Facile Peptide Macrocyclization and Multifunctionalization via Cyclen Installation.

Cyclen-peptide bioconjugates are usually prepared in multiple steps that require individual preparation and purification of the cyclic peptide and hydrophilic cyclen derivatives. An efficient strategy is discovered for peptide cyclization and functionalization toward lanthanide probe via three components intermolecular crosslinking on solid-phase peptide synthesis with high conversion yield. Multifunctionality can be conferred by introducing different modular parts or/and metal ions on the cyclen-embedded cyclopeptide. As a proof-of-concept, a luminescent Eu3+ complex and a Gd3+-based contrasting agent for in vitro optical imaging and in vivo magnetic resonance imaging, respectively, are demonstrated through utilizing this preparation of cyclen-embedded cyclic arginylglycylaspartic acid (RGD) peptide.

MSOT-Guided Nanotheranostics for Synergistic Mild Photothermal Therapy and Chemotherapy to Boost Necroptosis/Apoptosis.

The development of nanotheranostics for precision imaging-guided regulated cell death-mediated synergistic tumor therapy is still challenging. Herein, a novel multifunctional nanotheranostic agent, iRGD-coated maleimide-poly(ethylene glycol)-poly(lactic acid/glycolic acid)-encapsulated hydrophobic gold nanocages (AuNCs) and hydrophilic epigallocatechin gallate (EGCG) (PAuE) is developed for multispectral optoacoustic tomography (MSOT)-guided photothermal therapy (PTT) and chemotherapy. The portions of necroptotic and apoptotic tumor cells were 52.9 and 5.4%, respectively, at 6 h post-incubation after the AuNC-induced mild PTT treatment, whereas they became 14.0 and 46.1% after 24 h, suggesting that the switch of the cell death pathway is a time-dependent process. Mild PTT facilitated the release of EGCG which induces the downregulation of hypoxia-inducible factor-1 (HIF-1α) expression to enhance apoptosis at a later stage, realizing a remarkable tumor growth inhibition in vivo. Moreover, RNA sequence analyses provided insights into the significant changes in genes related to the cross-talk between necroptosis and apoptosis pathways via PAuE upon laser irradiation. In addition, the biodistribution and metabolic pathways of PAuE have been successfully revealed by 3D MSOT. Taken together, this strategy of first combination of EGCG and AuNC-based photothermal agent via triggering necroptosis/apoptosis to downregulate HIF-1α expression in a tumor environment provides a new insight into anti-cancer therapy.

Nitroreductase-Induced Aggregation of Gold Nanoparticles for "Off-On" Photoacoustic Imaging of Tumor Hypoxia.

Hypoxia is an important phenomenon due to insufficient oxygen supply in tumor tissue, and nitroreductase (NTR) is a characteristic enzyme used for evaluating hypoxia level in tumors. In this work, we designed a smart gold nanoparticle (AuNPs), modified by 16-mercaptoundecanoic acid (MHDA) and hypoxia-responsive 11-(2-nitro-1H-imidazol-1-yl)undecane-1-thiol (NI) ligand, that responds to the hypoxic environment in tumor sites. With proper surface ligand composition, the responsive nanoprobe exhibited aggregation through the bioreduction of the nitro group on NI ligands under hypoxic conditions and the UV-vis absorption peak maximum would shift to 630 nm from 530 nm, which acts as an "off-on" contrast agent for tumor hypoxic photoacoustic (PA) imaging. In vitro and in vivo experiments revealed that AuNPs@MHDA/NO2 exhibited an enhanced PA signal in hypoxic conditions. This study demonstrates the potential of hypoxia-responsive AuNPs as novel and sensitive diagnostic agents, which lays a firm foundation for precise cancer treatment in the future.

Lanthanide-tetrapyrrole complexes: synthesis, redox chemistry, photophysical properties, and photonic applications.

Tetrapyrrole derivatives such as porphyrins, phthalocyanines, naphthalocyanines, and porpholactones, are highly stable macrocyclic compounds that play important roles in many phenomena linked to the development of life. Their complexes with lanthanides are known for more than 60 years and present breath-taking properties such as a range of easily accessible redox states leading to photo- and electro-chromism, paramagnetism, large non-linear optical parameters, and remarkable light emission in the visible and near-infrared (NIR) ranges. They are at the centre of many applications with an increasing focus on their ability to generate singlet oxygen for photodynamic therapy coupled with bioimaging and biosensing properties. This review first describes the synthetic paths leading to lanthanide-tetrapyrrole complexes together with their structures. The initial synthetic protocols were plagued by low yields and long reaction times; they have now been replaced with much more efficient and faster routes, thanks to the stunning advances in synthetic organic chemistry, so that quite complex multinuclear edifices are presently routinely obtained. Aspects such as redox properties, sensitization of NIR-emitting lanthanide ions, and non-linear optical properties are then presented. The spectacular improvements in the quantum yield and brightness of YbIII-containing tetrapyrrole complexes achieved in the past five years are representative of the vitality of the field and open welcome opportunities for the bio-applications described in the last section. Perspectives for the field are vast and exciting as new derivatizations of the macrocycles may lead to sensitization of other LnIII NIR-emitting ions with luminescence in the NIR-II and NIR-III biological windows, while conjugation with peptides and aptamers opens the way for lanthanide-tetrapyrrole theranostics.

In vivo photoacoustic imaging for monitoring treatment outcome of corneal neovascularization with metformin eye drops.

Corneal neovascularization (CNV) compromises corneal avascularity and visual acuity. Current clinical visualization approaches are subjective and unable to provide molecular information. Photoacoustic (PA) imaging offers an objective and non-invasive way for angiogenesis investigation through hemodynamic and oxygen saturation level (sO2) quantification. Here, we demonstrate the utility of PA and slit lamp microscope for in vivo rat CNV model. PA images revealed untreated corneas exhibited higher sO2 level than treatment groups. The PA results complement with the color image obtained with slit lamp. These data suggest PA could offer an objective and non-invasive method for monitoring CNV progression and treatment outcome through the sO2 quantification.

Biomimetic Anti-PD-1 Peptide-Loaded 2D FePSe3 Nanosheets for Efficient Photothermal and Enhanced Immune Therapy with Multimodal MR/PA/Thermal Imaging.

Metal phosphorous trichalcogenides (MPX3) are novel 2D nanomaterials that have recently been exploited as efficient photothermal-chemodynamic agents for cancer therapy. As a representative MPX3, FePSe3 has the potential to be developed as magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) agents due to the composition of Fe and the previously revealed PA signal. Here, a FePSe3-based theranostic agent, FePSe3@APP@CCM, loaded with anti-PD-1 peptide (APP) as the inner component and CT26 cancer cell membrane (CCM) as the outer shell is reported, which acts as a multifunctional agent for MR and PA imaging and photothermal and immunotherapy against cancer. FePSe3@APP@CCM induces highly efficient tumor ablation and suppresses tumor growth by photothermal therapy under near-infrared laser excitation, which further activates immune responses. Moreover, APP blocks the PD-1/PD-L1 pathway to activate cytotoxic T cells, causing strong anticancer immunity. The combined therapy significantly prolongs the lifespan of experimental mice. The multimodal imaging and synergistic therapeutic effects of PTT and its triggered immune responses and APP-related immunotherapy are clearly demonstrated by in vitro and in vivo experiments. This work demonstrates the potential of MPX3-based biomaterials as novel theranostic agents.

pH-Triggered Poly(ethylene glycol)-Poly(lactic acid/glycolic acid)/Croconaine Nanoparticles-Assisted Multiplexed Photoacoustic Imaging and Enhanced Photothermal Cancer Therapy.

The most advantageous and attractive property of photoacoustic imaging is its capability to visualize and differentiate multiple species according to their unique absorbance profiles simultaneously in a single mixture. We here report the pH-sensitive near-infrared (NIR) croconaine (Croc) dyes-loaded copolymeric PEG-PLGA nanoparticles (NPs) for in vivo multiplexed PA imaging and pH-responsive photothermal therapy (PTT) in an orthotopic xenograft model. PEG chains on the polymeric NPs shell were conjugated with iRGD in another set of NPs to realize efficient tumor targeting. The distribution and the intensity of two sets of iRGD-targeted and nontargeted NPs inside tumors are simultaneously imaged and monitored in vivo. Meanwhile, the utilization of iRGD-targeted PPC815 NPs as a pH-active photothermal agent with promising tumor-inhibition efficacy was demonstrated. As a result, this nanoplatform is capable of assisting multiwavelength unmixing of PA imaging as well as providing remarkable photothermal ablation for anticancer treatment.

Multifunctional Nanotheranostic Gold Nanocage/Selenium Core-Shell for PAI-Guided Chemo-Photothermal Synergistic Therapy in vivo.

INTRODUCTION: Cancer theragnosis involving cancer diagnosis and targeted therapy simultaneously in one integrated system would be a promising solution of cancer treatment. Herein, a convenient and practical cancer theragnosis agent was constructed by combining gold nanocages (AuNCs) covered with selenium and a chitosan (CS) shell (AuNCs/Se) to incorporate the anti-cancer drug doxorubicin (DOX) as a multifunctional targeting nanocomposite (AuNCs/DOX@Se-iRGD) for photoacoustic imaging (PAI)-guided chemo-photothermal synergistic therapy that contributes to enhanced anti-cancer efficacy. The novel design of AuNCs/DOX@Se-iRGD gives the nanocomposite two outstanding properties: (1) AuNCs, with excellent LSPR property in the NIR region, act as a contrast agent for enhanced PAI and photothermal therapy (PTT); (2) Se acts as an anti-cancer nanoagent and drug delivery cargo. METHODS: The photothermal performance of these nanocomposites was evaluated in different concentrations with laser powder densities. These nanocomposites were also incubated in pH 5.3, 6.5, 7.4 PBS and NIR laser to study their drug release ability. The cellular uptake was studied by measuring the Se and Au concentrations inside the cells using inductively coupled plasma-mass spectrometry (ICP-MS). Besides, in vitro and in vivo anti-tumor activity were carried out by cytotoxicity assay MTT and tumor model nude mice, respectively. As for imaging, the PA value and images of these nanocomposites accumulated in the tumor site were sequentially collected at specific time points for 48 h. RESULTS AND DISCUSSION: The prepared AuNCs/DOX@Se-iRGD showed excellent biocompatibility and physiological stability in different media. In vivo results indicated that the targeting nanocomposite presented the strongest contrast-enhanced PAI signals, which could provide contour and location information of tumor, 24 h after intravenous injection. Likewise, the combined treatment of chemo- and photothermal synergistic therapy significantly inhibited tumor growth when compared with the two treatments carried out separately and showed negligible acute toxicity to the major organs. CONCLUSION: This study demonstrates that AuNCs/DOX@Se-iRGD has great prospect to become a multifunctional anti-tumor nanosystem for PAI-guided chemo- and photothermal synergistic therapy.

Catalytic asymmetric oxo-Diels-Alder reactions with chiral atropisomeric biphenyl diols.

New chiral atropisomeric biphenyl diols 3, 4 and 6 containing additional peripheral chiral centers with different steric bulkiness and/or electronic properties were synthesized. The X-ray crystal structure of 3 shows the formation of a supramolecular structure whereas that of 6, containing additional CF3 substituents, shows the formation of a monomeric structure. Diols 1-6 were found to be active organocatalysts in oxo-Diels-Alder reactions in which 2 recorded a 72% ee with trimethylacetaldehyde as a substrate.

Breaking the 1,2-HOPO barrier with a cyclen backbone for more efficient sensitization of Eu(iii) luminescence and unprecedented two-photon excitation properties.

A cyclen backbone was utilized to study the effect of backbone rigidity on Eu(iii) luminescence sensitization using a 1,2-HOPO derivative and 2-thenoyltrifluoroacetonate (TTA) as chromophores. The restriction of molecular movement of Eu-Cy-HOPO brought about by the increased rigidity provided a tightly packed coordination environment for the octadentate Eu(iii) center which resulted in the highest overall quantum yield (30.2%) and sensitization efficiency (64.6%) among 1,2-HOPO sensitized Eu(iii) complexes. Eu-Cy-HOPO is also the first 1,2-HOPO-based lanthanide complex to emit Eu(iii) luminescence under two-photon excitation.

Synthesis of a Conformationally Stable Atropisomeric Pair of Biphenyl Scaffold Containing Additional Stereogenic Centers.

The synthesis of a new CF3-containing stereogenic atropisomeric pair of ortho-disubstituted biphenyl scaffold is presented. The atropisomers are surprisingly conformationally stable for isolation. X-ray structures show that their stability comes from an intramolecular hydrogen bond formation from their two hydroxyl groups and renders the spatial arrangement of their peripheral CF3 and CH3 groups very different. The synthesized stereogenic scaffold proved to be effective in catalyzing the asymmetric N-nitroso aldol reaction of enamine and nitrosobenzene. Compared to similar scaffolds without CF3 groups, one of our atropisomer exhibits an increase in enantioselectivity in this reaction.

pH-responsive targeted gold nanoparticles for in vivo photoacoustic imaging of tumor microenvironments.

The acidic microenvironment of tumor tissues has been proven to be a major characteristic for differentiation from normal tissues, thereby providing a desirable target for both disease diagnosis and functional imaging. We herein introduce a way to endow gold nanoparticles with aggregation behaviour induced by pH tuning. The nanoparticle surface was modified with two thiol conjugate molecules, which could smartly stabilize it at the pH of blood and normal tissues but induce aggregation in response to the acidic extracellular pH in tumor. The surface conjugate molecule composition effect was studied systematically, and at the optimal surface conjugate molecule composition, a pH-responsive active tumor-targeting c(RGDyk)-MHDA/LSC@AuNP nanoprobe was successfully obtained and showed a significantly enhanced contrast effect for both in vitro and in vivo photoacoustic (PA) imaging. Intravenous administration of our nanoprobe to U87MG tumor-bearing nude mice showed PA imaging contrasts almost 3-fold higher than those for the blocking group. Quantitative biodistribution data revealed that 9.7 µg g-1 of nanoprobe accumulated in the U87MG tumor 4 h post-injection. These findings might provide an effective strategy for developing new classes of intelligent and biocompatible contrast agents with a high efficiency for PA imaging and PA imaging-guided cancer therapy.

808 nm excited energy migration upconversion nanoparticles driven by a Nd3+-Trinity system with color-tunability and superior luminescence properties.

We have developed energy migration upconversion (EMU) nanoparticles (UCNPs) with optimal Nd3+-sensitization under excitation of an 808 nm laser to avoid over-heating effects caused by a 980 nm laser while maximizing the excitation efficiency. To realize efficient 808 nm sensitization, a "Nd3+-Trinity system" was implemented in the energy migration upconversion (EMU) cores (NaGdF4:Yb,Tm@NaGdF4:Yb,X, X = Eu/Tb), resulting in a core-multishell structure of EMU cores (accumulation layer@activation layer)@transition layer@harvest layer@activation layer. The spatially separated dopants and optimized Yb3+/Nd3+ content effectively prevented severe quenching events in the UCNPs and their Nd3+-sensitized EMU-based photoluminescence mechanism was studied under 808 nm excitation. These Nd3+-Trinity EMU system UCNPs presented enhanced upconversion luminescence and prolonged lifetime compared to the 980 nm excited UCNPs of the EMU system. It is proposed that 975 nm and 1056 nm NIR photons induced from the Nd3+ → Yb3+ energy transfer facilitate the Tm3+ accumulation process due to the matched energy gaps, which contributes to the extended lifetimes. More importantly, the synthesized UCNPs had a small average size of sub-15 nm and they not only exhibited color-tunability via Eu3+/Tb3+ activators, but also released a larger portion of Tm3+ red emission at 647 nm and had better penetration ability in water under 808 nm excitation, which are favorable for bioimaging applications.

Gadolinium and Platinum in Tandem: Real-time Multi-Modal Monitoring of Drug Delivery by MRI and Fluorescence Imaging.

A novel dual-imaging cisplatin-carrying molecular cargo capable of performing simultaneous optical and MR imaging is reported herein. This long-lasting MRI contrast agent (r1 relaxivity of 23.4 mM-1s-1 at 3T, 25 oC) is a photo-activated cisplatin prodrug (PtGdL) which enables real-time monitoring of anti-cancer efficacy. PtGdL is a model for monitoring the drug delivery and anti-cancer efficacy by MRI with a much longer retention time (24 hours) in several organs such as renal cortex and spleen than GdDOTA and its motif control GdL. Upon complete release of cisplatin, all PtGdL is converted to GdL enabling subsequent MRI analyses of therapy efficacy within its reasonably short clearance time of 4 hours. There is also responsive fluorescence enhancement for monitoring by photon-excitation.

Chiral transcription in self-assembled tetrahedral Eu4L6 chiral cages displaying sizable circularly polarized luminescence.

Predictable stereoselective formation of supramolecular assembly is generally believed to be an important but complicated process. Here, we show that point chirality of a ligand decisively influences its supramolecular assembly behavior. We designed three closely related chiral ligands with different point chiralities, and observe their self-assembly into europium (Eu) tetrametallic tetrahedral cages. One ligand exhibits a highly diastereoselective assembly into homochiral (either ΔΔΔΔ or ΛΛΛΛ) Eu tetrahedral cages whereas the two other ligands, with two different approaches of loosened point chirality, lead to a significant breakdown of the diastereoselectivity to generate a mixture of (ΔΔΔΔ and ΛΛΛΛ) isomers. The cages are highly emissive (luminescence quantum yields of 16(1) to 18(1)%) and exhibit impressive circularly polarized luminescence properties (|g lum|: up to 0.16). With in-depth studies, we present an example that correlates the nonlinear enhancement of the chiroptical response to the nonlinearity dependence on point chirality.

Mechanistic Investigation of Inducing Triboluminescence in Lanthanide(III) ß-Diketonate Complexes.

In this work, we synthesized a series of lanthanide(III) ß-diketonate complexes to investigate the induction of triboluminescence. Triboluminescence (TL) spectra, solid-state emission spectra, and luminescence lifetimes of the complexes were obtained to prove consistent emitting species for steady-state and triboluminescence measurements. Detailed analyses of the crystal lattice packing were conducted in an attempt to correlate crystal symmetry, gas discharge, and structural arrangements with "triboexcitation", and it is found that either noncentrosymmetric or centrosymmetic compounds can be TL-active. Furthermore, an intensely TL compound, Eu(dbm)4TMP, was achieved, and its light emission can be seen under daylight upon mechanical stress.

Study of the Aggregation of DNA-Capped Gold Nanoparticles: A Smart and Flexible Aptasensor for Spermine Sensing.

A smart gold nanoparticle based aptasensor is developed for the sensing of this biomarker in a convenient and fast manner. A comprehensive study was performed to elucidate the driving force of DNA adsorption, different factors' effects, such as gold nanoparticle size, DNA length, concentration, and working pH towards spermine sensing by using UV/Vis absorption spectroscopy and isothermal titration calorimetry. It was found that the developed aptasensor could detect spermine by two different sensing mechanisms simply by adjusting the DNA concentration without complicated procedures. Good performance in complicated matrices was proven by the satisfactory results obtained in the spike analysis of both artificial urine and clinical urine samples. Such a flexible and smart approach described here would provide a useful tool for the fast sensing of spermine and prostate cancer screening.

New Class of Bright and Highly Stable Chiral Cyclen Europium Complexes for Circularly Polarized Luminescence Applications.

High glum values of +0.30 (ΔJ = 1, 591 nm, in DMSO) and -0.23 (ΔJ = 1, 589 nm, in H2O) were recorded in our series of newly designed macrocyclic europium(III) complexes. A sterically locking approach involving a bidentate chromophore is adopted to control the formation of one stereoisomer, giving rise to extreme rigidity, high stability, and high emission intensity. The combination of a chiral substituent on a macrocyclic chelate for lanthanide ions opens up new perspectives for the further development of circulary polarized luminescent chiral tags in optical and bioapplications.

Photo-reactive charge trapping memory based on lanthanide complex.

Traditional utilization of photo-induced excitons is popularly but restricted in the fields of photovoltaic devices as well as photodetectors, and efforts on broadening its function have always been attempted. However, rare reports are available on organic field effect transistor (OFET) memory employing photo-induced charges. Here, we demonstrate an OFET memory containing a novel organic lanthanide complex Eu(tta)3ppta (Eu(tta)3 = Europium(III) thenoyltrifluoroacetonate, ppta = 2-phenyl-4,6-bis(pyrazol-1-yl)-1,3,5-triazine), in which the photo-induced charges can be successfully trapped and detrapped. The luminescent complex emits intense red emission upon ultraviolet (UV) light excitation and serves as a trapping element of holes injected from the pentacene semiconductor layer. Memory window can be significantly enlarged by light-assisted programming and erasing procedures, during which the photo-induced excitons in the semiconductor layer are separated by voltage bias. The enhancement of memory window is attributed to the increasing number of photo-induced excitons by the UV light. The charges are stored in this luminescent complex for at least 10(4) s after withdrawing voltage bias. The present study on photo-assisted novel memory may motivate the research on a new type of light tunable charge trapping photo-reactive memory devices.

Highly luminescent Sm(III) complexes with intraligand charge-transfer sensitization and the effect of solvent polarity on their luminescent properties.

Samarium complexes with the highest quantum yields to date have been synthesized, and their luminescence properties were studied in 12 solvents. Sensitization via a nontriplet intraligand charge-transfer pathway was also successfully demonstrated in solution states with good quantum yields.