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Keratinocytes, the main cell type of the skin, are one of the most exposed cells to environmental factors, providing a first defence barrier for the host and actively participating in immune response. In fact, keratinocytes express pattern recognition receptors that interact with pathogen associated molecular patterns and damage associated molecular patterns, leading to the production of cytokines and chemokines, including interleukin (IL)-6. Herein, we investigated whether mechanical energy transported by low intensity ultrasound (US) could generate a mechanical stress able to induce the release of inflammatory cytokine such IL-6 in the human keratinocyte cell line, HaCaT. The extensive clinical application of US in both diagnosis and therapy suggests the need to better understand the related biological effects. Our results point out that US promotes the overexpression and secretion of IL-6, associated with the activation of nuclear factor-κB (NF-κB). Furthermore, we observed a reduced cell viability dependent on exposure parameters together with alterations in membrane permeability, paving the way for further investigating the molecular mechanisms related to US exposure.

Methods allowing for in situ dosimetry and range verification are essential in radiotherapy to reduce the safety margins required to account for uncertainties introduced in the entire treatment workflow. This study suggests a non-invasive dosimetry concept for carbon ion radiotherapy based on phase-change ultrasound contrast agents. Injectable nanodroplets made of a metastable perfluorobutane (PFB) liquid core, stabilized with a crosslinked poly(vinylalcohol) shell, are vaporized at physiological temperature when exposed to carbon ion radiation (C-ions), converting them into echogenic microbubbles. Nanodroplets, embedded in tissue-mimicking phantoms, are exposed at 37 °C to a 312 MeV/u clinical C-ions beam at different doses between 0.1 and 4 Gy. The evaluation of the contrast enhancement from ultrasound imaging of the phantoms, pre- and post-irradiation, reveals a significant radiation-triggered nanodroplets vaporization occurring at the C-ions Bragg peak with sub-millimeter shift reproducibility and dose dependency. The specific response of the nanodroplets to C-ions is further confirmed by varying the phantom position, the beam range, and by performing spread-out Bragg peak irradiation. The nanodroplets’ response to C-ions is influenced by their concentration and is dose rate independent. These early findings show the ground-breaking potential of polymer-shelled PFB nanodroplets to enable in vivo carbon ion dosimetry and range verification.

Low-intensity pulsed ultrasound (LIPUS) is a widely used non-invasive approach with therapeutic purposes since it provides physical stimulation with minimal thermal effects. The skin epithelium is the first barrier of the human body that interfaces with LIPUS and is subjected to the highest intensity. Little is known about the impact of LIPUS on the skin surface. This work investigates the biological effects of one-hour exposure to 1 MHz LIPUS on human keratinocytes HaCaT and tumoral SK-MEL-28 skin cells. Specifically, we evaluated the cellular state immediately after LIPUS treatment by analyzing cytogenetic endpoints and the response of cytoskeleton and cell junction proteins. Herein we demonstrate that LIPUS induces genomic damage as shown by an increase of chromosome malsegregation and a consequent decrease of cellular proliferation. The mechanical stimulus produced by LIPUS is also transmitted to the cytoskeletal compartment, inducing the expression and re-organization of junction proteins (i.e., E-cadherin and Desmosomes) and intermediate filaments (i.e., F-actin and Cytokeratins) with impact on cell morphology and cell adhesion. These in vitro results highlight the different outcomes following the cytogenetic damage and the resilience response exerted by the cytoskeleton upon mechanical stress, laying the foundation for future in vivo investigations.

Characterization of biopolymers in both dry and weakly hydrated amorphous states has implications for the pharmaceutical industry since it provides understanding of the effect of lyophilisation on stability and biological activity. Atomistic Molecular Dynamics (MD) simulations probe structural and dynamical features related to system functionality. However, while simulations in homogenous aqueous environments are routine, dehydrated model assemblies are a challenge with systems investigated in-silico needing careful consideration; simulated systems potentially differing markedly despite seemingly negligible changes in procedure. Here we propose an in-silico protocol to model proteins in lyophilised and weakly hydrated amorphous states that is both more experimentally representative and routinely applicable. Since the outputs from MD align directly with those accessed by neutron scattering, the efficacy of the simulation protocol proposed is shown by validating against experimental neutron data for apoferritin and insulin. This work also highlights that without cooperative experimental and simulative data, development of simulative procedures using MD alone would prove most challenging. Understanding the stability and activity of freeze-dried bio-macromolecules at low degrees of hydration is crucial for pharmaceutical and food industries, however, the building of in silico models for dynamical studies at a molecular level needs careful consideration. Here, the authors propose a modelling protocol that mimics experimental protein lyophilization, and proteins in weakly hydrated amorphous states, and validate it against experimental neutron scattering data.

Radiotherapy treatment plans have become highly conformal, posing additional constraints on the accuracy of treatment delivery. Here, we explore the use of radiation-sensitive ultrasound contrast agents (superheated phase-change nanodroplets) as dosimetric radiation sensors. In a series of experiments, we irradiated perfluorobutane nanodroplets dispersed in gel phantoms at various temperatures and assessed the radiation-induced nanodroplet vaporization events using offline or online ultrasound imaging. At 25 °C and 37 °C, the nanodroplet response was only present at higher photon energies (≥10 MV) and limited to <2 vaporization events per cm2 per Gy. A strong response (~2000 vaporizations per cm2 per Gy) was observed at 65 °C, suggesting radiation-induced nucleation of the droplet core at a sufficiently high degree of superheat. These results emphasize the need for alternative nanodroplet formulations, with a more volatile perfluorocarbon core, to enable in vivo photon dosimetry. The current nanodroplet formulation carries potential as an innovative gel dosimeter if an appropriate gel matrix can be found to ensure reproducibility. Eventually, the proposed technology might unlock unprecedented temporal and spatial resolution in image-based dosimetry, thanks to the combination of high-frame-rate ultrasound imaging and the detection of individual vaporization events, thereby addressing some of the burning challenges of new radiotherapy innovations.

This proof-of-concept study lays the foundations for the development of a delivery strategy for radioactive lanthanides, such as Yttrium-90, against recurrent glioblastoma. Our appealing hypothesis is that by taking advantage of the combination of biocompatible polyvinyl alcohol (PVA) microbubbles (MBs) and endovascular radiopharmaceutical infusion, a minimally invasive selective radioembolization can be achieved, which can lead to personalized treatments limiting off-target toxicities for the normal brain. The results show the successful formulation strategy that turns the ultrasound contrast PVA-shelled microbubbles into a microdevice, exhibiting good loading efficiency of Yttrium cargo by complexation with a bifunctional chelator. The selective targeting of Yttrium-loaded MBs on the glioblastoma-associated tumor endothelial cells can be unlocked by the biorecognition between the overexpressed αVβ3 integrin and the ligand Cyclo(Arg-Gly-Asp-D-Phe-Lys) at the PVA microbubble surface. Hence, we show the suitability of PVA MBs as selective Y-microdevices for in situ injection via the smallest (i.e., 1.2F) neurointerventional microcatheter available on the market and the accumulation of PVA MBs on the HUVEC cell line model of integrin overexpression, thereby providing ~6 × 10−15 moles of Y90 per HUVEC cell. We further discuss the potential impact of using such versatile PVA MBs as a new therapeutic chance for treating glioblastoma multiforme recurrence.

Background: Intra-arterial cerebral infusion (IACI) of radiotherapeutics is a promising treatment for glioblastoma (GBM) recurrence. We investigated the in silico feasibility and safety of Yttrium-90-Poly(vinyl alcohol)-Microbubble (90Y-PVA-MB) IACI in patients with recurrent GBM and compared the results with those of external beam radiation therapy (EBRT). Methods: Contrast-enhanced T1-weighted magnetic resonance imaging (T1W-MRI) was used to delineate the tumor volumes and CT scans were used to automatically segment the organs at risk in nine patients with recurrent GBM. Volumetric Modulated Arc Therapy (VMAT) treatment plans were generated using a clinical treatment planning system. Assuming the relative intensity of each voxel from the MR-T1W as a valid surrogate for the post-IACI 90Y-PVA-MB distribution, a specific 90Y dose voxel kernel was obtained through Monte Carlo (MC) simulations and convolved with the MRI, resulting in a 90Y-PVA-MB-based dose distribution that was then compared with the VMAT plans. Results: The physical dose distribution obtained from the simulation of 1GBq of 90Y-PVA-MBs was rescaled to ensure that 95% of the prescribed dose was delivered to 95% or 99% of the target (i.e., A95% and A99%, respectively). The calculated activities were A95% = 269.2 [63.6–2334.1] MBq and A99% = 370.6 [93.8–3315.2] MBq, while the mean doses to the target were 58.2 [58.0–60.0] Gy for VMAT, and 123.1 [106.9–153.9] Gy and 170.1 [145.9–223.8] Gy for A95% and A99%, respectively. Additionally, non-target brain tissue was spared in the 90Y-PVA-MB treatment compared to the VMAT approach, with a median [range] of mean doses of 12.5 [12.0–23.0] Gy for VMAT, and 0.6 [0.2–1.0] Gy and 0.9 [0.3–1.5] Gy for the 90Y treatments assuming A95% and A99%, respectively. Conclusions: 90Y-PVA-MB IACI using MR-T1W appears to be feasible and safe, as it enables the delivery of higher doses to tumors and lower doses to non-target volumes compared to the VMAT approach.

Nanodroplets have demonstrated potential for the range detection of hadron radiotherapies. Our formulation uses superheated perfluorobutane (C4F10) stabilized by a poly(vinyl-alcohol) shell. High-LET (linear energy transfer) particles vaporize the nanodroplets into echogenic microbubbles. Tailored ultrasound imaging translates the generated echo-contrast into a dose distribution map, enabling beam range retrieval. This work evaluates the response of size-sorted nanodroplets to carbon-ion radiation. We studied how thesize of nanodroplets affects their sensitivity at various beam-doses and energies, as a function of concentration and shell cross-linking. First, we show the physicochemical characterization of size-isolated nanodroplets by differential centrifugation. Then, we report on the irradiations of the nanodroplet samples in tissue-mimicking phantoms. We compared the response of large (≈900 nm) and small (≈400 nm) nanodroplets to different carbon-ions energies and evaluated their dose linearity and concentration detection thresholds by ultrasound imaging. Additionally, we verified the beam range detection accuracy for the nanodroplets samples. All nanodroplets exhibited sensitivity to carbon-ions with high range verification precision. However, smaller nanodroplets required a higher concentration sensitivity threshold. The vaporization yield depends on the carbon-ions energy and dose, which are both related to particle count/spot. These findings confirm the potential of nanodroplets for range detection, with performance depending on nanodroplets’ properties and beam parameters.

The discovery that the lower critical solution temperature (LCST) of poly(N-Isopropylacrylamide) (PNIPAM) in water is affected by the tacticity opens the perspective to tune the volume phase transition temperature of PNIPAM microgels by changing the content of meso dyads in the polymer network. The increased hydrophobicity of isotactic-rich PNIPAM originates from self-assembly processes in aqueous solutions also below the LCST. The present work aims to detect the characteristics of the pair interaction between polymer chains, occurring in a concentration regime close to the chain overlap concentration, by comparing atactic and isotactic-rich PNIPAM solutions. Using atomistic molecular dynamics simulations, we successfully modelled the increased association ability of the meso-dyad-rich polymer in water below the LCST, and gain information on the features of the interchain junctions as a function of tacticity. Simulations carried out above the LCST display the PNIPAM transition to the insoluble state and do not detect a relevant influence of stereochemistry on the structure of the polymer ensemble. The results obtained at 323 K provide an estimate of the swelling ratio of non-stereocontrolled PNIPAM microgels which is in agreement with experimental findings for microgels prepared with low cross-linker/monomer feed ratios. This study represents the first step toward the atomistic modelling of PNIPAM microgels with a controlled tacticity.

Poly(N-isopropylacrylamide) (PNIPAM) hydrogel microparticles with different core–shell morphologies have been designed, while maintaining an unvaried chemical composition: a morphology with (i) an un-crosslinked core with a crosslinked shell of PNIPAM chains and (ii) PNIPAM chains crosslinked to form the core with a shell consisting of tethered un-crosslinked PNIPAM chains to the core. Both morphologies with two different degrees of crosslinking have been assessed by confocal microscopy and tested with respect to their temperature responsivity and deformation by applying an osmotic stress. The thermal and mechanical behavior of these architectures have been framed within a Flory–Rehner modified model in order to describe the microgel volume shrinking occurring as response to a temperature increase or an osmotic perturbation. This study provides a background for assessing to what extent the mechanical features of the microgel particle surface affect the interactions occurring at the interface of a microgel particle with a cell, in addition to the already know ligand/receptor interaction. These results have direct implications in triggering a limited phagocytosis of microdevices designed as injectable drug delivery systems.