Mari Carmen Ortega-Liebana

Selective activation of chemotherapeutics at the tumor site via bioorthogonal catalysis is a promising strategy to reduce collateral damage to healthy tissues and organs. Despite significant advances in this field, targeted drug activation by transition-metal catalysts is still limited by insufficient spatiotemporal control over the metal-mediated uncaging process. Herein, we report the development of anisotropic Pd@Au plasmonic nanorods with the capacity to accelerate dealkylation reactions under near-infrared (NIR) irradiation, thereby enabling precise control over when and where these catalytic devices are switched on. We also show that the stability and in cellulo chemical properties of Pd@Au nanorods are enhanced by Au-S functionalization with PEGylated phospholipids and report the development of a novel masking group for prodyes and prodrugs: the POxOC group, designed to improve physicochemical properties and the rate of the Pd-triggered dye/drug release process. NIR-photoactivation of lipo-Pd@Au nanorods is able to catalyze the uncaging of inactive drug precursors and release heat to the environment, killing cancer cells in culture and xenografted in zebrafish. This work provides a novel targeted strategy for photothermal chemotherapy by NIR-laser focalization.

Flowing from the principles of bioorthogonality, the introduction of abiotic transition metals for the catalytic production of drugs at specific anatomical locations has carved new paths to face challenging diseases, including cancer. Despite ground-breaking advances in this area, the main barrier for the long-term application of bioorthogonal catalysis in medicine is catalyst inactivation by the surrounding environment. Herein we present a semipermeable membrane-inspired approach to separate the catalysts from the environment by incorporating them into a porous scaffold that minimizes interactions with surrounding biomolecules. Cross-linked lysozyme crystals of controlled size were functionalized with Pd(II) and reduced to Pd(0), operating as a size exclusion barrier for large macromolecules while enabling the traffic and chemical conversion of small molecule substrates with excellent efficiency, recyclability and tolerability. The capabilities of this catalytic system were harnessed ex vivo in salivary gland tissue to achieve epithelial progenitor cell differentiation by drug uncaging. This work provides a truly biocompatible strategy to extend catalytic processing and expands the scope of the field towards a new frontier: regenerative medicine. ^Cecilia Rocchi, Catherine Adam & Sara Illescas-Lopez are equal contributors.

Beyond their classical role as cytotoxics, Platinum (Pt) coordination complexes recently joined the selected group of transition metals capable of performing bioorthogonal reactions in living environments. To minimize their reactivity towards nucleophiles, which limit their catalytic performance, we investigated the use of Pt(0) with different forms, sizes and surface functionalization. We report herein the development of PEGylated Pt nanodendrites with the capacity to activate prodyes and prodrugs in cell culture and in vivo. Their dendritic morphology together with their surface shielding through Pt−S‐bonded PEGylation synergistically contributed to create catalytic nanoreactors compatible with the highly‐crowded and reductive environment of the cell cytoplasm, thereby facilitating in situ bioorthogonal drug uncaging in cancer cells in 2D and 3D culture, including in microfluidic systems, and xenografted in zebrafish.

Beyond their classical role as cytotoxics, Platinum (Pt) coordination complexes recently joined the selected group of transition metals capable of performing bioorthogonal reactions in living environments. To minimize their reactivity towards nucleophiles, which limit their catalytic performance, we investigated the use of Pt(0) with different forms, sizes and surface functionalization. We report herein the development of PEGylated Pt nanodendrites with the capacity to activate prodyes and prodrugs in cell culture and in vivo. Their dendritic morphology together with their surface shielding through Pt−S‐bonded PEGylation synergistically contributed to create catalytic nanoreactors compatible with the highly‐crowded and reductive environment of the cell cytoplasm, thereby facilitating in situ bioorthogonal drug uncaging in cancer cells in 2D and 3D culture, including in microfluidic systems, and xenografted in zebrafish.

Controlling the succession of chemical processes with high specificity in complex systems is advantageous for widespread applications, from biomedical research to drug manufacturing. Despite synthetic advances in bioorthogonal and photochemical methodologies, there is a need for generic chemical approaches that can universally modulate photodynamic reactivity in organic photosensitizers. Herein we present a strategy to fine-tune the production of singlet oxygen in multiple photosensitive scaffolds under the activation of bioresponsive and bioorthogonal stimuli. We demonstrate that the photocatalytic activity of nitrobenzoselenadiazoles can be fully blocked by site-selective incorporation of electron-withdrawing carbamate moieties and restored on demand upon uncaging with a wide range of molecular triggers, including abiotic transition-metal catalysts. We also prove that this strategy can be expanded to most photosensitizers, including diverse structures and spectral properties. Finally, we show that such advanced control of singlet oxygen generation can be broadly applied to the photodynamic ablation of human cells as well as to regulate the release of singlet oxygen in the semi-synthesis of natural product drugs.

We introduce hydrogel-coated surfaces loaded with tailored Pd-nanosheets which catalyze the release of antibiotics from inactive prodrugs to prevent the formation of Staphylococcus aureus biofilms.

Being recognized as the best‐tolerated of all metals, the catalytic potential of gold (Au) has thus far been hindered by the ubiquitous presence of thiols in organisms. Herein we report the development of a truly‐catalytic Au‐polymer composite by assembling ultrasmall Au‐nanoparticles at the protein‐repelling outer layer of a co‐polymer scaffold via electrostatic loading. Illustrating the in vivo‐compatibility of the novel catalysts, we show their capacity to uncage the anxiolytic agent fluoxetine at the central nervous system (CNS) of developing zebrafish, influencing their swim pattern. This bioorthogonal strategy has enabled ‐for the first time‐ modification of cognitive activity by releasing a neuroactive agent directly in the brain of an animal.

Being recognized as the best‐tolerated of all metals, the catalytic potential of gold (Au) has thus far been hindered by the ubiquitous presence of thiols in organisms. Herein we report the development of a truly‐catalytic Au‐polymer composite by assembling ultrasmall Au‐nanoparticles at the protein‐repelling outer layer of a co‐polymer scaffold via electrostatic loading. Illustrating the in vivo‐compatibility of the novel catalysts, we show their capacity to uncage the anxiolytic agent fluoxetine at the central nervous system (CNS) of developing zebrafish, influencing their swim pattern. This bioorthogonal strategy has enabled ‐for the first time‐ modification of cognitive activity by releasing a neuroactive agent directly in the brain of an animal.