FLASH radiotherapy: ultra-high dose rates to spare healthy tissue

A recent addition to the treatment options in external beam therapy, so-called FLASH radiotherapy, shows remarkable healthy-tissue-sparing properties in a number of pre-clinical studies without impacting the overall treatment efficacy. Its potential in clinical applications is attracting a great deal of interest in the medical community. The use of ultra-high dose rates at extremely short irradiation times has been shown to significantly enhance the differential effects between normal and tumor tissue. This makes it possible to increase treatment doses without further harming the surrounding healthy tissue. While most studies to date have focused on the use of electron beams, X-ray and proton FLASH radiotherapy have also shown beneficial effects, although for these latter two the results still need to be independently confirmed. Furthermore, the mechanisms underlying the biological effects remain to be elucidated. Very recently, the FLASH effect has been demonstrated in the first human patient, with promising results, supporting further clinical studies. This review will present an overview of the investigations into FLASH radiotherapy to date.Accepted Author ManuscriptRST/Radiation, Science and TechnologyRST/Applied Radiation & Isotope

Alpha Radionuclide Therapy Using Polymeric Nanocarriers: Solution to the Recoil Problem?

In radionuclide therapy, radioisotopes are used to irradiate tumours from within the body. Usually beta-emitters coupled to tumour-targeting molecules are used, which specifically accumulate at the tumour site. Instead of using beta-emitters, it is also possible to use radionuclides which emit an alpha particle upon decay. Alpha particles have a shorter range and are much more effective in destroying tumour cells. Alpha radionuclide therapy is steadily gaining interest, although currently in most studies radionuclides with relatively short half-life are used. Long lived radionuclides like the 225Ac employed in this thesis are ideal for the treatment of tumours which take a longer time to reach. The long halflife of 225Ac combined with four alpha particles in its decay chain ensure long irradiation of the targeted tissue. However, upon alpha-decay the daughter nuclide receives a recoil energy decoupling it from any targeting agent, allowing it to diffuse throughout the body to irradiate healthy tissue. The main goal of this thesis is to develop polymeric nanocarriers, so-called polymersomes, which retain the recoiling daughter atoms of 225Ac in order to limit healthy tissue toxicity in alpha radionuclide therapy.RST/Applied Radiation & Isotope

A Critical Review of Alpha Radionuclide Therapy: How to Deal with Recoiling Daughters?

This review presents an overview of the successes and challenges currently faced in alpha radionuclide therapy. Alpha particles have an advantage in killing tumour cells as compared to beta or gamma radiation due to their short penetration depth and high linear energy transfer (LET). Touching briefly on the clinical successes of radionuclides emitting only one alpha particle, the main focus of this article lies on those alpha-emitting radionuclides with multiple alpha-emitting daughters in their decay chain. While having the advantage of longer half-lives, the recoiled daughters of radionuclides like 224Ra (radium), 223Ra, and 225Ac (actinium) can do significant damage to healthy tissue when not retained at the tumour site. Three different approaches to deal with this problem are discussed: encapsulation in a nano-carrier, fast uptake of the alpha emitting radionuclides in tumour cells, and local administration. Each approach has been shown to have its advantages and disadvantages, but when larger activities need to be used clinically, nano-carriers appear to be the most promising solution for reducing toxic effects, provided there is no accumulation in healthy tissue.RST/Radiation, Science and TechnologyApplied Science

Nanocarrier-Mediated Photochemotherapy and Photoradiotherapy

Photothermal therapy (PTT) and photodynamic therapy (PDT) both utilize light to induce a therapeutic effect. These therapies are rapidly gaining importance due to the noninvasiveness of light and the limited adverse effect associated with these treatments. However, most preclinical studies show that complete elimination of tumors is rarely observed. Combining PDT and PTT with chemotherapy or radiotherapy can improve the therapeutic outcome and simultaneously decrease side effects of these conventional treatments. Nanocarriers can help to facilitate such a combined treatment. Here, the most recent advancements in the field of photochemotherapy and photoradiotherapy, in which nanocarriers are employed, are reviewed.Accepted Author ManuscriptRST/Applied Radiation & Isotope

The Role of Iron in Staphylococcus aureus Infection and Human Disease: A Metal Tug of War at the Host—Microbe Interface

Iron deficiency anemia can be treated with oral or intravenous Fe supplementation. Such supplementation has considerable effects on the human microbiome, and on opportunistic pathogenic micro-organisms. Molecular understanding of the control and regulation of Fe availability at the host-microbe interface is crucial to interpreting the side effects of Fe supplementation. Here, we provide a concise overview of the regulation of Fe by the opportunistic pathogen Staphylococcus aureus. Ferric uptake regulator (Fur) plays a central role in controlling Fe uptake, utilization and storage in order to maintain a required value. The micro-organism has a strong preference for heme iron as an Fe source, which is enabled by the Iron-regulated surface determinant (Isd) system. The strategies it employs to overcome Fe restriction imposed by the host include: hijacking host proteins, replacing metal cofactors, and replacing functions by non-metal dependent enzymes. We propose that integrated omics approaches, which include metalloproteomics, are necessary to provide a comprehensive understanding of the metal tug of war at the host-microbe interface down to the molecular level.RST/Applied Radiation & IsotopesBT/Biocatalysi

Efficient Radiolabeling of Block Copolymer Micelles through Radiometal Salt Precipitation for Theranostic Applications

A variety of polymer micelles are designed for the delivery of chemotherapeutic drugs to tumors. Although the promise of these nanocarriers is very high, in the clinic the effectivity is rather limited. Determining the in vivo fate of the micelles can greatly help to improve this treatment. Here, a simple and fast chelator-free method for radiolabeling of polymer micelles composed of different block copolymers is presented, which can allow evaluating the behavior of the nanocarriers in vivo using noninvasive nuclear imaging techniques (e.g., single photon computed tomography, SPECT). The radiolabeling method consists of adding the radioisotope ions, i.e., 111In(III), resulting in a high radiolabeling efficiencies up to 90%. The results suggest that the radiolabeling efficiency depends on two important factors: the properties of the hydrophobic block in the block copolymer composing the micelle core, and the speciation of the radiometal salts. The formation of metal hydroxides and their precipitation in the core of the micelles appears to be a key factor for high stability. Moreover, the method can be applied to radiolabel the micelles in the presence of chemotherapeutic drugs. Finally, a SPECT study shows that the radiolabeled samples are stable in vivo without any evident loss of 111In(III).RST/Applied Radiation & IsotopesRST/Technici PoolRST/Biomedical ImagingChemE/Advanced Soft Matte

Evaluation of two extraction chromatography resins for scandium and titanium separation for medical isotope production

Scandium-47 (47Sc) can be used in nuclear medicine as a therapeutic-diagnostic, or “theragnostic,” radioactive medical isotope for cancer detection and treatment. The 47Sc isotope can be produced through the photonuclear reaction 48Ti(γ,p)47Sc by irradiating enriched 48Ti target material. The enriched target material necessary for production is costly; 48TiO2 costs ~ 1550/g, and targets can be > 50 g (77,500) to produce medically relevant amounts of 47Sc. In order to keep costs low, a highly efficient separation of scandium from bulk titanium is desired, along with efficient methods for recycling the target material. This research is focused on evaluating efficient methods for the separation of scandium from bulk quantities of titanium using commercially available diglycolamide-based and hydroxamate-based extraction chromatography resins (DGA resin and ZR resin, respectively). The sorption of 47Sc and Ti on these resins were investigated at varying concentrations of HNO3, HCl, H2SO4, and HF to explore how they might be used in a large-scale production/processing setting.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.RST/Applied Radiation & Isotope

The in vivo fate of ²²⁵Ac daughter nuclides using polymersomes as a model carrier

Increasing attention is given to personalized tumour therapy, where α-emitters can potentially play an important role. Alpha particles are ideal for localized cell killing because of their high linear energy transfer and short ranges. However, upon the emission of an α particle the daughter nuclide experiences a recoil energy large enough to ensure decoupling from any chemical bond. These ‘free’ daughter nuclides are no longer targeted to the tumour and can accumulate in normal tissue. In this paper, we used polymersomes as model carrier to evaluate the retention of recoiling daughters of 225Ac in vivo, and assessed their suitability as therapeutic agents. Vesicles containing 225Ac were injected intravenously in healthy mice, and intratumourally in tumour-bearing mice, and the relocation of free 213Bi was assessed in different organs upon the injection [225Ac]Ac-polymersomes. The therapeutic effect of 225Ac-containing vesicles was studied upon intratumoural injection, where treatment groups experienced no tumour-related deaths over a 115 day period. While polymersomes containing 225Ac could be suitable agents for long-term irradiation of tumours without causing significant renal toxicity, there is still a significant re-distribution of daughter nuclides throughout the body, signifying the importance of careful evaluation of the effect of daughter nuclides in targeted alpha therapy.RST/Applied Radiation & Isotope

The therapeutic potential of polymersomes loaded with ²²⁵Ac evaluated in 2D and 3D in vitro glioma models

Alpha emitters have great potential in targeted tumour therapy, especially in destroying micrometastases, due to their high linear energy transfer (LET). To prevent toxicity caused by recoiled daughter atoms in healthy tissue, alpha emitters like 225Ac can be encapsulated in polymeric nanocarriers (polymersomes), which are capable of retaining the daughter atoms to a large degree. In the translation to a (pre-)clinical setting, it is essential to evaluate their therapeutic potential. As multicellular tumour spheroids mimic a tumour microenvironment more closely than a two-dimensional cellular monolayer, this study has focussed on the interaction of the polymersomes with U87 human glioma spheroids. We have found that polymersomes distribute themselves throughout the spheroid after 4 days which, considering the long half-life of 225Ac (9.9 d) (Vaidyanathan and Zalutsky, 1996), allows for irradiation of the entire spheroid. A decrease in spheroidal growth has been observed upon the addition of only 0.1 kBq 225Ac, an effect which was more pronounced for the 225Ac in polymersomes than when only coupled to DTPA. At higher activities (5 kBq), the spheroids have been found to be destroyed completely after two days. We have thus demonstrated that 225Ac containing polymersomes effectively inhibit tumour spheroid growth, making them very promising candidates for future in vivo testing.RST/Applied Radiation & IsotopesRST/Technici PoolImPhys/OpleidingTechnische Natuurkund

Thioanisole ester based logic gate cascade to control ROS-triggered micellar degradation

In certain tumor and diseased tissues, reactive oxygen species (ROS), such as H2O2, are produced in higher concentrations than in healthy cells. Drug delivery and release systems that respond selectively to the presence of ROS, while maintaining their stability in “healthy” biological conditions, have great potential as on-site therapeutics. This study presents polymer micelles with 4-(methylthio)phenyl ester functionalities as a ROS-responsive reactivity switch. Oxidation of the thioether moieties triggers ester hydrolysis, exposing a hydrophylic carboxylate and leading to micellar disassembly. At 37 °C, the micelles fall apart on a timescale of days in the presence of 2 mM H2O2 and within hours at higher concentrations of H2O2 (60-600 mM). In the same time frame, the nanocarriers show no hydrolysis in oxidant-free physiological or mildly acidic conditions. This logic gate cascade behavior represents a step forward to realize drug delivery materials capable of selective response to a biomarker input.ChemE/Advanced Soft MatterRST/Applied Radiation & Isotope