Development of a Novel Platform for MR-Guided Radiation Therapy

BackgroundThere are some motion platforms for radiotherapy quality assurance. However, no platform with two drive systems that can move along three axes is available.PurposeThe purpose of this study is to develop a dynamic motion platform with two drive systems capable of three‐axis motion and to evaluate its motion performance.MethodsThe developed moving platform had two drive systems that use the same equipment. Each axis of the platform used can support a maximum load of 10 kg. The motors for moving the platform in each direction are capable of a drive stroke up to 40 mm. The drive speed is 30 mm/s at maximum load fluctuation. To evaluate the static positional accuracy of this system with an arbitrary input movement, the XYZ position of each axis was measured using a coordinate measuring machine operating from 0 to 40 mm at 10 mm intervals. In addition, the accuracy of dynamic motion was verified with Sine waveform inputs of different patterns to the three axes for approximately 60 s, and they were compared with the resulting detected signals by SyncTrax.ResultsThe two drive systems were successfully operated on three axes by using independent control systems. For static position, the accuracies were within 0.2 mm, 0.05 mm, and 0.14 mm for lateral, longitudinal, and vertical directions, respectively. For dynamic motion, the mean absolute errors in the X, Y, and Z axes between the platform inputs and SyncTrax detected signals were 0.14 ± 0.10 mm, 0.16 ± 0.12 mm, and 0.16 ± 0.11 mm, respectively.ConclusionsA new dynamic platform for radiation therapy with two drive systems capable of three‐axis motion was developed, and the positional accuracy of the drive axes was confirmed to be less than 0.2 mm.

Polymeric cyclodextrin-based nanoparticles are currently undergoing clinical trials as nanotherapeutics. Using a non-covalent approach, we decorated two cross-linked cyclodextrin polymers of different molecular weights with an RGD peptide derivative to construct a novel carrier for the targeted delivery of doxorubicin. RGD is the binding sequence for the integrin receptor family that is highly expressed in tumour tissues. The assembled host-guest systems were investigated using NMR and DLS techniques. We found that, in comparison with free doxorubicin or the binary complex doxorubicin/cyclodextrin polymer, the RGD units decorating the cyclodextrin-based nanosystems improved the selectivity and cytotoxicity of the complexed doxorubicin towards cultured human tumour cell lines. Our results suggest that the nanocarriers under study may contribute to the development of new platforms for cancer therapy.

The development of multifunctional nanotheranostic platforms with stimuli-responsive capabilities holds significant potential for enhancing cancer diagnosis and treatment. Herein, a glutathione (GSH)-responsive semiconducting polymer (SP) nanotheranostic system, SP/DOX-SS-PEG nanoparticles (NPs), is presented, designed for combined near-infrared II (NIR-II) fluorescence imaging (FI) and chemo-photothermal therapy. The amphiphilic SP (SP-SS-PEG) is synthesized through a multi-step reaction sequence, including Suzuki coupling, amidation, and thiol-disulfide exchange reactions, and subsequently encapsulates the anticancer drug doxorubicin (DOX) through self-assembly, resulting in the formation of GSH-responsive SP/DOX-SS-PEG NPs. These SP/DOX-SS-PEG NPs exhibit high photothermal stability and significant GSH-triggered DOX release. In vitro studies demonstrate that SP/DOX-SS-PEG NPs display enhanced cellular uptake and robust cytotoxicity against 4T1 cancer cells under 808 nm laser irradiation. Upon intravenous injection in tumor-bearing mice, NIR-II FI reveals efficient tumor accumulation and prolonged retention of the NPs. In vivo anti-tumor efficacy studies indicate that SP/DOX-SS-PEG NPs combined with 808 nm laser irradiation achieve the most significant inhibition of tumor growth, with minimal systemic toxicity. Taken together, these findings highlight the promising potential of SP/DOX-SS-PEG NPs as a multifunctional platform for precision cancer theranostics, integrating efficient NIR-II imaging, GSH-triggered drug release, and dual chemo-photothermal therapy.

Nanomaterials are promising platforms for cancer therapy due to their innate passive targeting. The success of nanomaterials into the clinics depends on their blood circulation time and accumulation in the target tissue, factors related with their ability to evade the immune system. Cell-derived nanoplatforms are an emerging technology to enhance the delivery by active targeting the tumor site, without the perks of chemical conjugations. In this thesis we report the development of biomimetic novel platforms using the cell-derived technology and their in vitro interaction in cells from tumor microenvironment. To understand of the cell-derived nanoplatforms, two different nanomaterials were synthesized and further coated with extracellular vesicles and cell membrane extract from two different cell lines. First, gold nanorods (AuNRs) were coated with two macrophage derived vesicles, cell membrane extract and extracellular vesicles. Cell membrane-coated AuNRs interacted more with the metastatic cancer cells and the extracellular vesicles interacted more with the source cells. The main difference evaluated among the coatings was the presence of the tetraspanin CD47, an immunosuppressive marker for phagocytosis. Furthermore, we developed a paclitaxel-loaded polymeric nanoparticle carrier coated with metastatic breast cancer cell membrane. All cell lines showed a preferential uptake for the nanoparticles coated with the cell membrane, with stronger interaction with the source cell and the fibroblasts. Our results pointed to the role of adhesion molecules in the homotypic bind to cancer cells and the interaction with stroma cells as a heritage of the tumor progression pathways. As a consequence of the enhanced interaction of the nanocarriers with fibroblasts, the nanoparticles were significantly cytotoxic. We also explored the tunability of the plasmonic band in relation to their composition and size and evaluated basic culture parameters for extracellular vesicles isolation by means of size distribution and concentration.

Preparation of colloidal polydopamine/Au hollow spheres for enhanced ultrasound contrast imaging and photothermal therapy.

The development of a theranostic platform that integrates both diagnostic and therapeutic capabilities is in great need for precise and personalized medicine. Here, we present a novel nanoplatform (AuNS@CS-hpDNA) formulated by chitosan functionalized gold nanostar composites and further complexed with fluorescent hairpin DNA (hpDNA) probes for tumor-related miRNA imaging and photothermal therapy (PTT). The optimized AuNS@CS-hpDNA nanoplatform mediated efficient hpDNA probe loading and intracellular delivery. Subsequently, the cytosol transfer of the hpDNA probe enabled specific hybridization using the targeted miRNA, which triggered the recovery of fluorescence for the precise detection of biomarker miR21 in living cells and realized the distinguishing cancer cell line MCF-7 and normal cells. Meanwhile, the AuNS@CS-hpDNA nanoplatform exhibited excellent photothermal conversion properties, which induced efficient cancer cell killing under laser irradiation. Thus, the developed AuNS@CS-hpDNA nanoplatform could simultaneously realize the precise detection of cancer cells and accurately initiate efficient PTT, which represents a promising strategy for precise cancer therapy.

Recently, there have been tremendous advances in the development of various nanotechnology-based platforms for diagnosis and therapy. These nanoplatforms, which include liposomes, micelles, polymers, and dendrimers, comprise highly integrated nanoparticles that provide multiple functions, such as targeting, imaging, and therapy. This review focuses on dendrimer-based nanocarriers that have recently been developed for 'theranostics (or theragnosis)', a combination of therapy and diagnostics. We discuss the in vitro and in vivo applications of these nanocarriers in strategies against diseases including cancer. We also explore the use of dendrimers as imaging agents for fluorescence imaging, magnetic resonance imaging, X-ray computed tomography, and nuclear medical imaging.

PO-0935: Development of an open-source software platform for conventional and particle therapy

The cover picture shows several human mesenchymal stem cells (green with blue nuclei) clustered around a stiff polymeric microstructure (blue) in a three-dimensional matrix. The microstructures are fabricated using photolithographic techniques and then suspended with stem cells in the matrix. The stem cells migrate and attach to the microstructures, and although the volume percentage of the microstructures within the matrix is quite low (0.07%), stem-cell morphology, clustering, and gene expression are significantly different compared to without the microstructures. The knowledge of how physical and mechanical cues in three dimensions can influence cellular function is necessary for the development of novel platforms for regenerative therapy. For more information, please read the Communication “Three-Dimensional Culture with Stiff Microstructures Increases Proliferation and Slows Osteogenic Differentiation of Human Mesenchymal Stem Cells by B. Russell et al., beginning on page 355.

A Prospective Single-Arm Phase 2 Study of Stereotactic Magnetic Resonance Guided Adaptive Radiation Therapy for Prostate Cancer: Early Toxicity Results

BackgroundAccurate small‐field (SF) dosimetry is essential for Magnetic Resonance‐guided Radiation Therapy (MRgRT), particularly for stereotactic treatments. The static magnetic field (B‐field) alters detector response, necessitating detector‐specific correction factors kB,Qf,f to ensure dosimetric accuracy. While numerous studies have reported such factors, the published data shows considerable variability, creating uncertainty for clinical practice.PurposeThis study was undertaken to (1) systematically review the literature on SF photon dosimetry in MRgRT and (2) perform a meta‐analysis to pool quantitative data and investigate the sources of this variability.MethodsA systematic search of four databases was conducted following PRISMA 2020 guidelines. A qualitative synthesis was performed on all included studies (n = 86). A random‐effects meta‐analysis was performed on studies providing correction factors (beam quality correction factor, kmsr; field output correction factor, kclin) or uncorrected output factors (FOF) for fields ≤ 4 × 4 cm2 with associated uncertainties (n = 13 studies, 441 data points). Heterogeneity (I2) was quantified, and subgroup analyses (B‐field, detector model, and orientation) and meta‐regression (field size) were used to investigate its sources.ResultsThe qualitative review identified key themes in foundational physics, detector‐specific characteristics, and clinical quality assurance. The meta‐analysis revealed extremely high heterogeneity (I2 > 92%) across all pooled data, confirming that a single global‐average correction factor is statistically inappropriate. Subgroup analyses demonstrated that this heterogeneity is systematically driven by three main factors: magnetic field strength (e.g., 0.35 T vs. 1.5 T), specific detector model (with significant variations observed even among models of the same type), and detector orientation relative to the beam and B‐field. Meta‐regression showed that correction factors kmsr and kclin demonstrated no statistically significant dependence on field size in this SF regime, which suggests that the theoretical variation expected due to beam property changes is statistically masked by the high heterogeneity (I2 > 92) observed in the literature; conversely, FOFs showed a strong, statistically significant field‐size dependence.ConclusionThe findings confirm that detector response in MRgRT is a complex function of the measurement setup. A single correction factor is insufficient for clinical use. Dosimetric accuracy in MRgRT requires the use of correction factors that are specific to the MR‐Linac's B‐field strength, the exact detector model, and the measurement orientation. This analysis provides pooled, stratified data to support clinical physicists and inform the development of future dosimetry protocols.

MR-Guided Radiation Therapy With Concurrent Gemcitabine/Nab-Paclitaxel Chemotherapy in Inoperable Pancreatic Cancer: A TITE-CRM Phase I Trial

Quality of Life and Toxicity in Patients With Pancreatic Ductal Adenocarcinoma Treated With Online Adaptive Stereotactic Magnetic Resonance Guided Radiation Therapy.

Background: Radiation therapy in rectal cancer treatment is limited by variable tumor responses among patients and harmful effects on normal tissues. We developed a translational human tumoroid-organoid platform to assess novel tumor-specific strategies for radiation sensitization using matched patient-derived models. Methods: Fifteen rectal cancer-derived tumoroids and three matched normal tissue-derived organoids were established from patients, representing primary tumors, metastases, and recurrences. Four tumoroids were derived from a single patient, encompassing different disease stages: primary tumor and splenic metastasis (pre-progression), and rectal and vaginal recurrences (post-progression). To evaluate tumor-specific radiation sensitizers, both tumoroids and their matched normal organoids were treated with 5-fluorouracil (5-FU), one of four DNA damage repair inhibitors (DDRis; ATMi, DNA-PKi, PARPi, or ATRi), or a DMSO control. Following treatment, samples were irradiated, and cell viability was measured. We assessed intrinsic radiation sensitivity under control conditions and radiosensitizer efficacy using a linear regression model with log-transformed cell viability as the outcome. Whole-exome sequencing characterized the mutation profiles of the tumoroids. Results: Intrinsic radiosensitivity was heterogeneous among tumoroids, with a 10–28% decrease in cell growth per unit increase in radiation dose. Critically, when comparing tumoroids to their matched normal organoids, we observed greater sensitization in tumoroids across all cases and for all DDRis, demonstrating tumor-specific radiosensitization. The most potent radiosensitizer relative to DMSO was DNA-PKi in 7 tumoroids, ATMi in 4 tumoroids, and PARPi in 1 tumoroid. Tumoroids derived after disease progression exhibited increased resistance to radiation and a diminished degree of sensitization with DDRi treatment compared to pre-progression tumoroids. Despite variations in radiation sensitivity and DDRi responses, the genetic profiles of the tumoroids remained largely unchanged. Conclusion: We developed a translational ex vivo tumoroid-organoid platform using matched patient-derived models to test tumor-specific radiation sensitizers in rectal cancer. This platform allowed us to determine tumor-specific sensitization by directly comparing tumoroids with matched normal organoids, demonstrating greater sensitization in tumoroids. Our findings highlight the potential of this platform to uncover precise, tumor-selective treatment options, improve patient responses, reduce toxicity, and address resistant tumors in patients with disease progression. Citation Format: Wini Zambare, Chao Wu, Hannah Kalvin, Hanchen Huang, Sara Yoder, Michael Del Latto, Maria Kierstead, Satoru Meguro, Xi Steven Chen, Mithat Gonen, J. Joshua Smith, Paul B. Romesser. Development of a translational tumoroid-organoid platform revealing tumor-specific radiosensitization in rectal cancer using matched patient-derived models. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A012.

The electronic view box: A software tool for radiation therapy treatment verification