Ligand Regulation Strategy to Modulate ROS Nature in a Rhodamine-Iridium(III) Hybrid System for Phototherapy.

The efficacy of photodynamic therapy (PDT) is highly dependent on the photosensitizer features. The reactive oxygen species (ROS) generated by photosensitizers is proven to be associated with immunotherapy by triggering immunogenic cell death (ICD) as well. In this work, we establish a rhodamine-iridium(III) hybrid model functioning as a photosensitizer to comprehensively understand its performance and potential applications in photodynamic immunotherapy. Especially, the correlation between the ROS generation efficiency and the energy level of the Ir(III)-based excited state (T1'), modulated by the cyclometalating (C∧N) ligand, is systematically investigated and correlated. We prove that in addition to the direct population of the rhodamine triplet state (T1) formed through the intersystem crossing process with the assistance of a heavy Ir(III) metal center, the fine-tuned T1' state could act as a relay to provide an additional pathway for promoting the cascade energy transfer process that leads to enhanced ROS generation ability. Moreover, type I ROS can be effectively produced by introducing sulfur-containing thiophene units in C∧N ligands, providing a stronger M1 macrophage-activation efficiency under hypoxia to evoke in vivo antitumor immunity. Overall, our work provides a fundamental guideline for the molecular design and exploration of advanced transition-metal-based photosensitizers for biomedical applications.

Direct Construction of Corrole-Peptide Conjugates by Controllable Bilane Formation on Resin.

Corroles have attracted increasing research interests in recent decades owing to their unique properties over porphyrins. However, the relatively inefficient and tedious synthetic procedures of corrole building blocks with functional groups for bioconjugation hindered their bioapplications. Herein, we report a highly efficient protocol to synthesize corrole-peptide conjugates with good yields (up to 63 %) without using prepared corrole building blocks. By condensing two -COOH-bearing-dipyrromethane molecules onto an aldehyde group on resin-bound peptide chains in a controllable manner, a series of desired products with long (up to 25 residues) and bioactive peptide chains were obtained with at most one chromatographic purification. The synthesized compounds exhibited potential applications as chelators for metal ions for biomedical applications, as building blocks for supramolecular materials, as well as targeted fluorescent probes.

Upconversion in a d-f [RuYb3] Supramolecular Assembly.

We have prepared a hetero-tetrametallic assembly consisting of three ytterbium ions coordinated to a central [Ru(bpm)3]2+ (bpm = 2,2'-bipyrimidine) motif. Irradiation into the absorption band of the peripheral ytterbium ions at 980 nm engenders emission of the 3MLCT state of the central [Ru(bpm)3]2+ core at 636 nm, which represents the first example of f → d molecular upconversion (UC). Time-resolved measurements reveal a slow rise of the UC emission, which was modeled with a mathematical treatment of the observed kinetics according to a cooperative photosensitization mechanism using a virtual Yb centered doubly excited state followed by energy transfer to the Ru centered 1MLCT state.

Polymeric Dendrimers as Nanocarrier Vectors for Neurotheranostics.

Dendrimers are polymers with well-defined 3D branched structures that are vastly utilized in various neurotheranostics and biomedical applications, particularly as nanocarrier vectors. Imaging agents can be loaded into dendrimers to improve the accuracy of diagnostic imaging processes. Likewise, combining pharmaceutical agents and anticancer drugs with dendrimers can enhance their solubility, biocompatibility, and efficiency. Practically, by modifying ligands on the surface of dendrimers, effective therapeutic and diagnostic platforms can be constructed and implemented for targeted delivery. Dendrimer-based nanocarriers also show great potential in gene delivery. Since enzymes can degrade genetic materials during their blood circulation, dendrimers exhibit promising packaging and delivery alternatives, particularly for central nervous system (CNS) treatments. The DNA and RNA encapsulated in dendrimers represented by polyamidoamine that are used for targeted brain delivery, via chemical-structural adjustments and appropriate generation, significantly improve the correlation between transfection efficiency and cytotoxicity. This article reports a comprehensive review of dendrimers' structures, synthesis processes, and biological applications. Recent progress in diagnostic imaging processes and therapeutic applications for cancers and other CNS diseases are presented. Potential challenges and future directions in the development of dendrimers, which provide the theoretical basis for their broader applications in healthcare, are also discussed.

Incorporation of Fmoc-Dab(Mtt)-OH during solid-phase peptide synthesis: a word of caution.

As a commercially available and orthogonally protected amino acid building block, Fmoc-Dab(Mtt)-OH showed abnormally poor coupling efficiency during solid-phase peptide synthesis (SPPS). Herein, we reveal that Fmoc-Dab(Mtt)-OH undergoes rapid lactamization under a series of conditions with various coupling reagents. Although the complete incorporation of Fmoc-Dab(Mtt)-OH can be achieved using a multi-time and preincubation-free protocol with the coupling reagent DEPBT, alternative orthogonally protected building blocks are suggested to be used for avoiding such a costly and tedious procedure.

Correction: Incorporation of Fmoc-Dab(Mtt)-OH during solid-phase peptide synthesis: a word of caution.

Correction for 'Incorporation of Fmoc-Dab(Mtt)-OH during solid-phase peptide synthesis: a word of caution' by Pak-Lun Lam et al., Org. Biomol. Chem., 2022, DOI: 10.1039/d2ob00070a.

Energy Transfer Mechanism and Quantitative Modeling of Rate from an Antenna to a Lanthanide Ion.

The excitation energy transfer (ET) pathway and mechanism from an organic antenna to a lanthanide ion has been the subject of discussion for many decades. In the case of europium (Eu3+), it has been suggested that the transfer originates from the ligand singlet state or a triplet state. Taking the lanthanide complex Eu(TTA)3(H2O)2 as an example, we have investigated the spectra and luminescence kinetics, mainly at room temperature and 77 K, to acquire the necessary experimental data. We put forward an experimental and theoretical approach to measure the energy transfer rates from the antenna to different Eu3+ levels using the Dexter formulation. We find that transfer from the ligand singlet state to Eu3+ may account for the ET pathway, by combined electric dipole-electric dipole (ED-ED) and ED-electric quadrupole (EQ) mechanisms. The contributions from the triplet state by these mechanisms are very small. An independent systems rate equation approach can effectively model the experimental kinetics results. The model utilizes the cooperative processes that take place on the metal ion and ligand and considers S0, S1, and T1 ligand states in addition to 7F0,1, 5D0, 5D1, and 5DJ (=5L6, 5D3, 5D2 combined) Eu3+ states. The triplet exchange ET rate is estimated to be of the order 107 s-1. The observation of a nanosecond risetime for the Eu3+ 5D1 level does not enable the assignment of the ET route or the mechanism. Furthermore, the 5D1 risetime may be contributed by several processes. Observation of its temperature dependence and also that of the ground-state population can supply useful information concerning the mechanism because the change in metal-ion internal conversion rate has a greater effect than changes in singlet or triplet nonradiative rates. A critical comparison is included for the model of Malta employed in the online software LUMPAC and JOYSpectra. The theoretical treatment of the exchange mechanism and its contribution are now being considered.

Reactivation of Epstein-Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function.

Epstein-Barr nuclear antigen 1 (EBNA1) plays a vital role in the maintenance of the viral genome and is the only viral protein expressed in nearly all forms of Epstein-Barr virus (EBV) latency and EBV-associated diseases, including numerous cancer types. To our knowledge, no specific agent against EBV genes or proteins has been established to target EBV lytic reactivation. Here we report an EBNA1- and Zn2+-responsive probe (ZRL5P4) which alone could reactivate the EBV lytic cycle through specific disruption of EBNA1. We have utilized the Zn2+ chelator to further interfere with the higher order of EBNA1 self-association. The bioprobe ZRL5P4 can respond independently to its interactions with Zn2+ and EBNA1 with different fluorescence changes. It can selectively enter the nuclei of EBV-positive cells and disrupt the oligomerization and oriP-enhanced transactivation of EBNA1. ZRL5P4 can also specifically enhance Dicer1 and PML expression, molecular events which had been reported to occur after the depletion of EBNA1 expression. Importantly, we found that treatment with ZRL5P4 alone could reactivate EBV lytic induction by expressing the early and late EBV lytic genes/proteins. Lytic induction is likely mediated by disruption of EBNA1 oligomerization and the subsequent change of Dicer1 expression. Our probe ZRL5P4 is an EBV protein-specific agent that potently reactivates EBV from latency, leading to the shrinkage of EBV-positive tumors, and our study also suggests the association of EBNA1 oligomerization with the maintenance of EBV latency.

The design of responsive luminescent lanthanide probes and sensors.

The principles of the design of responsive luminescent probes and sensors based on lanthanide emission are summarised, based on a mechanistic understanding of their mode of action. Competing kinetic pathways for deactivation of the excited states that occur are described, highlighting the need to consider each of the salient quenching processes. Such an analysis dictates the choice of both the ligand and its integral sensitising moiety for the particular application. The key aspects of quenching involving electron transfer and vibrational and electronic energy transfer are highlighted and exemplified. Responsive systems for pH, pM, pX and pO2 and selected biochemical analytes are distinguished, according to the nature of the optical signal observed. Signal changes include both simple and ratiometric intensity measurements, emission lifetime variations and the unique features associated with the observation of circularly polarised luminescence (CPL) for chiral systems. A classification of responsive lanthanide probes is introduced. Examples of the operation of probes for reactive oxygen species, citrate, bicarbonate, α1-AGP and pH are used to illustrate reversible and irreversible transformations of the ligand constitution, as well as the reversible changes to the metal primary and secondary coordination sphere that sensitively perturb the ligand field. Finally, systems that function by modulation of dynamic quenching of the ligand or metal excited states are described, including real time observation of endosomal acidification in living cells, rapid urate analysis in serum, accurate temperature assessment in confined compartments and high throughput screening of drug binding to G-protein coupled receptors.

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.

Enhancing Hybrid Upconversion Nanosystems via Synergistic Effects of Moiety Engineered NIR Dyes.

Hybrid upconversion nanosystems have been reported to improve the low absorption efficiency of lanthanide-doped upconversion nanoparticles (UCNPs). However, the low quantum yield and poor photostability of NIR dyes pose challenges for practical uses. Here, we introduce a bulky moiety, 4-(1,2,2-triphenylvinyl)-1,1'-biphenyl (TPEO), to enhance its quantum yield by suppressing the bond rotation and improve the stability by deactivating the photoinduced oxidization. Compared with the conventional IR806, the formed NIR dye, TPEO-Cy, has been characterized to deliver three times higher quantum yield and seven times better photostability. Moreover, we take advantage of the strong affinity of sulfonate chains on the TPEO-Cy to bind to the surface of UCNPs. Taking together the synergistic effect, we have achieved a 242-fold upconversion emission enhancement over the benchmark of IR806-sensitized system and an ∼800 000-fold increase than the bare UCNPs. Our design of the NIR dyes suggests a new scope to search for more efficient upconversion nanohybrids.

Versatile Synthesis of Multivalent Porphyrin-Peptide Conjugates by Direct Porphyrin Construction on Resin.

Multifunctional porphyrin-peptide conjugates with different propensities for self-assembly into various supramolecular nanoarchitectures play important roles in advanced materials and biomedical research. However, preparing prefunctionalized core porphyrins by traditional low-yielding statistical synthesis and purifying them after peptide ligation through many rounds of HPLC purification is tedious and unsustainable. Herein, we report a novel integrated solid-phase synthetic protocol for the construction of porphyrin moieties from simple aldehydes and dipyrromethanes on resin-bound peptides directly to form mono-, cis/trans-di-, and trivalent porphyrin-peptide conjugates in a highly efficient and controllable manner; moreover, only single final-stage HPLC purification of the products is needed. This efficient strategy enables the rapid, greener, and substrate-controlled diversity-oriented synthesis of multivalent porphyrin-(long) peptide conjugate libraries for multifarious biological and materials applications.

Solid-Phase Peptide Macrocyclization and Multifunctionalization via Dipyrrin Construction.

We introduce a new and highly efficient synthetic protocol towards multifunctional fluorescent cyclopeptides by solid-phase peptide macrocyclization via dipyrrin construction, with full scope of proteinogenic amino acids and different ring sizes. Various bicyclic peptides can be created by dipyrrin-based crosslinking and double dipyrrin-ring formation. The embedded dipyrrin can be either transformed to fluorescent BODIPY and then utilized as cancer-selective targeted protein imaging probe in vitro, or directly employed as a selective metal sensor in aqueous media. This work provides a valuable addition to the peptide macrocyclization toolbox, and a blueprint for the development of multifunctional dipyrrin linkers in cyclopeptides for a wide range of potential bioapplications.

Frequency-Upconverted Stimulated Emission by Up to Six-Photon Excitation from Highly Extended Spiro-Fused Ladder-Type Oligo(p-phenylene)s.

Frequency-upconverted fluorescence and stimulated emission induced by multiphoton absorption (MPA) have attracted much interest. As compared with low-order MPA processes, the construction of high-order MPA processes is highly desirable and rather attractive, yet remains a formidable challenge due to its inherent low transition probability. We report the observation of the first experimental frequency-upconverted fluorescence and stimulated emission by simultaneous six-photon excitation in an organic molecular system. The well-designed organic conjugated system based on cross-shaped spiro-fused ladder-type oligo(p-phenylene)s (SpL-z, z=1-3) manifests reasonably high MPA cross-sections and brilliant luminescence emission simultaneously. The six-photon absorption cross-section of SpL-3 with an extended π-conjugation was evaluated as 8.67×10-169  cm12 s5 photon-5 . Exceptionally efficient 2- to 6-photon excited stimulated emission was achieved under near-infrared laser excitation.

Importance of Volume Ratio in Photonic Effects of Lanthanide-Doped LaPO4 Nanocrystals.

Experimental variation of the volume ratio (filling factor: i.e., volume of nanoparticles (NPs) compared with that of medium) of nanocomposite materials with doped lanthanide ions demonstrates that it has a significant affect upon local field effects. Lanthanum orthophosphate NPs are doped with Eu3+ and/or Tb3+ and immersed in organic solvents and lead borate glasses for Tb3+ 5 D4 lifetime measurements. For media with a refractive index (nmed ) less than that of LaPO4 (nnp = 1.79), the 5 D4 emission decay rate increases with increasing volume ratio of the NPs, whereas for nmed > 1.79, the decay rate decreases with increasing volume ratio. Fitting with the model of Pukhov provides an estimation of the radiative lifetime of 5 D4 and the quantum yield. Energy transfer (ET) from Tb3+ to Eu3+ occurs in co-doped LaPO4 NPs with excitation into a Tb3+ absorption band. The ET rate is independent on nmed and the energy transfer efficiency decreases with an increase in nmed . The behavior of ET rate with regard to the local field is consistent with the Dexter, but not Förster, equation for ET rate involving the electric dipole-electric dipole mechanism. This has consequences when using the spectroscopic ruler approach to measure distances between donor-acceptor chromophores.

Ultrabright Terbium Nanoparticles for FRET Biosensing and in Situ Imaging of Epidermal Growth Factor Receptors*.

Lanthanide-doped nanoparticles (LnNPs) have become an important class of fluorophores for advanced biosensing and bioimaging. LnNPs that are photosensitized by surface-attached antenna ligands can possess exceptional brightness. However, their functional bioconjugation remains an important challenge for their translation into bioanalytical applications. To solve this problem, we designed a ligand that can be simultaneously applied as efficient light harvesting antenna for Tb surface ions and strong linker of biomolecules to the LnNPs surfaces. To demonstrate generic applicability of the photosensitized TbNP-bioconjugates, we applied them in two prototypical applications for biosensing and bioimaging. First, in-solution biorecognition was shown by time-resolved Förster resonance energy transfer (FRET) between streptavidin-functionalized TbNPs to biotinylated dyes (ATTO 610). Second, in situ detection of ligand-receptor binding on cells was accomplished with TbNP-antibody (Matuzumab) conjugates that could specifically bind to transmembrane epidermal growth factor receptors (EGFR). High specificity and sensitivity were demonstrated by time-gated imaging of EGFR on both strongly (A431) and weakly (HeLa and Cos7) EGFR-expressing cell lines, whereas non-expressing cell lines (NIH3T3) and EGFR-passivated A431 cells did not show any signals. Despite the relatively large size of TbNP-antibody conjugates, they could be internalized by A431 cells upon binding to extracellular EGFR, which showed their potential as bright and stable luminescence markers for intracellular signaling.

Photodynamic and photothermal synergistic behavior of triphenylamine-porphyrin nanoparticles for DNA interaction, cellular cytotoxicity and localization.

In this paper, amphiphilic conjugated triphenylamine-porphyrins TPA-Por-TPA and TPA-Por were designed and synthesized. The water-soluble nanostructures TPA-Por-TPA NPs and TPA-Por NPs spontaneously assembled after π-π stacking, which can be changed by improving the internal transfer ability of electrons. The intercalation and external binding modes of these free porphyrins and nanoporphyrins interacting with ct-DNA were confirmed by UV-vis and fluorescence spectroscopy. Reactive oxygen species (ROS) production was studied by 2',7'-dichlorofluorescein diacetate, demonstrating that the rate of production of ROS is TPA-Por-TPA NPs > TPA-Por-TPA > TPA-Por NPs > TPA-Por. In addition, the structure of the NP enhanced the acceptor-donor conjugated structure, resulting in fluorescence quenching and promoting non-radiative heat generation. The photothermal conversion efficiencies of the TPA-Por-TPA NPs and TPA-Por NPs were measured and calculated to be 34.89% and 37.99%, respectively. At the same time, the three nanomaterials showed good photocytotoxicity, and the IC50 of the TPA-Por-TPA NPs and TPA-Por NPs was 32.18 and 36.62 µg ml-1, respectively, at 10 min after laser irradiation. The cellular uptake and subcellular localization of these NPs were further evaluated through a confocal laser scanning microscope. The results showed that the conjugated NPs have good biocompatibility properties in the cancer cells. These properties make it possible for triphenylamine porphyrin NPs to become photosensitizers for the photodynamic and photothermal synergistic treatment of tumors, and have potential prospects for applications in cancer diagnosis and treatment.

Misconceptions in electronic energy transfer: bridging the gap between chemistry and physics.

Many treatments of energy transfer (ET) phenomena in current literature employ incorrect arguments and formulae and are not quantitative enough. This is unfortunate because we witness important breakthroughs from ET experiments in nanoscience. This review aims to clarify basic principles by focusing upon Förster-Dexter electric dipole-electric dipole (ED-ED) ET. The roles of ET in upconversion, downconversion and the antenna effect are described and the clichés and simple formulae to be avoided in ET studies are highlighted with alternative treatments provided.

Impact of Lanthanide Nanomaterials on Photonic Devices and Smart Applications.

Half a century after its initial emergence, lanthanide photonics is facing a profound remodeling induced by the upsurge of nanomaterials. Lanthanide-doped nanomaterials hold promise for bioapplications and photonic devices because they ally the unmatched advantages of lanthanide photophysical properties with those arising from large surface-to-volume ratios and quantum confinement that are typical of nanoobjects. Cutting-edge technologies and devices have recently arisen from this association and are in turn promoting nanophotonic materials as essential tools for a deeper understanding of biological mechanisms and related medical diagnosis and therapy, and as crucial building blocks for next-generation photonic devices. Here, the recent progress in the development of nanomaterials, nanotechnologies, and nanodevices for clinical uses and commercial exploitation is reviewed. The candidate nanomaterials with mature synthesis protocols and compelling optical uniqueness are surveyed. The specific fields that are directly driven by lanthanide doped nanomaterials are emphasized, spanning from in vivo imaging and theranostics, micro-/nanoscopic techniques, point-of-care medical testing, forensic fingerprints detection, to micro-LED devices.

Reversible and Sensitive Hg2+ Detection by a Cell-Permeable Ytterbium Complex.

A cell-permeable ytterbium complex shows reversible binding with Hg2+ in aqueous solution and in vitroby off-on visible and NIR emission. The fast response and 150 nM sensitivity of Hg2+ detection is based upon FRET and the lanthanide antenna effect. The reversible Hg2+ detection can be performed in vitro, and the binding mechanism is suggested by NMR employing the motif structure in a La complex and by DFT calculations.