An Indocyanine Green-Based Nanoprobe for In Vivo Detection of Cellular Senescence.

There is an urgent need to improve conventional cancer-treatments by preventing detrimental side effects, cancer recurrence and metastases. Recent studies have shown that presence of senescent cells in tissues treated with chemo- or radiotherapy can be used to predict the effectiveness of cancer treatment. However, although the accumulation of senescent cells is one of the hallmarks of cancer, surprisingly little progress has been made in development of strategies for their detection in vivo. To address a lack of detection tools, we developed a biocompatible, injectable organic nanoprobe (NanoJagg), which is selectively taken up by senescent cells and accumulates in the lysosomes. The NanoJagg probe is obtained by self-assembly of indocyanine green (ICG) dimers using a scalable manufacturing process and characterized by a unique spectral signature suitable for both photoacoustic tomography (PAT) and fluorescence imaging. In vitro, ex vivo and in vivo studies all indicate that NanoJaggs are a clinically translatable probe for detection of senescence and their PAT signal makes them suitable for longitudinal monitoring of the senescence burden in solid tumors after chemotherapy or radiotherapy.

Transient Host-Guest Complexation To Control Catalytic Activity.

Signal transduction mechanisms are key to living systems. Cells respond to signals by changing catalytic activity of enzymes. This signal responsive catalysis is crucial in the regulation of (bio)chemical reaction networks (CRNs). Inspired by these networks, we report an artificial signal responsive system that shows signal-induced temporary catalyst activation. We use an unstable signal to temporarily activate an out of equilibrium CRN, generating transient host-guest complexes to control catalytic activity. Esters with favorable binding toward the cucurbit[7]uril (CB[7]) supramolecular host are used as temporary signals to form a transient complex with CB[7], replacing a CB[7]-bound guest. The esters are hydrolytically unstable, generating acids and alcohols, which do not bind to CB[7], leading to guest reuptake. We demonstrate the feasibility of the concept using signal-controlled temporary dye release and reuptake. The same signal controlled system was then used to tune the reaction rate of aniline catalyzed hydrazone formation. Varying the ester structure and concentration gave access to different catalyst liberation times and free catalyst concentration, regulating the overall reaction rate. With temporary signal controlled transient complex formation we can tune the kinetics of a second chemical reaction, in which the signal does not participate. This system shows promise for building more complex nonbiological networks, to ultimately arrive at signal transduction in organic materials.

Tuneable Control of Organocatalytic Activity through Host-Guest Chemistry.

Dynamic regulation of chemical reactivity is important in many complex chemical reaction networks, such as cascade reactions and signal transduction processes. Signal responsive catalysts could play a crucial role in regulating these reaction pathways. Recently, supramolecular encapsulation was reported to regulate the activities of artificial catalysts. We present a host-guest chemistry strategy to modulate the activity of commercially available synthetic organocatalysts. The molecular container cucurbit[7]uril was successfully applied to change the activity of four different organocatalysts and one initiator, enabling up- or down-regulation of the reaction rates of four different classes of chemical reactions. In most cases CB[7] encapsulation results in catalyst inhibition, however in one case catalyst activation by binding to CB[7] was observed. The mechanism behind this unexpected behavior was explored by NMR binding studies and pKa measurements. The catalytic activity can be instantaneously switched during operation, by addition of either supramolecular host or competitive binding molecules, and the reaction rate can be predicted with a kinetic model. Overall, this signal responsive system proves a promising tool to control catalytic activity.