Chronic Inflammatory Demyelinating Polyneuropathy as the Initial Presentation of Systemic Lupus Erythematosus Successfully Treated With Cyclophosphamide.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that can manifest with a wide range of clinical features, including peripheral nervous system involvement. Among the neurological complications associated with SLE, chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare but significant entity. This case report explores the complex relationship between CIDP and SLE, emphasizing the challenges in diagnosis and the complexities of treatment strategies. We present the case of a patient diagnosed with CIDP as the initial manifestation of SLE, who exhibited a remarkable response to a unique treatment approach. This case underscores the potential overlap of these two conditions, the need for individualized diagnostic, and the importance of considering lupus activity when making therapeutic decisions. While conventional treatment approaches for CIDP are established, the management of CIDP in the context of SLE requires a thorough approach. This report presents a case where early intervention with steroids and cyclophosphamide yielded favorable outcomes, providing insights into alternative treatment options. As this subset of patients remains underrepresented in clinical trials, further research is needed to establish clear guidelines for the management of CIDP in SLE, optimizing patient care while minimizing risks associated with immunomodulatory therapies.

Formylation as a Chemical Tool to Modulate the Performance of Photosensitizers Based on Boron Dipyrromethene Dimers.

Heavy-atom-free photosensitizers are envisioned as the next generation of photoactive molecules for photo-theragnosis. In this approach, and after suitable irradiation, a single molecular scaffold is able to visualize and kill tumour cells by fluorescence signalling and photodynamic therapy (PDT), respectively, with minimal side effects. In this regard, BODIPY-based orthogonal dimers have irrupted as suitable candidates for this aim. Herein, we analyse the photophysical properties of a set of formyl-functionalized BODIPY dimers to ascertain their suitability as fluorescent photosensitizers. The conducted computationally aided spectroscopic study determined that the fluorescence/singlet oxygen generation dual performance of these valuable BODIPY dimers not only depends on the BODIPY-BODIPY linkage and the steric hindrance around it, but also can be modulated by proper formyl functionalization at specific chromophoric positions. Thus, we propose regioselective formylation as an effective tool to modulate such a delicate photonic balance in BODIPY-based dimeric photosensitizers. The taming of the excited-state dynamics, in particular intramolecular charge transfer as the key underlying process mediating fluorescence deactivation vs. intersystem crossing increasing, could serve to increase fluorescence for brighter bioimaging, enhance the generation of singlet oxygen for killing activity, or balance both for photo-theragnosis.

Halogen-free photosensitizers based on meso-enamine-BODIPYs for bioimaging and photodynamic therapy.

The search for efficient heavy atom free photosensitizers (PSs) for photodynamic therapy (PDT) is a very active field. We describe herein a simple and easily accessible molecular design based on the attachment of an enamine group as an electron-donor moiety at the meso position of the BODIPY core with different alkylation patterns. The effect of the alkylation degree and solvent polarity on the photophysical properties in terms of splitting absorption bands, fluorescence efficiencies and singlet oxygen production is analyzed in depth experimentally using spectroscopic techniques, including femtosecond and nanosecond transient absorption (fs- and ns-TA) and using computational simulations based on time-dependent density functional theory. The correlation between the theoretical/experimental results permits the rationalization of the observed photophysical behavior exhibited by meso-enamine-BODIPY compounds and the determination of mechanistic details, which rule the population of the triplet state manifold. The potential applicability as a theragnostic agent for the most promising compound is demonstrated through in vitro assays in HeLa cells by analyzing the internalization, localization and phototoxic action.

Development of Geometry-Controlled All-Orthogonal BODIPY Trimers for Photodynamic Therapy and Phototheragnosis.

We have established an easy synthetic protocol for selectively developing all-orthogonal BODIPY trimers with unprecedented geometries on the basis of selecting methyl oxidation versus electrophilic formylation of key dimeric precursors. Photophysical characterization together with biological assays unraveled the most suitable BODIPY-BODIPY geometrical arrangements within the trimer, forcing them to serve as molecular platforms for the development of new, advanced heavy-atom-free photosensitizers for photodynamic therapy and phototheragnosis.

Generation of multiple triplet states in an orthogonal bodipy dimer: a breakthrough spectroscopic and theoretical approach.

Generation of triplet states in assemblies of organic chromophores is extremely appealing for their potential use in optoelectronic applications. In this work, we investigate the intricacies of triplet state generation in an orthogonal BODIPY dimer by combining delayed photoemission techniques with electronic structure calculations. Our analysis provides a deep understanding of the electronic states involved, and describes different competing deactivation channels beyond prompt radiative decay. In particular, we identify charge-transfer (CT) mediated intersystem crossing (ISC) as the most likely mechanism for the triplet state generation in this system. The different emission bands at long times can be associated with delayed fluorescence, CT emission and phosphorescence from multiple low-energy triplets. Interestingly, the dependence of the yield of triplet state population and emission profiles with the solvent polarity evidences the decisive role of the CT configuration in the fate of the photoactivated dimer, controlling the relative ISC, reverse ISC, and internal conversion efficiencies. Overall, the present results provide a rather complete description of the delayed photophysics in the BODIPY dimer, but are not able to fully rationalize the unexpected photoluminescence recorded at long wavelengths (≥ 900 nm). We hypothesize that the origin of this emission, not present in BODIPY monomers, emerges from intermonomer interactions triggered by intramolecular distortions opening up a new vision in the controverted mechanism driving the photophysical behavior from orthogonally linked organic monomers.

Functionalization of Photosensitized Silica Nanoparticles for Advanced Photodynamic Therapy of Cancer.

BODIPY dyes have recently attracted attention as potential photosensitizers. In this work, commercial and novel photosensitizers (PSs) based on BODIPY chromophores (haloBODIPYs and orthogonal dimers strategically designed with intense bands in the blue, green or red region of the visible spectra and high singlet oxygen production) were covalently linked to mesoporous silica nanoparticles (MSNs) further functionalized with PEG and folic acid (FA). MSNs approximately 50 nm in size with different functional groups were synthesized to allow multiple alternatives of PS-PEG-FA decoration of their external surface. Different combinations varying the type of PS (commercial Rose Bengal, Thionine and Chlorine e6 or custom-made BODIPY-based), the linkage design, and the length of PEG are detailed. All the nanosystems were physicochemically characterized (morphology, diameter, size distribution and PS loaded amount) and photophysically studied (absorption capacity, fluorescence efficiency, and singlet oxygen production) in suspension. For the most promising PS-PEG-FA silica nanoplatforms, the biocompatibility in dark conditions and the phototoxicity under suitable irradiation wavelengths (blue, green, or red) at regulated light doses (10-15 J/cm2) were compared with PSs free in solution in HeLa cells in vitro.

From photosensitizers to light harvesters adapting the molecular structure in all-BODIPY assemblies.

Herein we detail a protocol to design dyads and triads based solely on BODIPY dyes as halogen-free singlet oxygen photosensitizers or energy transfer molecular cassettes. The conducted photonic characterization reveals the key role of the BODIPY-BODIPY linkage to finely modulate the balance between the triplet state population and fluorescence decay.

Mitochondria selective trackers for long-term imaging based on readily accessible neutral BODIPYs.

We report the design of a new model based on a small neutral 8-aryl-3-formylBODIPY and its suitability to develop privileged highly bright and photostable fluorescent probes for selective and, more importantly, covalent staining of mitochondria.

First Lanthanide Complex for De Novo Phasing in Native Protein Crystallography at 1 Å Radiation.

Phasing agents enabling de novo protein structure determination at ca. 1 Å, the wavelength corresponding to the maximum intensity of the synchrotron facilities applied in biomacromolecular crystallography, have been long sought-after. The first phasing agent designed for solving native protein structures at 0.97934 Å is described herein. The agent consists of a neutral ytterbium(III)-caged complex that exhibits higher anomalous signals at shorter wavelengths when compared to the best, currently applied lanthanide-based phasing agents, all of them based on gadolinium or terbium. As a proof of principle, the complex allows determining the 3D structure of a 36 kDa protein without setting the incident beam wavelength at the metal absorption edge, the strategy followed to date to gain the strongest anomalous signal even at the expense of crystallographic resolution. The agent becomes nondisruptive to the diffraction quality of the marked crystals and allows determining accurate phases, both leading to high-quality electron-density maps that enable the full tracing of the protein structure only with one agent unit bound to the protein. The high phasing power, efficient binding to the protein, low metal-macromolecule ratio, and easy handling support the developed Yb(III) complex as the best phasing agent for X-ray crystallography of a complex biomacromolecule without using modified analogues.

Red/NIR Thermally Activated Delayed Fluorescence from Aza-BODIPYs.

The search for long-lived red and NIR fluorescent dyes is challenging and hitherto scarcely reported. Herein, the viability of aza-BODIPY skeleton as a promising system for achieving thermal activated delayed fluorescent (TADF) probes emitting in this target region is demonstrated for the first time. The synthetic versatility of this scaffold allows the design of energy and charge transfer cassettes modulating the stereoelectronic properties of the energy donors, the spacer moieties and the linkage positions. Delayed emission from these architectures is recorded in the red spectral region (695-735 nm) with lifetimes longer than 100 µs in aerated solutions at room temperature. The computational-aided photophysical study under mild and hard irradiation regimes disclose the interplay between molecular structure and photonic performance to develop long-lived fluorescence red emitters through thermally activated reverse intersystem crossing. The efficient and long-lasting NIR emission of the newly synthesized aza-BODIPY systems provides a basis to develop advanced optical materials with exciting and appealing photonic response.

Exploring BODIPY Derivatives as Singlet Oxygen Photosensitizers for PDT.

This minireview is devoted to honoring the memory of Dr. Thomas Dougherty, a pioneer of modern photodynamic therapy (PDT). It compiles the most important inputs made by our research group since 2012 in the development of new photosensitizers based on BODIPY chromophore which, thanks to the rich BODIPY chemistry, allows a finely tuned design of the photophysical properties of this family of dyes to serve as efficient photosensitizers for the generation of singlet oxygen. These two factors, photophysical tuning and workable chemistry, have turned BODIPY chromophore as one of the most promising dyes for the development of improved photosensitizers for PDT. In this line, this minireview is mainly related to the establishment of chemical methods and structural designs for enabling efficient singlet oxygen generation in BODIPYs. The approaches include the incorporation of heavy atoms, such as halogens (iodine or bromine) in different number and positions on the BODIPY scaffold, and also transition metal atoms, by their complexation with Ir(III) center, for instance. On the other hand, low-toxicity approaches, without involving heavy metals, have been developed by preparing several orthogonal BODIPY dimers with different substitution patterns. The advantages and drawbacks of all these diverse molecular designs based on BODIPY structural framework are described.

BODIPYs revealing lipid droplets as valuable targets for photodynamic theragnosis.

Endowing BODIPY PDT agents with the ability to probe lipid droplets is demonstrated to boost their phototoxicity, allowing the efficient use of highly fluorescent dyes (poor ROS sensitizers) as phototoxic agents. Conversely, this fact opens the way to the development of highly bright ROS photosensitizers for performing photodynamic theragnosis (fluorescence bioimaging and photodynamic therapy) from a single simple agent. On the other hand, the noticeable capability of some of the reported dyes to probe lipid droplets in different cell lines under different conditions reveals their use as privileged probes for advancing the study of interesting lipid droplets by fluorescence microscopy.

Manipulating Charge-Transfer States in BODIPYs: A Model Strategy to Rapidly Develop Photodynamic Theragnostic Agents.

On the basis of a family of BINOL (1,1'-bi-2-naphthol)-based O-BODIPY (dioxyboron dipyrromethene) dyes, it is demonstrated that chemical manipulation of the chromophoric push-pull character, by playing with the electron-donating capability of the BINOL moiety (BINOL versus 3,3'-dibromoBINOL) and with the electron-acceptor ability of the BODIPY core (alkyl substitution degree), is a workable strategy to finely balance fluorescence (singlet-state emitting action) versus the capability to photogenerate cytotoxic reactive oxygen species (triplet-state photosensitizing action). It is also shown that the promotion of a suitable charge-transfer character in the involved chromophore upon excitation enhances the probability of an intersystem crossing phenomenon, which is required to populate the triple state enabling singlet oxygen production. The reported strategy opens up new perspectives for rapid development of smarter agents for photodynamic theragnosis, including heavy-atom-free agents, from a selected organic fluorophore precursor.

FormylBODIPYs by PCC-Promoted Selective Oxidation of α-MethylBODIPYs. Synthetic Versatility and Applications.

An efficient synthesis of formylBODIPYs has been established based on an oxidation with PCC of 3-methylBODIPYs. It has been demonstrated that this reagent can oxidize methyl groups at such position of the BODIPY core, regardless of its substitution pattern. Moreover, through this procedure it is possible to synthesize 8-aryl-3,5-diformylBODIPYs, which are otherwise difficult to obtain. These precursors have been functionalized to develop fluorescent sensors of amino acids or photosensitizers for singlet oxygen generation.

Singlet Fission Mediated Photophysics of BODIPY Dimers.

The photodynamics of an orthogonal BODIPY dimer, particularly the formation of triplet states, has been explored by femtosecond and nanosecond transient absorption measurements. The short time scale data show the appearance of transient features of triplet character that, according to quantitative analysis of their intensities, account for more than 100% of the initially excited molecules, which reveals the occurrence of a singlet fission process in the isolated dimers. The formation rate of the triplet correlated state 1(TT) is found to depend on the solvent polarity, pointing to the mediation of a charge transfer character state. The dissociation of the 1(TT) state into pairs of individual triplets determines the triplet yield measured in the long time scales. The kinetic model derived from the results provides a comprehensive view of the photodynamics of BODIPY dimers and permits rationalization of the photophysical parameters of these systems.

Adapting BODIPYs to singlet oxygen production on silica nanoparticles.

A modified Stöber method is used to synthesize spherical core-shell silica nanoparticles (NPs) with an external surface functionalized by amino groups and with an average size around 50 nm. Fluorescent dyes and photosensitizers of singlet oxygen were fixed, either separately or conjointly, respectively in the core or in the shell. Rhodamines were encapsulated in the core with relatively high fluorescence quantum yields (Φfl ≥ 0.3), allowing fluorescence tracking of the particles. Various photosensitizers of singlet oxygen (PS) were covalenty coupled to the shell, allowing singlet oxygen production. The stability of NP suspensions strongly deteriorated upon grafting the PS, affecting their apparent singlet oxygen quantum yields. Agglomeration of NPs depends both on the type and on the amount of grafted photosensitizer. New, lab-made, halogenated 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPY) grafted to the NPs achieved higher singlet oxygen quantum yields (ΦΔ âˆ¼ 0.35-0.40) than Rose Bengal (RB) grafted NPs (ΦΔ âˆ¼ 0.10-0.27). Finally, we combined both fluorescence and PS functions in the same NP, namely a rhodamine in the silica core and a BODIPY or RB grafted in the shell, achieving the performance Φfl ∼ 0.10-0.20, ΦΔ âˆ¼ 0.16-0.25 with a single excitation wavelength. Thus, proper choice of the dyes, of their concentrations inside and on the NPs and the grafting method enables fine-tuning of singlet oxygen production and fluorescence emission.

AcetylacetonateBODIPY-Biscyclometalated Iridium(III) Complexes: Effective Strategy towards Smarter Fluorescent Photosensitizer Agents.

Biscyclometalated IrIII complexes involving boron-dipyrromethene (BODIPY)-based ancillary ligands, where the BODIPY unit is grafted to different chelating cores (acetylacetonate for Ir-1 and Ir-2, and bipyridine for Ir-3) by the BODIPY meso position, have been synthesized and characterized. Complexes with the BODIPY moiety directly grafted to acetylacetonate (Ir-1 and Ir-2) exhibit higher absorption coefficients (ϵ≈4.46×104 m-1 cm-1 and 3.38×104 m-1  cm-1 at 517 nm and 594 nm, respectively), higher moderate fluorescence emission (φfl ≈0.08 and 0.22 at 528 nm and 652 nm, respectively) and, in particular, more efficient singlet oxygen generation upon visible-light irradiation (φΔ ≈0.86 and 0.59, respectively) than that exhibited by Ir-3 (φΔ ≈0.51, but only under UV light). Phosphorescence emission, nanosecond time-resolved transient absorption, and DFT calculations suggest that BODIPY-localized long-lived 3 IL states are populated for Ir-1 and Ir-2. In vitro photodynamic therapy (PDT) activity studied for Ir-1 and Ir-2 in HeLa cells shows that such complexes are efficiently internalized into the cells, exhibiting low dark- and high photocytoxicity, even at significantly low complex concentration, making them potentially suitable as theranostic agents.

Rational Design of Advanced Photosensitizers Based on Orthogonal BODIPY Dimers to Finely Modulate Singlet Oxygen Generation.

The synthesis, photophysical characterization, and modeling of a new library of halogen-free photosensitizers (PS) based on orthogonal boron dipyrromethene (BODIPY) dimers are reported. Herein we establish key structural factors in order to enhance singlet oxygen generation by judiciously choosing the substitution patterns according to key electronic effects and synthetic accessibility factors. The photosensitization mechanism of orthogonal BODIPY dimers is demonstrated to be strongly related to their intrinsic intramolecular charge transfer (ICT) character through the spin-orbit charge-transfer intersystem crossing (SOCT-ISC) mechanism. Thus, singlet oxygen generation can be effectively modulated through the solvent polarity and the presence of electron-donating or withdrawing groups in one of the BODIPY units. The photodynamic therapy (PDT) activity is demonstrated by in vitro experiments, showing that selected photosensitizers are efficiently internalized into HeLa cells, exhibiting low dark toxicity and high phototoxicity, even at low PS concentration (0.05-5×10-6 m).

Towards improved halogenated BODIPY photosensitizers: clues on structural designs and heavy atom substitution patterns.

The singlet oxygen (1O2) production quantum yield (ΦΔ) of 14 halogenated BODIPY dyes has been determined (0.01 < ΦΔ < 0.99). 1O2 production and photostability have been evaluated considering the BODIPY structure, the substitution pattern, and the number and type of heavy atoms and quenching rate constants of 1O2 by the sensitizer. In view of the experimental results and principal component analysis (PCA), guidelines for an improved design of efficient and photostable halo-BODIPY sensitizers are proposed.