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This article presents bioconjugates combining nanoparticles (AGuIX) with nanobodies (VHH) targeting Programmed Death-Ligand 1 (PD-L1, A12 VHH) and Cluster of Differentiation 47 (CD47, A4 VHH) for active tumor targeting. AGuIX nanoparticles offer theranostic capabilities and an efficient biodistribution/pharmacokinetic profile (BD/PK), while VHH's reduced size (15 kDa) allows efficient tumor penetration. Site-selective sortagging and click chemistry were compared for bioconjugation. While both methods yielded bioconjugates with similar functionality, click chemistry demonstrated higher yield and could be used for the conjugation of various VHH. The specific targeting of AGuIX@VHH has been demonstrated in both in vitro and ex vivo settings, paving the way for combined targeted immunotherapies, radiotherapy, and cancer imaging.

Background and Objective: A significant proportion of women of childbearing age have psoriasis. The aim of this study was to examine family planning concerns in this population., Material and Methods: Observational, descriptive, cross-sectional, multicenter study conducted between March 2020 and October 2021. We collected sociodemographic data and analyzed responses to a family planning questionnaire administered to women aged 18 to 45 years with plaque psoriasis who were candidates for systemic treatment., Results: We studied 153 patients (mean [SD] age, 35.4 [8.0] years; mean disease duration, 16.7 years) being treated at 11 Spanish hospitals. Overall, 38.4% of women were considered to have moderate to severe psoriasis by their physicians; perceived severity ratings were significantly higher among women. Psoriasis affected the women's desire to become pregnant or led to their delaying pregnancy in 1 in 3 respondents. They were concerned that their condition might worsen if they had to discontinue or switch treatment or that the treatment might harm the baby. Approximately half of the women had not received family planning counseling from their physicians, and this was more likely to be the case among never-pregnant women. Women on biologic therapy (58.7%) had better psoriasis control and a better quality of life than women on other treatments. Their sexual health was also less affected., Conclusions: Women with psoriasis have numerous family planning concerns, which in some cases can lead them to delay pregnancy or affect their desire to become pregnant. Dermatologists need to receive better training regarding family planning in women with psoriasis so that they can provide their patients with more and better information., (Copyright © 2023 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: The introduction of magnetic resonance (MR)-guided radiation treatment planning has opened a new space for theranostic nanoparticles to reduce acute toxicity while improving local control. In this work, second-generation AGuIX ® nanoparticles (AGuIX-Bi) are synthesized and validated. AGuIX-Bi are shown to maintain MR positive contrast while further amplifying the radiation dose by the replacement of some Gd 3+ cations with higher Z Bi 3+ . These next-generation nanoparticles are based on the AGuIX ® platform, which is currently being evaluated in multiple Phase II clinical trials in combination with radiotherapy. Methods: In this clinically scalable methodology, AGuIX ® is used as an initial chelation platform to exchange Gd 3+ for Bi 3+ . AGuIX-Bi nanoparticles are synthesized with three ratios of Gd/Bi, each maintaining MR contrast while further amplifying radiation dose relative to Bi 3+ . Safety, efficacy, and theranostic potential of the nanoparticles were evaluated in vitro and in vivo in a human non-small cell lung cancer model. Results: We demonstrated that increasing Bi 3+ in the nanoparticles is associated with more DNA damage and improves in vivo efficacy with a statistically significant delay in tumor growth and 33% complete regression for the largest Bi/Gd ratio tested. The addition of Bi 3+ by our synthetic method leads to nanoparticles that present slightly altered pharmacokinetics and lengthening of the period of high tumor accumulation with no observed evidence of toxicity. Conclusions: We confirmed the safety and enhanced efficacy of AGuIX-Bi with radiation therapy at the selected ratio of 30Gd/70Bi. These results provide crucial evidence towards patient translation., Competing Interests: Competing Interests: François Lux and Olivier Tillement have to disclose the patent WO2011/135101. François Lux, Olivier Tillement, and Ross Berbeco have to disclose the patent US62431607. Paul Rocchi, Léna Carmès Tristan Doussineau, and Sandrine Dufort are employees of NH TherAguix which develops AGuIX® nanoparticles. François Lux, Olivier Tillement, Tristan Doussineau, and Sandrine Dufort possess shares in the company, NH TherAguix., (© The author(s).)

Objective: Field hospitals, also known as alternative care sites, have been an important healthcare reinforcement during the SARS-CoV-2 pandemic worldwide. In the Valencian Community, three of these hospitals were opened, one for each province. Our study aimed to make a comprehensive analysis of this resource in Castellon., Methods: A retrospective observational study was carried out with an analytical and statistical component of 3 aspects: infrastructure, satisfaction and clinical data from COVID-positive hospitalized patients. The sources of information were primary, institutional for the infrastructure and personal for the satisfaction surveys and clinical data., Results: A set of 6x3 metres polyvalent tents was chosen, which joined formed a single-floor area of about 3.500 m 2 . Although hospital opened for approximately a year and a half with multiple uses, most in relation to the COVID pandemic (vaccination center, emergency room observation, hospital assistance, warehouse...), reception of positive patients for the virus began during the third wave of the pandemic, remaining active for eleven days. A total of thirty-one patients with a mean age of 56 years were admitted. 41.9% did not have any comorbidity and 54.8% needed treatment with oxygen therapy. Furthermore, the length of stay was three days, finding a significant relationship between this one, the oxygen flow required during admission and the age. Satisfaction was measured by a survey of seventeen questions where an average satisfaction of 8.33/10., Conclusions: This is one of the few studies in the literature in which a field hospital is analyzed from such different points of view. After this analysis, it is concluded that it is an extraordinary and temporary resource whose use is useful without reflecting an increase of morbidity/mortality among our patients and with a very favorable subjective assessment., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Introduction: Teledermatology is the application of new technologies for the care of skin diseases. Its application in prisons allows the diagnosis and treatment of prisoners without the need to transfer them to the hospital, avoiding the problems associated with travel., Material and Method: The objective of this work is to analyze the usefulness of teledermatology in prisons, through a retrospective observational study in the Castellón II-Albocàsser penitentiary., Results: The study sample consisted of 37 patients and 43 interconsultations. All the consultations corresponded to men, with a mean age of 42.43 years. 95.3% of the consultations were asynchronous and in 86% of them a diagnosis and a complete treatment plan were established. Only 18.6% of the consultations required a face-to-face consultation., Discussion: It is concluded that teledermatology in prisons is effective in the care and resolution of dermatological problems.

Electromagnetic radiation-triggered therapeutic effect has attracted a great interest over the last 50 years. However, translation to clinical applications of photoactive molecular systems developed to date is dramatically limited, mainly because their activation requires excitation by low-energy photons from the ultraviolet to near infra-red range, preventing any activation deeper than few millimetres under the skin. Herein we conceive a strategy for photosensitive-system activation potentially adapted to biological tissues without any restriction in depth. High-energy stimuli, such as those employed for radiotherapy, are used to carry energy while molecular activation is provided by local energy conversion. This concept is applied to azobenzene, one of the most established photoswitches, to build a radioswitch. The radiation-responsive molecular system developed is used to trigger cytotoxic effect on cancer cells upon gamma-ray irradiation. This breakthrough activation concept is expected to expand the scope of applications of photosensitive systems and paves the way towards the development of original therapeutic approaches., (© 2022. The Author(s).)

The huge gap between 2D in vitro assays used for drug screening and the in vivo 3D physiological environment hampered reliable predictions for the route and accumulation of nanotherapeutics in vivo. For such nanotherapeutics, multi-cellular tumour spheroids (MCTS) are emerging as a good alternative in vitro model. However, the classical approaches to produce MCTS suffer from low yield, slow process, difficulties in MCTS manipulation and compatibility with high-magnification fluorescence optical microscopy. On the other hand, spheroid-on-chip set-ups developed so far require a practical knowledge of microfluidics difficult to transfer to a cell biology laboratory. We present here a simple yet highly flexible 3D model microsystem consisting of agarose-based microwells. Fully compatible with the multi-well plate format conventionally used in cell biology, our simple process enables the formation of hundreds of reproducible spheroids in a single pipetting. Immunostaining and fluorescence imaging including live high-resolution optical microscopy can be performed in situ, with no manipulation of spheroids. As a proof of principle of the relevance of such an in vitro platform for nanotherapeutic evaluation, this study investigates the kinetics and localisation of nanoparticles within colorectal cancer MCTS cells (HCT-116). The nanoparticles chosen are sub-5 nm ultrasmall nanoparticles made of polysiloxane and gadolinium chelates that can be visualized in MRI (AGuIX®, currently implicated in clinical trials as effective radiosensitizers for radiotherapy) and confocal microscopy after addition of Cy5.5. We show that the amount of AGuIX® nanoparticles within cells is largely different in 2D and 3D. Using our flexible agarose-based microsystems, we are able to resolve spatially and temporally the penetration and distribution of AGuIX® nanoparticles within MCTS. The nanoparticles are first found in both extracellular and intracellular space of MCTS. While the extracellular part is washed away after a few days, we evidenced intracellular localisation of AGuIX®, mainly within the lysosomal compartment, but also occasionally within mitochondria. Hence, our agarose-based microsystem appears as a promising 3D in vitro user-friendly platform for investigation of nanotherapeutic transport, ahead of in vivo studies.

Interest of tumor targeting through EPR effect is still controversial due to intrinsic low targeting efficacy and rare translation to human cancers. Moreover, due to different reasons, it has generally been described for relatively large nanoparticles (NPs) (hydrodynamic diameter > 10 nm). In this review EPR effect will be discussed for ultrasmall NPs using the example of the AGuIX® NP (Activation and Guiding of Irradiation by X-ray) recently translated in clinic. AGuIX® NP is a 4 ± 2 nm hydrodynamic diameter polysiloxane based NP. Since AGuIX® NP biodistribution is monitored by magnetic resonance imaging (MRI) and its activation is triggered by irradiation upon X-rays, this NP is well adapted for a theranostic approach of radiotherapy cancer treatment. Here we show that AGuIX® NP is particularly well suited to benefit from EPR-mediated tumor targeting thanks to an ultrasmall size and efficacy under irradiation at small dose. Indeed, intravenously-injected AGuIX® NP into rodent cancer models passively reached the tumor and revealed no toxicity, favoured by renal clearance. Moreover, translation of AGuIX® NP accumulation and retention into humans carrying brain metastases was validated during a first-in-man phase Ib trial taking advantage of easy biodistribution monitoring by MRI., Competing Interests: Competing Interests: F.L. and O.T. have one patent (WO2011135101) protecting the AGuIX® NP, are employed by NH TherAguix owner of AGuIX® NP, and possess shares of this company. S.D. is employed by NH TherAguix and possesses shares of this company. Y.C. is employed by NH TherAguix., (© The author(s).)

Background: Secukinumab is a first-in-class interleukin 17A monoclonal antibody that has demonstrated an excellent safety and efficacy profile in phase 3 studies., Objective: To evaluate the effectiveness of secukinumab in daily clinical practice and to understand the clinical and epidemiologic characteristics of patients treated with secukinumab in clinical settings., Methods: In this multicenter prospective observational study, we recruited adult patients with moderate-to-severe plaque psoriasis from 12 hospitals in Spain during January-December 2016. These patients were treated with secukinumab and prospectively followed at 12-week intervals for 52 weeks., Results: In total, 158 patients were recruited to the study. A Psoriasis Area and Severity Index (PASI) score improvement ≥75% over baseline (PASI-75) was achieved by 57%, 83.5%, 89%, and 78.5% of patients at weeks 4, 12, 24, and 52, respectively. PASI-90 was achieved in 27.8%, 62%, 64.6%, and 63.2% of patients at weeks 4, 12, 24, and 52, respectively; PASI-75 and PASI-90 responders were significantly more common among patients with a body mass index <30 kg/cm 2 and patients without previous biologic therapy failures., Limitations: Observational study. Time from onset of psoriasis was not evaluated., Conclusion: Secukinumab is a safe treatment with effectiveness rates similar to those found in its phase 3 studies. These rates endure up to a year from start of treatment., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

AGuIX ® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.

Once introduced in the organism, the interaction of nanoparticles with various biomolecules strongly impacts their fate. Here we show that nanoparticles made of the squalene derivative of gemcitabine (SQGem) interact with lipoproteins (LPs), indirectly enabling the targeting of cancer cells with high LP receptors expression. In vitro and in vivo experiments reveal preeminent affinity of the squalene-gemcitabine bioconjugates towards LP particles with the highest cholesterol content and in silico simulations further display their incorporation into the hydrophobic core of LPs. To the best of our knowledge, the use of squalene to induce drug insertion into LPs for indirect cancer cell targeting is a novel concept in drug delivery. Interestingly, not only SQGem but also other squalene derivatives interact similarly with lipoproteins while such interaction is not observed with liposomes. The conjugation to squalene represents a versatile platform that would enable efficient drug delivery by simply exploiting endogenous lipoproteins.

While important efforts were made in the development of positron emission tomography (PET) tracers for the in vivo molecular diagnosis of Alzheimer's disease, very few investigations to develop magnetic resonance imaging (MRI) probes were performed. Here, a new generation of Gd(III)-based contrast agents (CAs) is proposed to detect the amyloid β-protein (Aβ) aggregates by MRI, one of the earliest biological hallmarks of the pathology. A building block strategy was used to synthesize a library of 16 CAs to investigate structure-activity relationships (SARs) on physicochemical properties and binding affinity for the Aβ aggregates. Three types of blocks were used to modulate the CA structures: (i) the Gd(III) chelates (Gd(III)-DOTA and Gd(III)-PCTA), (ii) the biovectors (2-arylbenzothiazole, 2-arylbenzoxazole and stilbene derivatives) and (iii) the linkers (neutrals, positives and negatives with several lengths). These investigations revealed unexpected SARs and a difficulty of these probes to cross the blood-brain barrier (BBB). General insights for the development of Gd(III)-based CAs to detect the Aβ aggregates are described., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Molecular systems that can be remotely controlled by light are gaining increasing importance in cell biology, physiology, and neurosciences because of the spatial and temporal precision that is achievable with laser microscopy. Two-photon excitation has significant advantages deep in biological tissues, but raises problems in the design of "smart" probes compatible with cell physiology. This Review discusses the chemical challenges in generating suitable two-photon probes., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The Pittsburgh compound-B ([11C]PIB) is a highly interesting radiotracer for imaging amyloid plaques in Alzheimer's disease by positron emission tomography (PET). An increasing number of PET centres schedule its transfer for clinical studies and therefore are interested in its automated synthesis., Method: With the aim of flexibility, we reported the first fully automated synthesis of [11C]PIB with the coupling of two commercial synthesizers., Results: [11C]PIB was prepared from 2-(4'-aminophenyl)-6-hydroxybenzothiazole by [11C]methyl triflate methylation reacting in an high-performance liquid chromatography loop and resulting in a total radiochemical yield of 13+/-15% after a synthesis time of 25 min. The specific activity of [11C]PIB was 20-60 GBq/micromol and its radiochemical purity is more than 99%., Conclusion: The rapid synthesis and the automatic auto-cleaning procedure allow convenient and reproducible [11C]PIB synthesis to be performed during the same day for preclinical or clinical PET scans.