Transdermal Hydrogen Sulfide Delivery Enabled by Open-Metal-Site Metal-Organic Frameworks.

Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter involved in many physiological processes that are integral to proper cellular functioning. Due to its profound anti-inflammatory and antioxidant properties, H2S plays important roles in preventing inflammatory skin disorders and improving wound healing. Transdermal H2S delivery is a therapeutically viable option for the management of such disorders. However, current small-molecule H2S donors are not optimally suited for transdermal delivery and typically generate electrophilic byproducts that may lead to undesired toxicity. Here, we demonstrate that H2S release from metal-organic frameworks (MOFs) bearing coordinatively unsaturated metal centers is a promising alternative for controlled transdermal delivery of H2S. Gas sorption measurements and powder X-ray diffraction (PXRD) studies of 11 MOFs support that the Mg-based framework Mg2(dobdc) (dobdc4- = 2,5-dioxidobenzene-1,4-dicarboxylate) is uniquely well-suited for transdermal H2S delivery due to its strong yet reversible binding of H2S, high capacity (14.7 mmol/g at 1 bar and 25 °C), and lack of toxicity. In addition, Rietveld refinement of synchrotron PXRD data from H2S-dosed Mg2(dobdc) supports that the high H2S capacity of this framework arises due to the presence of three distinct binding sites. Last, we demonstrate that transdermal delivery of H2S from Mg2(dobdc) is sustained over a 24 h period through porcine skin. Not only is this significantly longer than sodium sulfide but this represents the first example of controlled transdermal delivery of pure H2S gas. Overall, H2S-loaded Mg2(dobdc) is an easily accessible, solid-state source of H2S, enabling safe storage and transdermal delivery of this therapeutically relevant gas.

Gas Delivery Relevant to Human Health using Porous Materials.

Gases are essential for various applications relevant to human health, including in medicine, biomedical imaging, and pharmaceutical synthesis. However, gases are significantly more challenging to safely handle than liquids and solids. Herein, we review the use of porous materials, such as metal-organic frameworks (MOFs), zeolites, and silicas, to adsorb medicinally relevant gases and facilitate their handling as solids. Specific topics include the use of MOFs and zeolites to deliver H2S for therapeutic applications, 129Xe for magnetic resonance imaging, O2 for the treatment of cancer and hypoxia, and various gases for use in organic synthesis. This Perspective aims to bring together the organic, inorganic, medicinal, and materials chemistry communities to inspire the design of next-generation porous materials for the storage and delivery of medicinally relevant gases.

Targeted, Molecular Europium(III) Probes Enable Luminescence-Guided Surgery and 1 Photon Post-Surgical Luminescence Microscopy of Solid Tumors.

Discrete luminescent lanthanide complexes represent a potential alternative to organic chromophores due to their tunability of optical properties, insensitivity to photobleaching, and large pseudo-Stokes shifts. Previously, we demonstrated that the lack of depth penetration of UV excitation required to sensitize discrete terbium and europium complexes can be overcome using Cherenkov radiation emitted by clinically employed radioisotopes in situ. Here, we show that the second-generation europium complexes [Eu(III)(pcta-PEPA2)] and [Eu(III)(tacn-pic-PEPA2)] (Φ = 57% and 76%, respectively) lower the limit of detection (LoD) to 1 nmol in the presence of 10 µCi of Cherenkov emitting isotopes, 18F and 68Ga. Bifunctionalization provides access to cysteine-linked peptide conjugates with comparable brightness and LoD. The conjugate, [Eu(tacn-(pic-PSMA)-PEPA2)], displays high binding affinity to prostate-specific membrane antigen (PSMA)-expressing PC-3 prostate cancer cells in vitro and can be visualized in the membrane-bound state using confocal microscopy. Biodistribution studies with the [86Y][Y(III)(tacn-(pic-PSMA)-PEPA2)] analogue in a mouse xenograft model were employed to study pharmacokinetics. Systemic administration of the targeted Cherenkov emitter, [68Ga][Ga(III)(PSMA-617)], followed by intratumoral injection or topical application of 20 or 10 nmol [Eu(III)(tacn-(pic-PSMA)-PEPA2)], respectively, in live mice resulted in statistically significant signal enhancement using conventional small animal imaging (620 nm bandpass filter). Optical imaging informed successful tumor resection. Ex vivo imaging of the fixed tumor tissue with 1 and 2 photon excitation further reveals the accumulation of the administered Eu(III) complex in target tissues. This work represents a significant step toward the application of luminescent lanthanide complexes for optical imaging in a clinical setting.