Novel Foscan®-derived ring-fused chlorins for photodynamic therapy of cancer.

Photodynamic therapy (PDT) is an established anticancer treatment that combines the use of a photosensitiser (PS) and a light source of a specific wavelength for the generation of reactive oxygen species (ROS) that are toxic to the tumour cells. Foscan® (mTHPC) is a clinically-approved chlorin used for the PDT treatment of advanced head and neck, prostate and pancreatic cancers but is characterized by being photochemically unstable and associated with prolonged skin photosensitivity. Herein, we report the synthesis of new 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, having the meso-tetra(3-hydroxyphenyl)macrocycle core of mTHPC, by exploring the [8π + 2π] cycloaddition of a meso-tetra(3-hydroxyphenyl)porphyrin derivative with diazafulvenium methides. These chlorins have photochemical properties similar to Foscan® but are much more photostable. Among the novel compounds, two chlorins with a hydroxymethyl group and its azide derivative present in the 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused system, are promising photodynamic agents with activity in the 100 nM range against triple-negative breast cancer cells and, in the case of azidomethyl chlorin, a safer phototherapeutic index compared to Foscan®.

Conformational Dynamics of the Soluble and Membrane-Bound Forms of Interleukin-1 Receptor Type-1: Insights into Linker Flexibility and Domain Orientation.

Interleukin-1 receptor type 1 (IL-1R1) is a key player in inflammation and immune responses. This receptor regulates IL-1 activity in two forms: as a membrane-bound form and as a soluble ectodomain. The details and differences between the conformational dynamics of the membrane-bound and the soluble IL-1R1 ectodomains (ECDs) remain largely elusive. Here, we study and compare the structural dynamics of the soluble and membrane-bound IL-1R1-ECDs using molecular dynamics (MD) simulations, focusing on the flexible interdomain linker of the ECD, as well as the spatial rearrangements between the Ig-like domains of the ECD. To explore the membrane-bound conformations, a full-length IL-1R1 structural model was developed and subjected to classical equilibrium MD. Comparative analysis of multiple MD trajectories of the soluble and the membrane-bound IL-1R1-ECDs reveals that (i) as somewhat expected, the extent of the visited "open-to-closed" transitional states differs significantly between the soluble and membrane-bound forms; (ii) the soluble form presents open-closed transitions, sampling a wider rotational motion between the Ig-like domains of the ECD, visiting closed and "twisted" conformations in higher extent, whereas the membrane-bound form is characterized by more conformationally restricted states; (iii) interestingly, the backbone dihedral angles of residues Glu202, Glu203 and Asn204, located in the flexible linker, display the highest variations during the transition between discrete conformational states detected in IL-1R1, thus appearing to work as the "central wheel of a clock's movement". The simulations and analyses presented in this contribution offer a deeper insight into the structure and dynamics of IL-1R1, which may be explored in a drug discovery setting.

Ligand-Targeted Delivery of Photosensitizers for Cancer Treatment.

Photodynamic therapy (PDT) is a promising cancer treatment which involves a photosensitizer (PS), light at a specific wavelength for PS activation and oxygen, which combine to elicit cell death. While the illumination required to activate a PS imparts a certain amount of selectivity to PDT treatments, poor tumor accumulation and cell internalization are still inherent properties of most intravenously administered PSs. As a result, common consequences of PDT include skin photosensitivity. To overcome the mentioned issues, PSs may be tailored to specifically target overexpressed biomarkers of tumors. This active targeting can be achieved by direct conjugation of the PS to a ligand with enhanced affinity for a target overexpressed on cancer cells and/or other cells of the tumor microenvironment. Alternatively, PSs may be incorporated into ligand-targeted nanocarriers, which may also encompass multi-functionalities, including diagnosis and therapy. In this review, we highlight the major advances in active targeting of PSs, either by means of ligand-derived bioconjugates or by exploiting ligand-targeting nanocarriers.

Efficient and Selective, In Vitro and In Vivo, Antimicrobial Photodynamic Therapy with a Dicationic Chlorin in Combination with KI.

Various cationic photosensitizers employed in antimicrobial photodynamic therapy (aPDT) have the ability to photoinactivate planktonic bacteria under conditions of low phototoxicity to mammalian cells and without generating antimicrobial resistance (AMR). However, the photoinactivation of biofilms requires orders-of-magnitude higher photosensitizer concentrations, which become toxic to host cells. Remarkably, the bactericidal effect of a dicationic di-imidazolyl chlorin toward planktonic S. aureus and E. coli was observed in this work for concentrations below 400 nM under illumination at 660 nm and below 50 µM for the corresponding biofilms. At the latter concentrations, the chlorin is phototoxic toward human keratinocyte cells. However, in the presence of 50 mM KI, bactericidal concentrations are reduced to less than 50 nM for planktonic bacteria and to less than 1 µM for biofilms. It is shown that the potentiation with KI involves the triiodide anion. This potentiation elicits a bactericidal effect without appreciable cytotoxicity to keratinocytes. It becomes possible to selectively inactivate biofilms with aPDT. An exploratory study treating mice with wounds infected with E. coli expressing GFP with 20 µM chlorin and 120 J cm-2 at 652 nm confirmed the potential of this chlorin to control localized infections.

Observation of naturally canalized phonon polaritons in LiV2O5 thin layers.

Polariton canalization is characterized by intrinsic collimation of energy flow along a single crystalline axis. This optical phenomenon has been experimentally demonstrated at the nanoscale by stacking and twisting van der Waals (vdW) layers of α-MoO3, by combining α-MoO3 and graphene, or by fabricating an h-BN metasurface. However, these material platforms have significant drawbacks, such as complex fabrication and high optical losses in the case of metasurfaces. Ideally, it would be possible to canalize polaritons "naturally" in a single pristine layer. Here, we theoretically predict and experimentally demonstrate naturally canalized phonon polaritons (PhPs) in a single thin layer of the vdW crystal LiV2O5. In addition to canalization, PhPs in LiV2O5 exhibit strong field confinement ( λ p ~ λ 0 27 ), slow group velocity (0.0015c), and ultra-low losses (lifetimes of 2 ps). Our findings are promising for the implementation of low-loss optical nanodevices where strongly directional light propagation is needed, such as waveguides or optical routers.

Unveiling the Mechanism of Phonon-Polariton Damping in α-MoO3.

Phonon polaritons (PhPs), light coupled to lattice vibrations, in the highly anisotropic polar layered material molybdenum trioxide (α-MoO3) are currently the focus of intense research efforts due to their extreme subwavelength field confinement, directional propagation, and unprecedented low losses. Nevertheless, prior research has primarily concentrated on exploiting the squeezing and steering capabilities of α-MoO3 PhPs, without inquiring much into the dominant microscopic mechanism that determines their long lifetimes, which is key for their implementation in nanophotonic applications. This study delves into the fundamental processes that govern PhP damping in α-MoO3 by combining ab initio calculations with scattering-type scanning near-field optical microscopy (s-SNOM) and Fourier transform infrared (FTIR) spectroscopy measurements across a broad temperature range (8-300 K). The remarkable agreement between our theoretical predictions and experimental observations allows us to identify third-order anharmonic phonon-phonon scattering as the main damping mechanism of α-MoO3 PhPs. These findings shed light on the fundamental limits of low-loss PhPs, which is a crucial factor for assessing their implementation into nanophotonic devices.

An Innovative Sequence-to-Structure-Based Approach to Drug Resistance Interpretation and Prediction: The Use of Molecular Interaction Fields to Detect HIV-1 Protease Binding-Site Dissimilarities.

In silico methodologies have opened new avenues of research to understanding and predicting drug resistance, a pressing health issue that keeps rising at alarming pace. Sequence-based interpretation systems are routinely applied in clinical context in an attempt to predict mutation-based drug resistance and thus aid the choice of the most adequate antibiotic and antiviral therapy. An important limitation of approaches based on genotypic data exclusively is that mutations are not considered in the context of the three-dimensional (3D) structure of the target. Structure-based in silico methodologies are inherently more suitable to interpreting and predicting the impact of mutations on target-drug interactions, at the cost of higher computational and time demands when compared with sequence-based approaches. Herein, we present a fast, computationally inexpensive, sequence-to-structure-based approach to drug resistance prediction, which makes use of 3D protein structures encoded by input target sequences to draw binding-site comparisons with susceptible templates. Rather than performing atom-by-atom comparisons between input target and template structures, our workflow generates and compares Molecular Interaction Fields (MIFs) that map the areas of energetically favorable interactions between several chemical probe types and the target binding site. Quantitative, pairwise dissimilarity measurements between the target and the template binding sites are thus produced. The method is particularly suited to understanding changes to the 3D structure and the physicochemical environment introduced by mutations into the target binding site. Furthermore, the workflow relies exclusively on freeware, making it accessible to anyone. Using four datasets of known HIV-1 protease sequences as a case-study, we show that our approach is capable of correctly classifying resistant and susceptible sequences given as input. Guided by ROC curve analyses, we fined-tuned a dissimilarity threshold of classification that results in remarkable discriminatory performance (accuracy ≈ ROC AUC ≈ 0.99), illustrating the high potential of sequence-to-structure-, MIF-based approaches in the context of drug resistance prediction. We discuss the complementarity of the proposed methodology to existing prediction algorithms based on genotypic data. The present work represents a new step toward a more comprehensive and structurally-informed interpretation of the impact of genetic variability on the response to HIV-1 therapies.

Infrared Permittivity of the Biaxial van der Waals Semiconductor α-MoO3 from Near- and Far-Field Correlative Studies.

The biaxial van der Waals semiconductor α-phase molybdenum trioxide (α-MoO3 ) has recently received significant attention due to its ability to support highly anisotropic phonon polaritons (PhPs)-infrared (IR) light coupled to lattice vibrations-offering an unprecedented platform for controlling the flow of energy at the nanoscale. However, to fully exploit the extraordinary IR response of this material, an accurate dielectric function is required. Here, the accurate IR dielectric function of α-MoO3 is reported by modeling far-field polarized IR reflectance spectra acquired on a single thick flake of this material. Unique to this work, the far-field model is refined by contrasting the experimental dispersion and damping of PhPs, revealed by polariton interferometry using scattering-type scanning near-field optical microscopy (s-SNOM) on thin flakes of α-MoO3 , with analytical and transfer-matrix calculations, as well as full-wave simulations. Through these correlative efforts, exceptional quantitative agreement is attained to both far- and near-field properties for multiple flakes, thus providing strong verification of the accuracy of this model, while offering a novel approach to extracting dielectric functions of nanomaterials. In addition, by employing density functional theory (DFT), insights into the various vibrational states dictating the dielectric function model and the intriguing optical properties of α-MoO3 are provided.

Development of a PCR assay for Streptococcus iniae based on the lactate oxidase (lctO) gene with potential diagnostic value.

Streptococcus iniae is a well-known pathogen of both fish and humans that is difficult to identify by conventional biochemical tests. A PCR assay based on the lactate oxidase (lctO) gene of S. iniae was developed for the rapid and specific detection and identification of this pathogen from different sources. The PCR assay had a detection limit of 62-31 cells, and 25 pg of DNA per PCR reaction mixture. The PCR was also effective in detecting the bacterium from inoculated tissue homogenates, suggesting its potential use for a rapid and accurate diagnosis of S. iniae infections.