐Containing Fluorophore Capable of Selectively Inducing Apoptosis in Cancer Cells

“…Indeed, the US Food and Drug Administration (FDA) has approved more than 200 anticancer drugs over the past few decades. However, one factor that continues to complicate treatment is the off‐target toxicity observed for commonly used chemotherapeutic drugs . Recently, drug‐discovery campaigns have turned towards the development of targeted molecules with tissue‐specific activities .…”