Functionalizing Collagen with Vessel‐Penetrating Two‐Photon Phosphorescence Probes: A New In Vivo Strategy to Map Oxygen Concentration in Tumor Microenvironment and Tissue Ischemia

Abstract

The encapsulation and/or surface modification can stabilize and protect the phosphorescence bio-probes but impede their intravenous delivery across biological barriers. Here, a new class of biocompatible rhenium (Re I ) diimine carbonyl complexes is developed, which can efficaciously permeate normal vessel walls and then functionalize the extravascular collagen matrixes as in situ oxygen sensor. Without protective agents, Re I -diimine complex already exhibits excellent emission yield (34%, 𝝀 em = 583 nm) and large two-photon absorption cross-sections (𝝈 2 = 300 GM @ 800 nm) in water (pH 7.4). After extravasation, remarkably, the collagen-bound probes further enhanced their excitation efficiency by increasing the deoxygenated lifetime from 4.0 to 7.5 μs, paving a way to visualize tumor hypoxia and tissue ischemia in vivo. The post-extravasation functionalization of extracellular matrixes demonstrates a new methodology for biomaterial-empowered phosphorescence sensing and imaging.

Luminescent and Photofunctional Transition Metal Complexes: From Molecular Design to Diagnostic and Therapeutic Applications

“…20 A rhenium(I) complex (1) (Chart 1) featuring a long emission lifetime (τ o = 4.05 μs) and large TPA cross-section (δ 800 nm = 300 GM) has been designed for visualizing tissue ischemia and tumor hypoxia in vivo using PLIM. 22 The anionic sulfonate groups allow the complex to interact with collagen in the extracellular matrix after extravasation to form a stable conjugate for longterm O 2 mapping. A dinuclear ruthenium(II) complex (2), where the two ruthenium(II) units [Ru(bpy) 2 (phen)] 2+ (phen = 1,10-phenanthroline) are bridged with a mitochondria penetrating peptide (MPP; FrFKFrFK) (r = D-arginine), has been developed to monitor the mitochondrial O 2 level.…”

“…51 The ionized carboxylate groups of complex 21c suppress the internalization of the complex, facilitating the SPAAC reaction with membrane-bound azide units. Related rhenium(I) (22) 52 and ruthenium(II) DIBO complexes (23) 53 intracellular trafficking dynamics of plasma membrane glycans. A novel "labeling after recognition" approach has been designed for the detection of caspase-3 activity in apoptotic cells.…”

“…Luminescent transition metal complexes are promising candidates for monitoring the O 2 level in a nondestructive, real-time, and reversible manner because the collisional interaction between the triplet emissive state of the complex and the triplet ground state of O 2 results in emission quenching . A rhenium­(I) complex ( 1 ) (Chart ) featuring a long emission lifetime (τ o = 4.05 μs) and large TPA cross-section (δ 800 nm = 300 GM) has been designed for visualizing tissue ischemia and tumor hypoxia in vivo using PLIM . The anionic sulfonate groups allow the complex to interact with collagen in the extracellular matrix after extravasation to form a stable conjugate for long-term O 2 mapping.…”

Shining New Light on Biological Systems: Luminescent Transition Metal Complexes for Bioimaging and Biosensing Applications

“…Liu, Tunik, Koshevoy, Chou, and co-workers have designed a rhenium (I) dicarbonyl complex (16) (Chart 6) for O 2 sensing. 82 Compared to its tricarbonyl counterpart, the complex displays red-shifted emission with an increased emission quantum yield and lifetime (λ em = 583 nm, Φ em = 0.34, τ o = 4.05 μs) and possesses a larger TPA cross-section (δ 800nm = 300 GM) in aqueous solution. The anionic sulfonate groups on the phosphine ligands allow the complex to interact with collagen in the extracellular matrix after extravasation, facilitating the visualization of tissue ischemia and tumor hypoxia in vivo using two-photon excitation PLIM (TP-PLIM).…”

Rhenium fac-Tricarbonyl Bisimine Chalcogenide Complexes: Synthesis, Photophysical Studies, and Confocal and Time-Resolved Cell Microscopy

“…While there are many reports of the application of these complexes in biological imaging, and of their long lifetimes, there are relatively few reports of the application of such complexes in time-resolved imaging studies, − while iridium and ruthenium complexes, for example, are commonly used in this way. − Time-resolved microscopy with triplet emitters takes advantage of their long lifetimes in a variety of different ways, principally time gating or lifetime mapping. Time-gated techniques differentiate between short-lived emission from singlet emitters such as autofluorescence or organic fluorophores by separating the long-lived components of a decay from the shorter components and generating images consisting solely of the light emitted after a given time period, illustrating the distribution of the metal complexes. , Lifetime mapping generates a single image containing all of the decay components but with each pixel colored on a lifetime scale rather than by intensity or wavelength of emission, giving an image that visually presents differences in excited-state lifetime across the cells.…”