Fast detection of liver fibrosis with collagen-binding single-nanometer iron oxide nanoparticles via T1-weighted MRI.

SNIO-CBP, a single-nanometer iron oxide (SNIO) nanoparticle functionalized with a type I collagen-binding peptide (CBP), was developed as a T1-weighted MRI contrast agent with only endogenous elements for fast and noninvasive detection of liver fibrosis. SNIO-CBP exhibits 6.7-fold higher relaxivity compared to a molecular gadolinium-based collagen-binding contrast agent CM-101 on a per CBP basis at 4.7 T. Unlike most iron oxide nanoparticles, SNIO-CBP exhibits fast elimination from the bloodstream with a 5.7 min half-life, high renal clearance, and low, transient liver enhancement in healthy mice. We show that a dose of SNIO-CBP that is 2.5-fold lower than that for CM-101 has comparable imaging efficacy in rapid (within 15 min following intravenous injection) detection of hepatotoxin-induced liver fibrosis using T1-weighted MRI in a carbon tetrachloride-induced mouse liver injury model. We further demonstrate the applicability of SNIO-CBP in detecting liver fibrosis in choline-deficient L-amino acid-defined high-fat diet mouse model of nonalcoholic steatohepatitis. These results provide a platform with potential for the development of high relaxivity, gadolinium-free molecular MRI probes for characterizing chronic liver disease.

Dual Hydrazine-Equipped Turn-On Manganese-Based Probes for Magnetic Resonance Imaging of Liver Fibrogenesis.

Liver fibrogenesis is accompanied by upregulation of lysyl oxidase enzymes, which catalyze oxidation of lysine ε-amino groups on the extracellular matrix proteins to form the aldehyde containing amino acid allysine (LysAld). Here, we describe the design and synthesis of novel manganese-based MRI probes with high signal amplification for imaging liver fibrogenesis. Rational design of a series of stable hydrazine-equipped manganese MRI probes gives Mn-2CHyd with the highest affinity and turn-on relaxivity (4-fold) upon reaction with LysAld. A dynamic PET-MRI study using [52Mn]Mn-2CHyd showed low liver uptake of the probe in healthy mice. The ability of the probe to detect liver fibrogenesis was then demonstrated in vivo in CCl4-injured mice. This study enables further development and application of manganese-based hydrazine-equipped probes for imaging liver fibrogenesis.

Bioorthogonal Lanthanide Molecular Probes for Near-Infrared Fluorescence and Mass Spectrometry Imaging.

We report here the development of clickable and highly near-infrared (NIR) fluorescent lanthanide (Ln) complexes for bioorthogonal labeling of biomolecules. These azide- or alkyne-functionalized Ln complexes are hydrophilic and fluorogenic, exhibiting a strong increase of NIR fluorescence upon conjugation with biomolecules. Metabolic labeling of biomolecules with azide or alkyne, followed by click labeling with the Ln complexes, enables NIR fluorescence (NIRF) imaging of DNA, RNA, proteins, and glycans in cells. Furthermore, multicolor imaging is performed by combining click-labeling with the Ln complexes and immunostaining. In addition, the Ln complexes is compatible with click-expansion microscopy (click-ExM), which enables high-resolution NIRF imaging of cellular glycoproteins. Finally, the Ln complexes can be used for time-of-flight secondary-ion mass spectrometry (ToF-SIMS) imaging, thus achieving the first example of dual-modal imaging combining NIRF and SIMS microscopies.

Bioinspired Design of seco-Chlorin Photosensitizers to Overcome Phototoxic Effects in Photodynamic Therapy.

Photodynamic therapy (PDT) is a non-invasive treatment modality against a range of cancers and nonmalignant diseases, however one must be aware of the risk of causing phototoxic reactions after treatment. We herein report a bioinspired design of next-generation photosensitizers (PSs) that not only effectively produce ROS but undergo fast metabolism after treatment to overcome undesirable side effects. We constructed a series of ß-pyrrolic ring-opening seco-chlorins, termed beidaphyrin (BP), beidapholactone (BPL), and their zinc(II) derivatives (ZnBP and ZnBPL), featuring intense near-infrared absorption and effective O2 photosensitization. Irradiation of ZnBPL led to a non-cytotoxic, metabolizable beidaphodiacetamide (ZnBPD) via in situ generated O2.- but not 1 O2 , as revealed by mechanistic studies including time-resolved absorption, kinetics, and isotope labeling. Furthermore, water-soluble ZnBPL showed an effective therapeutic outcome, fast metabolism, and negligible phototoxic reactions.

Split and Use: Structural Isomers for Diagnosis and Therapy.

Diagnostics and therapeutics are generally separate entities in medicine. Theranostics, agents that provide for both modalities, are being developed. However, they often require complex syntheses so as to incorporate within one molecular structure both diagnostic and therapeutic elements. Moreover, their use is often complicated by the disparate dosage requirements for diagnosis and therapy. Herein, we report that closely related porphyrinoid regioisomers produced from the same 1,3-dipolar cycloaddition reaction give rise to products that as their corresponding ytterbium(III) complexes may be split and used for the separate biological functions that are required for theranostics. Specifically, the cis isomer is luminescent and suitable for NIR imaging, while the trans isomer produces singlet oxygen with a good quantum yield and is thus attractive for use in photodynamic therapy (PDT). Both in vitro and in vivo experiments provide support for the complementary biological functions of the two regioisomers. The present study reveals how ostensibly related regioisomers may be used to switch between diagnosis and therapy. More broadly, it serves to highlight a new approach to creating paired sets of molecules that may be used in combination as effective theranostics.

Tri-Manganese(III) Salen-Based Cryptands: A Metal Cooperative Antioxidant Strategy that Overcomes Ischemic Stroke Damage In Vivo.

Oxidative stress is one of the hallmarks of ischemic stroke. Catalase-based (CAT) biomimetic complexes are emerging as promising therapeutic candidates that are expected to act as neuroprotectants for ischemic stroke by decreasing the damaging effects from H2O2. Unfortunately, these molecules result in the unwanted production of the harmful hydroxyl radical, HO•. Here, we report a series of salen-based tri-manganese (Mn(III)) metallocryptands (1-3) that function as catalase biomimetics. These cage-like molecules contain a unique "active site" with three Mn centers in close proximity, an arrangement designed to facilitate metal cooperativity for the effective dismutation of H2O2 with minimal HO• production. In fact, significantly greater oxygen production is seen for 1-3 as compared to the monomeric Mn(Salen) complex, 1c. The most promising system, 1, was studied in further detail and found to confer a greater therapeutic benefit both in vitro and in vivo than the monomeric control system, 1c, as evident from inter alia studies involving a rat model of ischemic stroke damage and supporting histological analyses. We thus believe that metallocryptand 1 and its analogues represent a new and seemingly promising strategy for treating oxidative stress related disorders.

Porpholactone Chemistry: An Emerging Approach to Bioinspired Photosensitizers with Tunable Near-Infrared Photophysical Properties.

Chlorophylls, known as the key building blocks of natural light-harvesting antennae, are essential to utilize solar energy from visible to near-infrared (NIR) region during the photosynthesis process. The fundamental studies for the relationship between structure and photophysical properties of chlorophylls disclosed the importance of ß-peripheral modification and thus boosted the fast growth of NIR absorbing/emissive porphyrinoids via altering the extent of π-conjugation and the degree of distortion from the planarity of macrocycle. Despite the tremendous progress made in various porphyrin-based synthetic models, it still remains a challenge to precisely modulate photophysical properties through fine-tuning of ß-peripheral structures in the way natural chlorophylls do. With this in mind, we initiated a program and focused on meso-C6F5-substituted porpholactone (F20TPPL), in which one ß-pyrrolic double bond was replaced by a lactone moiety, as an attractive platform to construct the bioinspired library of NIR porphyrinoids. In this Account, we summarize our recent contributions to the bioinspired design, synthesis, photophysical characterization, and applications of porpholactones and their derivatives. We have developed a general, convenient method to directly prepare porpholactones in large scale up to gram, which forms the chemical basis of porpholactone chemistry. By modulation of the saturation level and in particular regioisomerization of ß-dilactone moieties, a synthetic library constituted by a series of porpholactones and their derivatives has been established. Thanks to the electron-withdrawing nature of lactone moiety, derivation of the saturation levels gives help to build stable models for chlorin, bacteriochlorin, and tunichlorin. It is worth noting that regioisomerization of dilactone moieties mimics the relative orientation of ß-substituents in natural chlorophylls and hemes, which was considered as the key factor to tune NIR absorption and reactivity. Porpholactones can illustrate the capability of fine-tuning photophysical properties including the excited triplet states by subtle alteration of ß-peripheral structures in the presence of transition metals and lanthanides (Ln). Furthermore, they can serve as efficient photosensitizers for singlet oxygen and NIR Ln, showing potential applications in cell imaging and photocytotoxicity studies. The high luminescence, tunable structures, high cellular uptake, and intense NIR absorption render them as promising and competitive candidates for theranostics in vitro and in vivo. Therefore, extending the studies of "porpholactone chemistry" not only tests the fundamental understanding of the structure-function relationship that governs NIR photophysical properties of natural tetrapyrrole cofactors such as chlorophylls but also provides the guiding principles for the bioinspired design of NIR luminescent molecular probes with various applications. Taken together, as a new synthetic porphyrin derivative, porpholactone chemistry shines light on synthetic porphyrin, bioinorganic, and lanthanide chemistry.

Angstrom Scale Chemical Analysis of Metal Supported Trans- and Cis-Regioisomers by Ultrahigh Vacuum Tip-Enhanced Raman Mapping.

Real space chemical analysis of two structurally very similar components, that is, regioisomers lies at the heart of heterogeneous catalysis reactions, modern-age electronic devices, and various other surface related problems in surface science and nanotechnology. One of the big challenges in surface chemistry is to identify different surface adsorbed molecules and analyze their chemical properties individually. Herein, we report a topological and chemical analysis of two regioisomers, trans- and cis-tetrakispentafluorophenylporphodilactone ( trans- and cis-H2F20TPPDL) molecules by high-resolution scanning tunneling microscopy, and ultrahigh vacuum tip-enhanced Raman spectroscopy (UHV-TERS). Both isomeric structures are investigated individually on Ag(100) at liquid nitrogen temperature. Following that, we have successfully distinguished these two regioisomeric molecules simultaneously through TERS with an angstrom scale (8 Å) spatial resolution. Also, the two-component organic heterojunction has been characterized at large scale using high-resolution two-dimensional mapping. Combined with time-dependent density functional theory simulations, we explain the TERS spectral discrepancies for both isomers in the fingerprint region.

Strong Fluorescent Lanthanide Salen Complexes: Photophysical Properties, Excited-State Dynamics, and Bioimaging.

The synthesis, excited-state dynamics, and biological application of luminescent lanthanide salen complexes (Ln = Lu, Gd, Eu, Yb, salen = N, N'-bis(salicylidene)ethylenediamine-based ligands) with sandwich structures are described. Among them, Lu(III) complexes show unusually strong ligand-centered fluorescence with quantum yields up to 62%, although the metal center is close to a chromophore ligand. The excited-state dynamic studies including ultrafast spectroscopy for Ln-salen complexes revealed that their excited states are solely dependent on the salen ligands and the ISC rates are slow (108-109 s-1). Importantly, time-dependent density functional theory calculations attribute the low energy transfer efficiency to the weak spin-orbital coupling (SOC) between the singlet and triplet excited states. More importantly, Lu-salen has been applied as a molecular platform to construct fluorescence probes with organelle specificity in living cell imaging, which demonstrates the advantages of the sandwich structures as being capable of preventing intramolecular metal-ligand interactions and behaviors different from those of the previously reported Zn-salens. Most importantly, the preliminary study for in vivo imaging using a mouse model demonstrated the potential application of Ln coordination complexes in therapeutic and diagnostic bioimaging beyond living cells or in vitro.

Design of Near-Infrared Luminescent Lanthanide Complexes Sensitive to Environmental Stimulus through Rationally Tuning the Secondary Coordination Sphere.

The design of near-infrared (NIR) emissive lanthanide (Ln) complexes sensitive to external stimulus is fundamentally important for the practical application of Ln materials. Because NIR emission from Ln is extremely sensitive to X-H (X = C, N and O) bond vibration, we herein report to harness the secondary coordination sphere to design NIR luminescent lanthanide sensors. Toward this goal, we designed and synthesized two isomeric [(η5-C5H5)Co{(D3CO)2P = O}3]-Yb(III)-7,8,12,13,17,18-hexafluoro-5,10,15,20-tetrakis(pentafluorophenyl)porpholactol NIR emitters, Yb-up and Yb-down, based on the stereoisomerism of porphyrin peripheral ß-hydroxyl group. Yb-up, in which ß-OH is at the same side of Yb(III) center, can form an intramolecular hydrogen bond with the axial Kläui ligand, whereas Yb-down cannot because its ß-OH is opposite to Yb(III) center. X-ray crystal structures and photophysical studies suggested that the intramolecular hydrogen bond plays important roles on the NIR luminescence of ytterbium(III), which shortens the distance between ß-OH and Yb(III) and facilitates the nonradiative deactivation of Ln excited state. Importantly, Yb-up/down were demonstrated to be highly sensitive toward temperature and viscosity. The PMMA polymer using Yb-up as the dopant NIR emitter showed thermosensitivity up to 6.0% °C-1 in the wide temperature range of 77-400 K, higher than that of Yb-down (3.8% °C-1). These complexes were also explored as the first NIR viscosity sensor, revealing their potential applications as optical sensors without visible light interference. This work demonstrates the importance of secondary coordination sphere on designing NIR Ln luminescent functional materials.

Bioinspired Orientation of ß-Substituents on Porphyrin Antenna Ligands Switches Ytterbium(III) NIR Emission with Thermosensitivity.

"Configurational isomerism" is an important approach found in naturally occurring chlorophylls to modulate light harvesting function without significant structural changes; however, this feature has been seldom applied in design of antenna ligands for lanthanide (Ln) sensitization. In this work, we introduced a bioinspired approach by orientation of ß-dilactone moieties on porphyrinates, namely cis-/trans-porphodilactones, to modulate the energy transfer process from the lowest triplet excited state of the ligand (T1) to the emitting level of ytterbium(III) (2F5/2, Yb*). Interestingly, near-infrared (NIR) emission of Yb(III) could be switched "on" by the cis-porphodilactone ligand, while the trans-isomer renders Yb(III) emission "off" and the ratio of quantum yields is ∼8. Analysis of the structure-photophysical properties relationship suggests that the significant emission difference is correlated to the energy gaps between T1 and Yb* (1152 cm-1 in the cis- vs -25 cm-1 in the trans-isomer). More interestingly, due to back energy transfer (BEnT), the Yb(III) complex of cis-porphodilactone exhibits NIR emission with high thermosensitivity (4.0%°C-1 in solution and 4.9%°C-1 in solid state), comparable to previously reported terbium (Tb) and europium (Eu) visible emitters, in contrast to the trivial emission changes of the trans-isomer and porphyrin and porpholactone analogues. This work opens up new access to design NIR emissive Ln complexes by bioinspired modification of antenna ligands.

Gadolinium(III) Porpholactones as Efficient and Robust Singlet Oxygen Photosensitizers.

Construction of Gd(III) photosensitizers is important for designing theranostic agents owing to the unique properties arising from seven unpaired f electrons of the Gd(3+) ion. Combining these with the advantages of porpholactones with tunable NIR absorption, we herein report the synthesis of Gd(III) complexes Gd-1-4 (1, porphyrin; 2, porpholactone; 3 and 4, cis- and trans-porphodilactone, respectively) and investigated their function as singlet oxygen ((1) O2 ) photosensitizers. These Gd complexes displayed (1) O2 quantum yields (ΦΔ s) from 0.64-0.99 with the order Gd-1

Fine-Tuning of ß-Substitution to Modulate the Lowest Triplet Excited States: A Bioinspired Approach to Design Phosphorescent Metalloporphyrinoids.

Learning nature's approach to modulate photophysical properties of NIR porphyrinoids by fine-tuning ß-substituents including the number and position, in a manner similar to naturally occurring chlorophylls, has the potential to circumvent the disadvantages of traditional "extended π-conjugation" strategy such as stability, molecular size, solubility, and undesirable π-π stacking. Here we show that such subtle structural changes in Pt(II) or Pd(II) cis/trans-porphodilactones (termed by cis/trans-Pt/Pd) influence photophysical properties of the lowest triplet excited states including phosphorescence, Stokes shifts, and even photosensitization ability in triplet-triplet annihilation reactions with rubrene. Prominently, the overall upconversion capability (η, η = ε·Φ(UC)) of Pd or Pt trans-complex is 10(4) times higher than that of cis-analogue. Nanosecond time-resolved infrared (TR-IR) spectroscopy experiments showed larger frequency shift of ν(C═O) bands (ca. 10 cm(-1)) of cis-complexes than those of trans-complexes in the triplet excited states. These spectral features, combining with TD-DFT calculations, suggest the strong electronic coupling between the lactone moieties and the main porphyrin chromophores and thus the importance of precisely positioning ß-substituents by mimicking chlorophylls, as an alternative to "extended π-conjugation", in designing NIR active porphyrinoids.

Structure and Properties of Exopolysaccharide Produced by Gluconobacter frateurii and Its Potential Applications.

An exopolysaccharide (EPS)-producing bacterium was isolated from apricot fermentation broth and identified as Gluconobacter frateurii HDC-08 (accession number: OK036475.1). HDC-08 EPS is a linear homopolysaccharide mainly composed of glucose linked by α-(1,6) glucoside bonds. It contains C, H, N and S elements, with a molecular weight of 4.774 × 106 Da. Microscopically, it has a smooth, glossy and compact sheet structure. It is an amorphous noncrystalline substance with irregular coils. Moreover, the EPS showed surface hydrophobicity and high thermal stability with a degradation temperature of 250.76 °C. In addition, it had strong antioxidant properties against DPPH radicals, ABPS radicals, hydroxyl radicals and H2O2. The EPS exhibited high metal-chelating activity and strong emulsifying ability for soybean oil, petroleum ether and diesel oil. The milk solidification test indicated that the EPS had good potential in fermented dairy products. In general, all the results demonstrate that HDC-08 EPS has promise for commercial applications as a food additive and antioxidant.

Simultaneous Positron Emission Tomography and Molecular Magnetic Resonance Imaging of Cardiopulmonary Fibrosis in a Mouse Model of Left Ventricular Dysfunction.

BACKGROUND: Aging-associated left ventricular dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in a left ventricular dysfunction model. METHODS AND RESULTS: Left ventricular dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone mice, a subset of mice that received sham surgery. Three weeks after surgery, mice underwent simultaneous PET-MRI at 4.7 T. Collagen-targeted PET and fibrogenesis magnetic resonance (MR) probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio. Percent signal intensity increase and Δ lung-to-muscle ratio were computed from the pre-/postinjection magnetic resonance images. Elevated allysine in the heart (P=0.02) and lungs (P=0.17) of TAC mice corresponded to an increase in myocardial magnetic resonance imaging percent signal intensity increase (P<0.0001) and Δlung-to-muscle ratio (P<0.0001). Hydroxyproline in the heart (P<0.0001) and lungs (P<0.01) were elevated in TAC mice, which corresponded to an increase in heart (myocardium-to-muscle ratio, P=0.02) and lung (lung-to-muscle ratio, P<0.001) PET measurements. Pressure-volume loop and echocardiography demonstrated adverse left ventricular remodeling, function, and increased right ventricular systolic pressure in TAC mice. CONCLUSIONS: Administration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-magnetic resonance imaging signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-magnetic resonance imaging protocol.

Two birds one stone: ß-fluoropyrrolyl-cysteine SNAr chemistry enabling functional porphyrin bioconjugation.

Bioconjugation, a synthetic tool that endows small molecules with biocompatibility and target specificity through covalent attachment of a biomolecule, holds promise for next-generation diagnosis or therapy. Besides the establishment of chemical bonding, such chemical modification concurrently allows alteration of the physicochemical properties of small molecules, but this has been paid less attention in designing novel bioconjugates. Here, we report a "two birds one stone" methodology for irreversible porphyrin bioconjugation based on ß-fluoropyrrolyl-cysteine SNAr chemistry, in which the ß-fluorine of porphyrin is selectively replaced by a cysteine in either peptides or proteins to generate novel ß-peptidyl/proteic porphyrins. Notably, due to the distinct electronic nature between fluorine and sulfur, such replacement makes the Q band red-shift to the near-infrared region (NIR, >700 nm). This facilitates intersystem crossing (ISC) to enhance the triplet population and thus singlet oxygen production. This new methodology features water tolerance, a fast reaction time (15 min), good chemo-selectivity, and broad substrate scope, including various peptides and proteins under mild conditions. To demonstrate its potential, we applied porphyrin ß-bioconjugates in several scenarios, including (1) cytosolic delivery of functional proteins, (2) metabolic glycan labeling, (3) caspase-3 detection, and (4) tumor-targeting phototheranostics.

Optimization of an Allysine-Targeted PET Probe for Quantifying Fibrogenesis in a Mouse Model of Pulmonary Fibrosis.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a destructive lung disease with a poor prognosis, an unpredictable clinical course, and inadequate therapies. There are currently no measures of disease activity to guide clinicians making treatment decisions. The aim of this study was to develop a PET probe to identify lung fibrogenesis using a pre-clinical model of pulmonary fibrosis, with potential for translation into clinical use to predict disease progression and inform treatment decisions. METHODS: Eight novel allysine-targeting chelators, PIF-1, PIF-2, …, PIF-8, with different aldehyde-reactive moieties were designed, synthesized, and radiolabeled with gallium-68 or copper-64. PET probe performance was assessed in C57BL/6J male mice 2 weeks after intratracheal bleomycin challenge and in naïve mice by dynamic PET/MR imaging and with biodistribution at 90 min post injection. Lung hydroxyproline and allysine were quantified ex vivo and histological staining for fibrosis and aldehyde was performed. RESULTS: In vivo screening of probes identified 68GaPIF-3 and 68GaPIF-7 as probes with high uptake in injured lung, high uptake in injured lung versus normal lung, and high uptake in injured lung versus adjacent liver and heart tissue. A crossover, intra-animal PET/MR imaging study of 68GaPIF-3 and 68GaPIF-7 confirmed 68GaPIF-7 as the superior probe. Specificity for fibrogenesis was confirmed in a crossover, intra-animal PET/MR imaging study with 68GaPIF-7 and a non-binding control compound, 68GaPIF-Ctrl. Substituting copper-64 for gallium-68 did not affect lung uptake or specificity indicating that either isotope could be used. CONCLUSION: A series of allysine-reactive PET probes with variations in the aldehyde-reactive moiety were evaluated in a pre-clinical model of lung fibrosis. The hydrazine-bearing probe, 68GaPIF-7, exhibited the highest uptake in fibrogenic lung, low uptake in surrounding liver or heart tissue, and low lung uptake in healthy mice and should be considered for further clinical translation.

Recent progress in metal-based molecular probes for optical bioimaging and biosensing.

Biological imaging and biosensing from subcellular/cellular level to whole body have enabled non-invasive visualisation of molecular events during various biological and pathological processes, giving great contributions to the rapid and impressive advances in chemical biology, drug discovery, disease diagnosis and prognosis. Optical imaging features a series of merits, including convenience, high resolution, good sensitivity, low cost and the absence of ionizing radiation. Among different luminescent probes, metal-based molecules offer unique promise in optical bioimaging and biosensing in vitro and in vivo, arising from their small sizes, strong luminescence, large Stokes shifts, long lifetimes, high photostability and tunable toxicity. In this review, we aim to highlight the design of metal-based molecular probes from the standpoint of synthetic chemistry in the last 2 years for optical imaging, covering d-block transition metal and lanthanide complexes and multimodal imaging agents.

Gadolinium(III) Porphyrinoid Phototheranostics.

Molecular phototheranostics as an emerging field of modern precision medicine has recently attracted increasing research attention owing to non-invasiveness, high precision, and controllable nature of light. In this work, we reported promising gadolinium (Gd3+ ) porphyrinoids as phototheranostic agents for magnetic resonance imaging (MRI) and photodynamic therapy (PDT). The synthesized Gd-1-4-Glu featured with meso-glycosylation and ß-lactonization to endow good biocompatibility and improved photophysical properties. In particular, ß-lactonization of glycosylated Gd3+ porphyrinoids substantially red-shifted Q band absorption to near-infrared (NIR) region and boosted generation of reactive oxygen species including 1 O2 , and some radical species that engaged in both type II and type I PDT pathways. In addition, the number and regioisomerism of ß-oxazolone moieties was observed to play an essential role in improving longitude relaxivity (r1 ) of Gd-1-4-Glu of up to 4.3±0.2 mM-1 s-1 by affecting environmental water exchange. Taking Gd-4-Glu as a promising complex, we further achieved real-time T1 -weighted MRI and PDT on HeLa tumour mice in vivo, revealing the appealing potential of Gd3+ porphyrinoids in phototheranostics.

Molecular MRI quantification of extracellular aldehyde pairs for early detection of liver fibrogenesis and response to treatment.

Liver fibrosis plays a critical role in the evolution of most chronic liver diseases and is characterized by a buildup of extracellular matrix, which can progress to cirrhosis, hepatocellular carcinoma, liver failure, or death. Now, there are no noninvasive methods available to accurately assess disease activity (fibrogenesis) to sensitively detect early onset of fibrosis or to detect early response to treatment. Here, we hypothesized that extracellular allysine aldehyde (LysAld) pairs formed by collagen oxidation during active fibrosis could be a target for assessing fibrogenesis with a molecular probe. We showed that molecular magnetic resonance imaging (MRI) using an extracellular probe targeting these LysAld pairs acts as a noninvasive biomarker of fibrogenesis and demonstrated its high sensitivity and specificity in detecting fibrogenesis in toxin- and dietary-induced mouse models, a cholestasis rat model of liver fibrogenesis, and in human fibrotic liver tissues. Quantitative molecular MRI was highly correlated with fibrogenesis markers and enabled noninvasive detection of early onset fibrosis and response to antifibrotic treatment, showing high potential for clinical translation.