The Use of Biomaterials in Internal Radiation Therapy

Radiotherapy has become one of the most prominent and effective modalities for cancer treatment and care. Ionising radiation, delivered either from external or internal sources, can be targeted to cancerous cells causing damage to DNA that can induce apoptosis. External beam radiotherapy delivers either photon radiation (x-rays or gamma rays) or particle radiation (neutrons or protons) in a targeted manner to specific tumour locations. Internal radiotherapy involves placing radioactive sources within the body to deliver localised doses of therapeutic radiation to tumours using short range radionuclides. Biomaterials have been developed to allow more precise targeting of radiotherapy in order to reduce toxicity to surrounding healthy tissues and increase treatment efficacy. These unique biomaterials have been developed from polymers, glasses and ceramics. Polymeric materials have been used to both displace healthy tissue from tumours receiving radiation, and to deliver radioactive sources into the body. These polymers can respond to various stimuli, such as radiation or reactive oxygen species, to deliver therapeutic payloads to target tissue during or post radiotherapy. Glass-based biomaterials doped with radionuclides have also been developed to provide in situ radiotherapy. Novel biomaterials that can enhance the synergistic effect of other treatment modalities, such as chemotherapy and immunotherapy, continue to be developed. Theranostic materials that are capable of providing diagnostic information whilst simultaneously delivering a therapeutic effect to enhance radiotherapy are also briefly reviewed

Real-time intrafraction motion monitoring in external beam radiotherapy

© 2019 Institute of Physics and Engineering in Medicine. Radiotherapy (RT) aims to deliver a spatially conformal dose of radiation to tumours while maximizing the dose sparing to healthy tissues. However, the internal patient anatomy is constantly moving due to respiratory, cardiac, gastrointestinal and urinary activity. The long term goal of the RT community to 'see what we treat, as we treat' and to act on this information instantaneously has resulted in rapid technological innovation. Specialized treatment machines, such as robotic or gimbal-steered linear accelerators (linac) with in-room imaging suites, have been developed specifically for real-time treatment adaptation. Additional equipment, such as stereoscopic kilovoltage (kV) imaging, ultrasound transducers and electromagnetic transponders, has been developed for intrafraction motion monitoring on conventional linacs. Magnetic resonance imaging (MRI) has been integrated with cobalt treatment units and more recently with linacs. In addition to hardware innovation, software development has played a substantial role in the development of motion monitoring methods based on respiratory motion surrogates and planar kV or Megavoltage (MV) imaging that is available on standard equipped linacs. In this paper, we review and compare the different intrafraction motion monitoring methods proposed in the literature and demonstrated in real-time on clinical data as well as their possible future developments. We then discuss general considerations on validation and quality assurance for clinical implementation. Besides photon RT, particle therapy is increasingly used to treat moving targets. However, transferring motion monitoring technologies from linacs to particle beam lines presents substantial challenges. Lessons learned from the implementation of real-time intrafraction monitoring for photon RT will be used as a basis to discuss the implementation of these methods for particle RT

A 3D US Guidance System for Permanent Breast Seed Implantation: Development and Validation

Permanent breast seed implantation (PBSI) is a promising breast radiotherapy technique that suffers from operator dependence. We propose and have developed an intraoperative 3D ultrasound (US) guidance system for PBSI. A tracking arm mounted to a 3D US scanner registers a needle template to the image. Images were validated for linear and volumetric accuracy, and image quality in a volunteer. The tracking arm was calibrated, and the 3D image registered to the scanner. Tracked and imaged needle positions were compared to assess accuracy and a patient-specific phantom procedure guided with the system. Median/mean linear and volumetric error was ±1.1% and ±4.1%, respectively, with clinically suitable volunteer scans. Mean tracking arm error was 0.43mm and 3D US target registration error ≤0.87mm. Mean needle tip/trajectory error was 2.46mm/1.55°. Modelled mean phantom procedure seed displacement was 2.50mm. To our knowledge, this is the first reported PBSI phantom procedure with intraoperative 3D image guidance

Samarium-Doped Fluorophosphate and Fluoroaluminate Glasses for High-Dose High-Resolution Dosimetry for Microbeam Radiation Therapy

Microbeam Radiation Therapy (MRT) is an important and developing radiotherapy technique that uses spatially fractionated doses, several orders of magnitude larger than that of the doses used in conventional radiation therapy. Healthy tissue displays remarkable resistance to damage caused from microscopically narrow, fractionated, planar beams of x-rays, while showing preferential damage towards cancerous growths, allowing for a high potential towards the treatment of often inoperable tumours. These synchrotron generated, spatially fractionated, planar beams are referred to as microbeams, and have a thickness of 20 – 50 µm and are separated by distances of 100 – 400 µm. The dose delivered at the center of the microbeam can be on the order of thousands of Grays (Gy), whereas the dose between each microbeam should be kept below tens of Gy. An important aspect of MRT is the spatial distribution of the dose delivered to the patient, which must be accurately measured. Ultimately, both high resolution and large dynamic range dosimetric measurements must be done simultaneously. The objective of this Ph.D. research involves the development and characterization of a dosimetric technique that fulfills the requirements of measuring dose distributions of microbeams. The proposed technique uses the indirect detection of x-rays, where the dose is recorded in a glass plate which can then be readout using a confocal microscopy system. The dose delivered is recorded by using trivalent samarium (Sm3+) doped fluoroaluminate and fluoro-phosphate glasses, where conversion from the trivalent form of samarium to the divalent form (Sm2+) occurs after exposure to x-rays. The extent of this conversion can be readout and digitized with high resolution using a confocal microscopy system that utilizes the easily distinguishable photoluminescent spectra of Sm3+ to Sm2+. The work carried out in this research involves the high resolution recording of microbeam profiles performed at the Canadian synchrotron, using samarium doped glass plates under a variety of irradiation parameters in order to determine their suitability for dosimetric applications. In particular, the dose rate and x-ray energy dependence of these materials is investigated, as well as the determination of the optimum Sm3+ dopant concentration. Further, the confocal measurement technique is investigated, as well as the suitability of ion implantation of samarium ions in order to improve the signal readout. Lastly, the change in dose distributions of microbeams is investigated by performing irradiations over a wide range of monochromatic x-rays, so that the potential effect of the selected energy on MRT treatment planning can be examined

Protective Embolization of the Gastroduodenal Artery with a One-HydroCoil Technique in Radioembolization Procedures

Purpose: Protective occlusion of the gastroduodenal artery (GDA) is required to avoid severe adverse effects and complications in radioembolization procedures. Because of the expandable features of HydroCoils, our goal was to occlude the GDA with only one HydroCoil to provide particle reflux protection. Methods: Twenty-three subjects with unresectable liver tumors, who were scheduled for protective occlusion of the GDA before radioembolization therapy, were included. The primary end point was to achieve a proximal occlusion of the GDA with only one detachable HydroCoil. Evaluated parameters were duration of deployment, and early (during the intervention) and late (7-21days) occlusion rates of GDA. Secondary end points included complete duration of the intervention, amount of contrast medium used, fluoroscopy rates, and adverse effects. Results: In all cases, the GDA was successfully occluded with only one HydroCoil. The selected diameter/length range was 4/10mm in 2 patients, 4/15mm in 6 patients, and 4/20mm in 15 patients. HydroCoils were implanted, on average, 3.75mm from the origin of the GDA (range 1.5-6.8mm), with an average deployment time of 2:47 (median 2:42, range 2:30-3:07) min. In 21 (91%) of 23 patients, a complete occlusion of the GDA was achieved during the first 30min after the coil implantation; however, in all patients, a late occlusion of the GDA was present after 6 to 29days. No clinical or technical complications were reported. Conclusion: We demonstrated that occlusion of the GDA with a single HydroCoil is a safe procedure and successfully prevents extrahepatic embolization before radioembolizatio

Preclinical evaluation of nanoparticle enhanced breast cancer diagnosis and radiation therapy

Triple negative breast cancer (TNBC) is an aggressive type of cancer which makes up 15-20% of all newly diagnosed cases, lacking the main target molecules for tumor specific treatment. Surgery or systemic therapy by chemotherapy are frequently used in the clinic and combined with radiation therapy to improve locoregional control in breast cancer patients after surgery. With a poor prognosis, there is a clear need to explore new treatment options for TNBC. The aim of the here presented PhD project was to evaluate the feasibility to enhance the biological effect of radiation therapy and increase tumor contrast for diagnosis by applying an in vivo microCT imaging system in combination with barium nanoparticles (BaNPs) in a pH8N8 WAP-T-NP8 mouse model for TNBC. Characterization of the BaNPs revealed strong x-ray attenuation and no toxic effects in different cancer and normal cell lines. Furthermore, irradiation of cancer cells using low energy x-rays in the keV range by a microCT resulted in a significant reduction on colony formation capability. In vitro, this low energy irradiation effect on clonogenic tumor cell survival was enhanced in the presence of BaNPs. Next, a subcutaneous lung cancer mouse model in immunodeficient mice and an orthotopic syngeneic mouse model for breast cancer was applied for further in vivo evaluation. Once the treatment plan was optimized regarding the applied x-ray doses and the frequency of irradiation, low energy radiation therapy within a classical in vivo microCT significantly reduced tumor growth or even resulted in shrinkage of the tumors without visible side effects and weight loss in comparison to untreated controls. However, the intratumoral application of BaNPs was not able to increase the irradiation effect on tumor growth kinetics. This might be in part due to inhomogeneous distribution of BaNPs within the tumor observed by microCT imaging. K-edge subtraction imaging as well as x-ray fluorescence of explanted tumor samples confirmed these findings. To localize the BaNPs in 3D to specific sites within the tumor environment and to detect morphological alterations within the tumor due to irradiation in proximity to BaNPs an ex-vivo imaging based analytic platform was established, utilizing co-registration of microCT and histology data. This imaging approach co-localized BaNPs with CD68 positive phagocytic cells and revealed a non-uniform distribution of the BaNPs within the tumor, however with no signs of locally enhanced radiation effects. Furthermore, antibody functionalized BaNPs were generated for systemic application. Analysis of biodistribution revealed that EpCAM labeled BaNPs did not reach the tumor after intra-venous administration, but accumulated in liver and spleen, demonstrated by a strong CT contrast within these organs. In summary, I showed that low energy radiation therapy by applying an in vivo microCT significantly reduced tumor volumes in comparison to untreated tumors in a syngeneic breast cancer tumor mouse model resembling TNBC. However, BaNPs while enhancing the effectiveness of irradiation on tumor cells in vitro, did not improve the irradiation effect on tumor growth in vivo.2021-07-1

Local delivery to malignant brain tumors: potential biomaterial-based therapeutic/adjuvant strategies

Glioblastoma (GBM) is the most aggressive malignant brain tumor and is associated with a very poor prognosis. The standard treatment for newly diagnosed patients involves total tumor surgical resection (if possible), plus irradiation and adjuvant chemotherapy. Despite treatment, the prognosis is still poor, and the tumor often recurs within two centimeters of the original tumor. A promising approach to improving the efficacy of GBM therapeutics is to utilize biomaterials to deliver them locally at the tumor site. Local delivery to GBM offers several advantages over systemic administration, such as bypassing the blood-brain barrier and increasing the bioavailability of the therapeutic at the tumor site without causing systemic toxicity. Local delivery may also combat tumor recurrence by maintaining sufficient drug concentrations at and surrounding the original tumor area. Herein, we critically appraised the literature on local delivery systems based within the following categories: polymer-based implantable devices, polymeric injectable systems, and hydrogel drug delivery systems. We also discussed the negative effect of hypoxia on treatment strategies and how one might utilize local implantation of oxygen-generating biomaterials as an adjuvant to enhance current therapeutic strategies. © 2021 The Royal Society of Chemistry