Catalytic activity imperative for nanoparticle dose enhancement in photon and proton therapy.

Nanoparticle-based radioenhancement is a promising strategy for extending the therapeutic ratio of radiotherapy. While (pre)clinical results are encouraging, sound mechanistic understanding of nanoparticle radioenhancement, especially the effects of nanomaterial selection and irradiation conditions, has yet to be achieved. Here, we investigate the radioenhancement mechanisms of selected metal oxide nanomaterials (including SiO2, TiO2, WO3 and HfO2), TiN and Au nanoparticles for radiotherapy utilizing photons (150 kVp and 6 MV) and 100 MeV protons. While Au nanoparticles show outstanding radioenhancement properties in kV irradiation settings, where the photoelectric effect is dominant, these properties are attenuated to baseline levels for clinically more relevant irradiation with MV photons and protons. In contrast, HfO2 nanoparticles retain some of their radioenhancement properties in MV photon and proton therapies. Interestingly, TiO2 nanoparticles, which have a comparatively low effective atomic number, show significant radioenhancement efficacies in all three irradiation settings, which can be attributed to the strong radiocatalytic activity of TiO2, leading to the formation of hydroxyl radicals, and nuclear interactions with protons. Taken together, our data enable the extraction of general design criteria for nanoparticle radioenhancers for different treatment modalities, paving the way to performance-optimized nanotherapeutics for precision radiotherapy

Assessment of iron nanoparticle distribution in mouse models using ultrashort echo-time magnetic resonance imaging

Microscopic magnetic field inhomogeneities caused by iron deposition or tissue-air interfaces may result in rapid decay of transverse magnetization in magnetic resonance imaging (MRI). The aim of this study is to detect and quantify the distribution of iron-based nanoparticles in mouse models applying ultrashort echo-time (UTE) sequences in tissues exhibiting extremely fast transverse relaxation. In 24 C57BL/6 mice (2 controls), suspensions containing either non-oxidic Fe or AuFeOx nanoparticles were injected into the tail vein at two doses (200 μg and 600 μg per mouse). Mice underwent MRI using a UTE sequence at 4.7T field strength with five different echo-times between 100 μs and 5000 μs. Transverse relaxation times T2* were computed for the lung, liver, and spleen by mono-exponential fitting. In UTE imaging, the MRI signal could reliably be detected even in liver parenchyma exhibiting the highest deposition of nanoparticles. In animals treated with Fe nanoparticles (600 μg per mouse), the relaxation time substantially decreased in the liver (3418±1534 μs (control) vs. 228±67 μs), the spleen (2170±728 μs vs. 299±97 μs), and the lungs (663±101 μs vs. 413±99 μs). The change in transverse relaxation was dependent on the amount and composition of the nanoparticles. By pixel-wise curve fitting, T2* maps were calculated showing nanoparticle distribution. In conclusion, UTE sequences may be used to assess and quantify nanoparticle distribution in tissues exhibiting ultra-fast signal decay in MRI

Exploiting Endogenous Surface Defects for Dynamic Nuclear Polarization of Silicon Micro- and Nanoparticles

Micro- and nanoparticles of elemental, crystalline silicon represent an attractive target for a wide range of applications spanning from quantum computing to contrast agents for biomedical imaging applications. To overcome the low sensitivity of the 29Si nuclei in magnetic resonance, dynamic nuclear polarization (DNP), which exploits the endogenous surface defects as a source of polarization, can be used to temporarily boost nuclear polarization of the 29Si spin bath. In the present work, we have assessed a number of commercially available silicon micro- and nanoparticles concerning properties and characteristics under DNP conditions. It has been found that optimal physical and chemical conditions, including surface-defect concentration adjusted to the particle size, are necessary to achieve a high level of polarization enhancement

Coercivity Determines Magnetic Particle Heating

Diseased cell treatment by heating with magnetic nanoparticles is hindered by their required high concentrations. A clear relationship between heating efficiency and magnetic properties of nanoparticles has not been attained experimentally yet due to limited availability of magnetic nanoparticles with varying size and composition. Here, versatile flame aerosol technology is used for the synthesis of 21 types of ferro-/ferrimagnetic nanocrystals with varying composition, size, and morphology for hyperthermia and thermoablation therapy. Heating efficiency, magnetic hysteresis, and first-order reversal curves of these materials are compared. The maximum heating performance occurs near the transition from superparamagnetic to single domain state, regardless of particle composition. Most importantly, the ratio between saturation magnetization and coercivity can be linked to the heating properties of magnetic nanoparticles. Magnetic interaction is controlled by changes in the architecture of the nanoparticles and closely analyzed by first-order reversal curves. Silica-coated nonstoichiometric Gd-Zn ferrite exhibits the most promising therapeutic capability at relatively low particle concentrations, as shown in vitro with cancerous prostate cells

Precision in Thermal Therapy: Clinical Requirements and Solutions from Nanotechnology

The heating of diseased tissue as a therapeutic measure has gained increased clinical attention, mostly due to its target‐specificity that minimizes side effects. However, to ensure a successful therapy, heating has to be homogeneous and highly localized, as well as, within a certain temperature range. Therefore, precise control over thermal treatments is a clinical prerequisite to minimize treatment and safety margins. Although this requirement is mentioned frequently, past research has focused predominantly on improving thermometry resolution and heating efficiency through tedious material optimization. Here, current clinical applications of thermal therapy with their challenges are first highlighted, especially with respect to treatment control and margins. Thereafter, it is quantitatively shown that clinically available thermometry fulfills the requirements and future research should focus on achieving better temperature control instead. With nanotechnology, novel strategies based on self‐limiting nanoparticle systems and particle‐based thermometers with active feed‐back control have also become available and are discussed. All of these approaches are systematically compared and analyzed with respect to their clinical applicability. The extent to which control over thermal therapy is necessary is also discussed alongside a presentation of the existing methods which fulfill the set requirements for clinical success and what issues remain to be tackled by research in the near future.ISSN:2366-398

Deep Tissue Imaging with Highly Fluorescent Near-Infrared Nanocrystals after Systematic Host Screening

Photoluminescent inorganic nanoparticles are attractive as bioimaging contrast agents because they do not degrade by photobleaching and do not suffer from concentration quenching as clinically applied organic dyes. Here, for the first time, a large variety of oxide, phosphate, and vanadate nanocrystals doped with Nd³⁺ are systematically examined and compared as down-converting photoluminescent contrast agents to understand underlying physical properties and to identify the brightest composition. These inorganic crystals are particularly attractive for bioimaging in the near-infrared (NIR) window, where absorption and scattering by human tissue are reduced drastically. Through close control of their crystal size, the resulting fluorescence properties are quantitatively compared under NIR excitation. Most interestingly, BiVO₄ doped with Nd³⁺ is shown to be the most efficient composition. Its application as a photoluminescent NIR imaging contrast agent is demonstrated <i>ex vivo</i> with chicken skeletal muscle and bovine liver tissues. Under a harmless laser power density (0.2 W/cm²), fluorescent BiVO₄ particles could be clearly detected at an injection depth of 20 mm by a simple commercial camera

Silica-Coated Nonstoichiometric Nano Zn-Ferrites for Magnetic Resonance Imaging and Hyperthermia Treatment

Large-scale and reproducible synthesis of nanomaterials is highly sought out for successful translation into clinics. Flame aerosol technology with its proven capacity to manufacture high purity materials (e.g., light guides) up to kg h(-1) is explored here for the preparation of highly magnetic, nonstoichiometric Zn-ferrite (Zn0.4 Fe2.6 O4 ) nanoparticles coated in situ with a nanothin SiO2 layer. The focus is on their suitability as magnetic multifunctional theranostic agents analyzing their T2 contrast enhancing capability for magnetic resonance imaging (MRI) and their magnetic hyperthermia performance. The primary particle size is closely controlled from 5 to 35 nm evaluating its impact on magnetic properties, MRI relaxivity, and magnetic heating performance. Most importantly, the addition of Zn in the flame precursor solution facilitates the growth of spinel Zn-ferrite crystals that exhibit superior magnetic properties over iron oxides typically made in flames. These properties result in strong MRI T2 contrast agents as shown on a 4.7 T small animal MRI scanner and lead to a more efficient heating with alternating magnetic fields. Also, by injecting Zn0.4 Fe2.6 O4 nanoparticle suspensions into pork tissue, MR-images are acquired at clinically relevant concentrations. Furthermore, the nanothin SiO2 shell facilitates functionalization with polymers, which improves the biocompatibility of the theranostic system

Multiscale Multimodal Investigation of the Intratissural Biodistribution of Iron Nanotherapeutics with Single Cell Resolution Reveals Co-Localization with Endogenous Iron in Splenic Macrophages

Imaging of iron-based nanoparticles (NPs) remains challenging because of the presence of endogenous iron in tissues that is difficult to distinguish from exogenous iron originating from the NPs. Here, an analytical cascade for characterizing the biodistribution of biomedically relevant iron-based NPs from the organ scale to the cellular and subcellular scales is introduced. The biodistribution on an organ level is assessed by elemental analysis and quantification of magnetic iron by electron paramagnetic resonance, which allowed differentiation of exogenous and endogenous iron. Complementary to these bulk analysis techniques, correlative whole-slide optical and electron microscopy provided spatially resolved insight into the biodistribution of endo- and exogenous iron accumulation in macrophages, with single-cell and single-particle resolution, revealing coaccumulation of iron NPs with endogenous iron in splenic macrophages. Subsequent transmission electron microscopy revealed two types of morphologically distinct iron-containing structures (exogenous nanoparticles and endogenous ferritin) within membrane-bound vesicles in the cytoplasm, hinting at an attempt of splenic macrophages to extract and recycle iron from exogenous nanoparticles. Overall, this strategy enables the distinction of endo- and exogenous iron across scales (from cm to nm, based on the analysis of thousands of cells) and illustrates distribution on organ, cell, and organelle levels

Chemically Stable, Strongly Adhesive Sealant Patch for Intestinal Anastomotic Leakage Prevention

Intestinal anastomotic leaking, which involves the discharge of chemically aggressive, non‐sterile fluids into the abdomen, remains one of the most dreaded postoperative complications of abdominal surgery. Depending on the site and the patient condition, incidence ranging between 4% and 21% and mortality rates up to 27% are reported. Currently available surgical sealants only poorly address the issue, especially since most commonly used fibrin glues fail due to insufficient adhesion and chemical instability. Here, a chemically highly resistive, leak‐tight, and mucoadhesive hydrogel sealant, which is grafted on the surface of the intestinal wall using a mutually interpenetrating network that traverses hydrogel and tissue is presented. In contrast to clinically used fibrin‐based sealants (including Tachosil), the developed adhesive poly(acrylamide‐methyl acrylate‐acrylic acid) patch does not degrade and exhibits strong tissue adhesion even when exposed to intestinal fluid. The biocompatible hydrogel patch effectively seals anastomotic leaks in ex vivo intestinal models, greatly surpassing commercial sealants (time to patch‐failure >24 h compared to 5 min for commonly used Tachosil). Importantly, the developed adhesive patch paves the way for the application of both mechanically and chemically robust sealants suitable for the treatment and prevention of intestinal leaks. © 2021 Wiley‐VCH GmbH.ISSN:1616-3028ISSN:1616-301