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.

This review summarizes recent developments in using bioorthogonal chemistry in prodrug design for the delivery of traditional small molecule- and gasotransmitter-based therapeutics.

Carbon monoxide is an intrinsic signaling molecule with importance on par with that of nitric oxide. During the past decade, pharmacological studies have amply demonstrated the therapeutic potential of carbon monoxide. However, such studies were mostly based on CO inhalation and metal-based CO releasing molecules (CO-RMs). The field is now at the stage that a major effort is needed to develop pharmaceutically acceptable forms of CO for delivery via various routes such as oral, injection, infusion, or topical applications. This review examines the state of the art, discusses existing hurdles to overcome, and proposes developmental strategies necessary to address remaining drug delivery issues.

Prodrugs that release hydrogen sulfide upon esterase-mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H2S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H2S donors. Additionally, such prodrugs can easily be conjugated to another non-steroidal anti-inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H2S prodrugs, the anti-inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS-induced TNF-α production in RAW 264.7 cells. This type of H2S prodrugs shows great potential as both research tools and therapeutic agents.

The mixed halide perovskites have become famous for their outstanding photoelectric conversion efficiency among new-generation solar cells. Unfortunately, for perovskites, little effort is focused on stress engineering, which should be emphasized for highly efficient solar cells like GaAs. Herein, polystyrene (PS) is introduced into the perovskite solar cells as the buffer layer between the SnO 2 and perovskite, which can release the residual stress in the perovskite during annealing because of its low glass transition temperature. The stress-free perovskite has less recombination, larger lattices, and a lower ion migration tendency, which significantly improves the cell's efficiency and device stability. Furthermore, the so-called inner-encapsulated perovskite solar cells are fabricated with another PS capping layer on the top of perovskite. As high as a 21.89% photoelectric conversion efficiency (PCE) with a steady-state PCE of 21.5% is achieved, suggesting that the stress-free cell can retain almost 97% of its initial efficiency after 5 days of "day cycle" stability testing.