A novel injectable radiopaque hydrogel with potent properties for multicolor CT imaging in the context of brain and cartilage regenerative therapy.

Cell therapy is promising to treat many conditions, including neurological and osteoarticular diseases. Encapsulation of cells within hydrogels facilitates cell delivery and can improve therapeutic effects. However, much work remains to be done to align treatment strategies with specific diseases. The development of imaging tools that enable monitoring cells and hydrogel independently is key to achieving this goal. Our objective herein is to longitudinally study an iodine-labeled hydrogel, incorporating gold-labeled stem cells, by bicolor CT imaging after in vivo injection in rodent brains or knees. To this aim, an injectable self-healing hyaluronic acid (HA) hydrogel with long-persistent radiopacity was formed by the covalent grafting of a clinical contrast agent on HA. The labeling conditions were tuned to achieve sufficient X-ray signal and to maintain the mechanical and self-healing properties as well as injectability of the original HA scaffold. The efficient delivery of both cells and hydrogel at the targeted sites was demonstrated by synchrotron K-edge subtraction-CT. The iodine labeling enabled to monitor the hydrogel biodistribution in vivo up to 3 days post-administration, which represents a technological first in the field of molecular CT imaging agents. This tool may foster the translation of combined cell-hydrogel therapies into the clinics.

High-resolution synchrotron K-edge subtraction CT allows tracking and quantifying therapeutic cells and their scaffold in a rat model of focal cerebral injury and can serve as a reference for spectral photon counting CT.

Background: The objective of this study was to demonstrate that synchrotron K-edge subtraction tomography (SKES-CT) can simultaneously track therapeutic cells and their encapsulating carrier, in vivo, in a rat model of focal brain injury using a dual-contrast agent approach. The second objective was to determine if SKES-CT could be used as a reference method for spectral photon counting tomography (SPCCT). Methods: Phantoms containing different concentrations of gold and iodine nanoparticles (AuNPS/INPs) were imaged with SKES-CT and SPCCT to assess their performances. A pre-clinical study was performed in rats with focal cerebral injury which intracerebrally received AuNPs-labelled therapeutic cells encapsulated in a INPs-labelled scaffold. Animals were imaged in vivo with SKES-CT and back-to-back with SPCCT. Results: SKES-CT revealed to be reliable for quantification of gold and iodine, whether alone or mixed. In the preclinical model, SKES-CT showed that AuNPs remained at the site of cell injection, while INPs expanded within and/or along the lesion border, suggesting dissociation of both components in the first days post-administration. Compared to SKES-CT, SPCCT was able to correctly locate gold, but not completely located iodine. When SKES-CT was used as reference, SPCCT gold quantification appeared very accurate both in vitro and in vivo. Iodine quantification by SPCCT was also quite accurate, albeit less so than for gold. Conclusion: We here provide the proof-of-concept that SKES-CT is a novel method of choice for performing dual-contrast agent imaging in the context of brain regenerative therapy. SKES-CT may also serve as ground truth for emerging technologies such as multicolour clinical SPCCT.

Use of metal-based contrast agents for in vivo MR and CT imaging of phagocytic cells in neurological pathologies.

The activation of phagocytic cells is a hallmark of many neurological diseases. Imaging them in their 3-dimensional cerebral environment over time is crucial to better understand their role in disease pathogenesis and to monitor their potential therapeutic effects. Phagocytic cells have the ability to internalize metal-based contrast agents both in vitro and in vivo and can thus be tracked by magnetic resonance imaging (MRI) or computed tomography (CT). In this review article, we summarize the different labelling strategies, contrast agents, and in vivo imaging modalities that can be used to monitor cells with phagocytic activity in the central nervous system using MRI and CT, with a focus on clinical applications. Metal-based nanoparticle contrast agents such as gadolinium, gold and iron are ideal candidates for these applications as they have favourable magnetic and/or radiopaque properties and can be fine-tuned for optimal uptake by phagocytic cells. However, they also come with downsides due to their potential toxicity, especially in the brain where they might accumulate. We therefore conclude our review by discussing the pitfalls, safety and potential for clinical translation of these metal-based neuroimaging techniques. Early results in patients with neuropathologies such as multiple sclerosis, stroke, trauma, cerebral aneurysm and glioblastoma are promising. If the challenges represented by safety issues are overcome, phagocytic cells imaging will be a very valuable tool for studying and understanding the inflammatory response and evaluating treatments that aim at mitigating this response in patients with neurological diseases.

Visualizing the cerebral distribution of chemical elements: A challenge met with LIBS elemental imaging.

Biological tissues contain various metals and metalloids ions with central role in the regulation of several pathophysiological functions. In parallel, the development and the evaluation of novel nanocompounds for biomedicine require the monitoring of their biodistribution in tissues of interest. Therefore, researchers need to use reliable and accessible techniques to detect and quantify major and trace elements in space-resolved manner. In this communication, we report how Laser-Induced Breakdown Spectroscopy (LIBS) can be used to image the distribution of chemical elements in brain tissues.

Stereotaxic Implantation of F98 Cells in Fischer Rats: A Syngeneic Model to Investigate Photodynamic Therapy Response in Glioma.

When investigating the promise of novel therapeutic modalities, the choice of an appropriate and reproducible in vivo model is critical to determine the relevance of the findings. In the case of glioblastoma, a high-grade glioma tumor that is clinically characterized by a high infiltrative pattern, no existing model exactly mimics the clinical features of these tumors. However, a syngeneic rat model of glioblastoma in which F98 cells are orthotopically implanted can recapitulate most of the characteristics of glioma as observed in patients, including a highly aggressive nature, a high degree of infiltration of cancer cells into healthy tissue, and a strong resistance to commonly used treatments including radiotherapy and chemotherapy. Here, we provide a detailed protocol to stereotaxically implant F98 cells in the rat brain and obtain a reproducible and clinically representative glioma model in rodents.

Brain virtual histology with X-ray phase-contrast tomography Part I: whole-brain myelin mapping in white-matter injury models.

White-matter injury leads to severe functional loss in many neurological diseases. Myelin staining on histological samples is the most common technique to investigate white-matter fibers. However, tissue processing and sectioning may affect the reliability of 3D volumetric assessments. The purpose of this study was to propose an approach that enables myelin fibers to be mapped in the whole rodent brain with microscopic resolution and without the need for strenuous staining. With this aim, we coupled in-line (propagation-based) X-ray phase-contrast tomography (XPCT) to ethanol-induced brain sample dehydration. We here provide the proof-of-concept that this approach enhances myelinated axons in rodent and human brain tissue. In addition, we demonstrated that white-matter injuries could be detected and quantified with this approach, using three animal models: ischemic stroke, premature birth and multiple sclerosis. Furthermore, in analogy to diffusion tensor imaging (DTI), we retrieved fiber directions and DTI-like diffusion metrics from our XPCT data to quantitatively characterize white-matter microstructure. Finally, we showed that this non-destructive approach was compatible with subsequent complementary brain sample analysis by conventional histology. In-line XPCT might thus become a novel gold-standard for investigating white-matter injury in the intact brain. This is Part I of a series of two articles reporting the value of in-line XPCT for virtual histology of the brain; Part II shows how in-line XPCT enables the whole-brain 3D morphometric analysis of amyloid- ß (A ß ) plaques.

Surgivisio® and O-arm®O2 cone beam CT mobile systems for guidance of lumbar spine surgery: Comparison of patient radiation dose.

PURPOSE: To compare patient radiation doses in cone beam computed tomography (CBCT) of two mobile systems used for navigation-assisted mini-invasive orthopedic surgery: O-arm®O2 and Surgivisio®. METHODS: The study focused on imaging of the spine. Thermoluminescent dosimeters were used to measure organs and effective doses (ED) during CBCT. An ionization-chamber and a solid-state sensor were used to measure the incident air-kerma (Ki) at the center of the CBCT field-of-view and Ki during 2D-imaging, respectively. The PCXMC software was used to calculate patient ED in 2D and CBCT configurations. The image quality in CBCT was evaluated with the CATPHAN phantom. RESULTS: The experimental ED estimate for the low-dose 3D-modes was 2.41 and 0.35 mSv with O-arm®O2 (Low Dose 3D-small-abdomen) and Surgivisio® (3DSU-91 images), respectively. PCXMC results were consistent: 1.54 and 0.30 mSv. Organ doses were 5 to 12 times lower with Surgivisio®. Ki at patient skin were comparable on lateral 2D-imaging (0.5 mGy), but lower with O-arm®O2 on anteroposterior (0.3 versus 0.9 mGy). Both systems show poor low contrast resolution and similar high contrast spatial resolution (7 line-pairs/cm). CONCLUSIONS: This study is the first to evaluate patient ED and organ doses with Surgivisio®. A significant difference in organs doses was observed between the CBCT systems. The study demonstrates that Surgivisio® used on spine delivers approximately five to six times less patient ED, compared to O-arm®O2, in low dose 3D-modes. Doses in 2D-mode preceding CBCT were higher with Surgivisio®, but negligible compared to CBCT doses under the experimental conditions tested.

Unexpected Benefits of Multiport Synchrotron Microbeam Radiation Therapy for Brain Tumors.

Delivery of high-radiation doses to brain tumors via multiple arrays of synchrotron X-ray microbeams permits huge therapeutic advantages. Brain tumor (9LGS)-bearing and normal rats were irradiated using a conventional, homogeneous Broad Beam (BB), or Microbeam Radiation Therapy (MRT), then studied by behavioral tests, MRI, and histopathology. A valley dose of 10 Gy deposited between microbeams, delivered by a single port, improved tumor control and median survival time of tumor-bearing rats better than a BB isodose. An increased number of ports and an accumulated valley dose maintained at 10 Gy delayed tumor growth and improved survival. Histopathologically, cell death, vascular damage, and inflammatory response increased in tumors. At identical valley isodose, each additional MRT port extended survival, resulting in an exponential correlation between port numbers and animal lifespan (r2 = 0.9928). A 10 Gy valley dose, in MRT mode, delivered through 5 ports, achieved the same survival as a 25 Gy BB irradiation because of tumor dose hot spots created by intersecting microbeams. Conversely, normal tissue damage remained minimal in all the single converging extratumoral arrays. Multiport MRT reached exceptional ~2.5-fold biological equivalent tumor doses. The unique normal tissue sparing and therapeutic index are eminent prerequisites for clinical translation.

Radiation Dose-Enhancement Is a Potent Radiotherapeutic Effect of Rare-Earth Composite Nanoscintillators in Preclinical Models of Glioblastoma.

To improve the prognosis of glioblastoma, innovative radiotherapy regimens are required to augment the effect of tolerable radiation doses while sparing surrounding tissues. In this context, nanoscintillators are emerging radiotherapeutics that down-convert X-rays into photons with energies ranging from UV to near-infrared. During radiotherapy, these scintillating properties amplify radiation-induced damage by UV-C emission or photodynamic effects. Additionally, nanoscintillators that contain high-Z elements are likely to induce another, currently unexplored effect: radiation dose-enhancement. This phenomenon stems from a higher photoelectric absorption of orthovoltage X-rays by high-Z elements compared to tissues, resulting in increased production of tissue-damaging photo- and Auger electrons. In this study, Geant4 simulations reveal that rare-earth composite LaF3:Ce nanoscintillators effectively generate photo- and Auger-electrons upon orthovoltage X-rays. 3D spatially resolved X-ray fluorescence microtomography shows that LaF3:Ce highly concentrates in microtumors and enhances radiotherapy in an X-ray energy-dependent manner. In an aggressive syngeneic model of orthotopic glioblastoma, intracerebral injection of LaF3:Ce is well tolerated and achieves complete tumor remission in 15% of the subjects receiving monochromatic synchrotron radiotherapy. This study provides unequivocal evidence for radiation dose-enhancement by nanoscintillators, eliciting a prominent radiotherapeutic effect. Altogether, nanoscintillators have invaluable properties for enhancing the focal damage of radiotherapy in glioblastoma and other radioresistant cancers.

Photodynamic Diagnosis and Therapy for Peritoneal Carcinomatosis: Emerging Perspectives.

Peritoneal carcinomatosis occurs frequently in patients with advanced stage gastrointestinal and gynecological cancers. The wide-spread peritoneal micrometastases indicate a poor outlook, as the tumors are difficult to diagnose and challenging to completely eradicate with cytoreductive surgery and chemotherapeutics. Photodynamic diagnosis (PDD) and therapy (PDT), modalities that use photosensitizers for fluorescence detection or photochemical treatment of cancer, are promising theranostic approaches for peritoneal carcinomatosis. This review discusses the leading clinical trials, identifies the major challenges, and presents potential solutions to advance the use of PDD and PDT for the treatment of peritoneal carcinomatosis. While PDD for fluorescence-guided surgery is practically feasible and has achieved clinical success, large randomized trials are required to better evaluate the survival benefits. Although PDT is feasible and combines well with clinically used chemotherapeutics, poor tumor specificity has been associated with severe morbidity. The major challenges for both modalities are to increase the tumor specificity of the photosensitizers, to efficiently treat peritoneal microtumors regardless of their phenotypes, and to improve the ability of the excitation light to reach the cancer tissues. Substantial progress has been achieved in (1) the development of targeted photosensitizers and nanocarriers to improve tumor selectivity, (2) the design of biomodulation strategies to reduce treatment heterogeneity, and (3) the development of novel light application strategies. The use of X-ray-activated PDT during whole abdomen radiotherapy may also be considered to overcome the limited tissue penetration of light. Integrated approaches that take advantage of PDD, cytoreductive surgery, chemotherapies, PDT, and potentially radiotherapy, are likely to achieve the most effective improvement in the management of peritoneal carcinomatosis.

Radiation therapy combined with intracerebral convection-enhanced delivery of cisplatin or carboplatin for treatment of the F98 rat glioma.

BACKGROUND: The purpose of this review is to summarize our own experimental studies carried out over a 13-year period of time using the F98 rat glioma as model for high grade gliomas. We evaluated a binary chemo-radiotherapeutic modality that combines either cisplatin (CDDP) or carboplatin, administered intracerebrally (i.c.) by means of convection-enhanced delivery (CED) or osmotic pumps, in combination with either synchrotron or conventional X-irradiation. METHODS: F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Approximately 14 days later, either CDDP or carboplatin was administered i.c. by CED, followed 24 h later by radiotherapy using either a synchrotron or, subsequently, megavoltage linear accelerators (LINAC). RESULTS: CDDP was administered at a dose of 3 µg in 5 µL, followed 24 h later with an irradiation dose of 15 Gy or carboplatin at a dose of 20 µg in 10 µL, followed 24 h later with 3 fractions of 8 Gy each, at the source at the European Synchrotron Radiation Facility (ESRF). This resulted in a median survival time (MeST) > 180 days with 33% long term survivors (LTS) for CDDP and a MeST > 60 days with 8 to 22% LTS, for carboplatin. Subsequently it became apparent that comparable survival data could be obtained with megavoltage X-irradiation using a LINAC source. The best survival data were obtained with a dose of 72 µg of carboplatin administered by means of Alzet® osmotic pumps over 7 days. This resulted in a MeST of > 180 days, with 55% LTS. Histopathologic examination of all the brains of the surviving rats revealed no residual tumor cells or evidence of significant radiation related effects. CONCLUSIONS: The results obtained using this combination therapy has, to the best of our knowledge, yielded the most promising survival data ever reported using the F98 glioma model.

Surface functionalization of gold nanoclusters with arginine: a trade-off between microtumor uptake and radiotherapy enhancement.

Ultra-small gold nanoclusters (AuNCs) are increasingly investigated for cancer imaging and radiotherapy enhancement. While fine-tuning the AuNC surface chemistry can optimize their pharmacokinetics, its effects on radiotherapy enhancement remain largely unexplored. This study demonstrates that optimizing the surface chemistry of AuNCs for increased tumor uptake can significantly affect its potential to augment radiotherapy outcomes.

Comparison of gadolinium nanoparticles and molecular contrast agents for radiation therapy-enhancement.

PURPOSE: Nanoparticles appear as a novel tool to enhance the effectiveness of radiotherapy in cancer treatments. Many parameters influence their efficacy, such as their size, concentration, composition, their cellular localization, as well as the photon source energy. The current Monte Carlo study aims at comparing the dose-enhancement in presence of gadolinium (Gd), either as isolated atoms or atoms clustered in nanoparticles (NPs), by investigating the role played by these physical parameters at the cellular and the nanometer scale. In parallel, in vitro assays were performed in presence of either the gadolinium contrast agent (GdCA) Magnevist® or ultrasmall gadolinium NPs (GdNPs, 3 nm) for comparison with the simulations. METHODS: PENELOPE Monte Carlo Code was used for in silico dose calculations. Monochromatic photon beams were used to calculate dose enhancements in different cell compartments and low-energy secondary electron spectra dependence with energy. Particular attention has been placed on the interplay between the X-ray beam energy, the Gd localization and its distance from cellular targets. Clonogenic assays were used to quantify F98 rat glioma cell survival after irradiation in the presence of GdNPs or GdCA, using monochromatic X-rays with energies in the 30 keV-80 keV range from a synchrotron and 1.25 MeV gamma photons from a cobalt-60 source. The simulations that correspond to the experimental conditions were compared with the experimental results. RESULTS: In silico, a highly heterogeneous and clustered Gd-atom distribution, a massive production of low energy electrons around GdNPs and an optimal X-ray beam energy, above the Gd K-edge, were key factors found to increase microscopic doses, which could potentially induce cell death. The different Gd localizations studied all resulted in a lower dose enhancement for the nucleus component than for cytoplasm or membrane compartments, with a maximum dose-enhancement factor (DEF) found at 65 keV and 58 keV, respectively. In vitro, radiosensitization was observed with GdNPs incubated 5 h with the cells (2.1 mg Gd/mL) at all energies. Experimental DEFs were found to be greater than computational DEFs but follow a similar trend with irradiation energy. However, an important radiosensitivity was observed experimentally with GdNPs at high energy (1.25 MeV), whereas no effect was expected from modeling. This effect was correlated with GdNPs incubation time. In vitro, GdCA provided no dose enhancement at 1.25 MeV energies, in agreement with computed data. CONCLUSIONS: These results provide a foundation on which to base optimizations of the physical parameters in Gd radiation-enhanced therapy. Strong evidence was provided that GdCA or GdNPs could both be used for radiation dose-enhancement therapy. There in vivo biological distribution, in the tumor volume and at the cellular scale, will be the key factor for providing large dose enhancements and determine their therapeutic efficacy.

In vivo pink-beam imaging and fast alignment procedure for rat brain tumor radiation therapy.

A fast positioning method for brain tumor microbeam irradiations for preclinical studies at third-generation X-ray sources is described. The three-dimensional alignment of the animals relative to the X-ray beam was based on the X-ray tomography multi-slices after iodine infusion. This method used pink-beam imaging produced by the ID17 wiggler. A graphical user interface has been developed in order to define the irradiation parameters: field width, height, number of angles and X-ray dose. This study is the first reporting an image guided method for soft tissue synchrotron radiotherapy. It allowed microbeam radiation therapy irradiation fields to be reduced by a factor of ∼20 compared with previous studies. It permitted more targeted, more efficient brain tumor microbeam treatments and reduces normal brain toxicity of the radiation treatment.

Gadolinium nanoparticles and contrast agent as radiation sensitizers.

The goal of the present study was to evaluate and compare the radiosensitizing properties of gadolinium nanoparticles (NPs) with the gadolinium contrast agent (GdCA) Magnevist(®) in order to better understand the mechanisms by which they act as radiation sensitizers. This was determined following either low energy synchrotron irradiation or high energy gamma irradiation of F98 rat glioma cells exposed to ultrasmall gadolinium NPs (GdNPs, hydrodynamic diameter of 3 nm) or GdCA. Clonogenic assays were used to quantify cell survival after irradiation in the presence of Gd using monochromatic x-rays with energies in the 25 keV-80 keV range from a synchrotron and 1.25 MeV gamma photons from a cobalt-60 source. Radiosensitization was demonstrated with both agents in combination with X-irradiation. At the same concentration (2.1 mg mL(-1)), GdNPS had a greater effect than GdCA. The maximum sensitization-enhancement ratio at 4 Gy (SER4Gy) was observed at an energy of 65 keV for both the nanoparticles and the contrast agent (2.44 ± 0.33 and 1.50 ± 0.20, for GdNPs and GdCA, respectively). At a higher energy (1.25 MeV), radiosensitization only was observed with GdNPs (1.66 ± 0.17 and 1.01 ± 0.11, for GdNPs and GdCA, respectively). The radiation dose enhancements were highly 'energy dependent' for both agents. Secondary-electron-emission generated after photoelectric events appeared to be the primary mechanism by which Gd contrast agents functioned as radiosensitizers. On the other hand, other biological mechanisms, such as alterations in the cell cycle may explain the enhanced radiosensitizing properties of GdNPs.

Photoactivation of gold nanoparticles for glioma treatment.

Radiosensitization efficacy of gold nanoparticles (AuNPs) with low energy radiations (88 keV) was evaluated in vitro and in vivo on rats bearing glioma. In vitro, a significant dose-enhancement factor was measured by clonogenic assays after irradiation with synchrotron radiation of F98 glioma cells in presence of AuNPs (1.9 and 15 nm in diameter). In vivo, 1.9 nm nanoparticles were found to be toxic following intracerebral delivery in rats bearing glioma, whether no toxicity was observed using 15 nm nanoparticles at the same concentration (50 mg/mL). The therapeutic efficacy of gold photoactivation was determined by irradiating the animals after intracerebral infusion of AuNPs. Survival of rats that had received the combination of treatments (AuNPs: 50 mg/mL, 15 Gy) was significantly increased in comparison with the survival of rats that had received irradiation alone. In conclusion, this experimental approach is promising and further studies are foreseen for improving its therapeutic efficacy. FROM THE CLINICAL EDITOR: These investigators report that gold nanoparticles of the correct size can be used to enhance the effects of irradiation in the context of a glioma model. Since many of the glioma varieties are currently incurable, this or similar approaches may find their way to clinical trials in the near future.

Photon activation therapy of RG2 glioma carrying Fischer rats using stable thallium and monochromatic synchrotron radiation.

75 RG2 glioma-carrying Fischer rats were treated by photon activation therapy (PAT) with monochromatic synchrotron radiation and stable thallium. Three groups were treated with thallium in combination with radiation at different energy; immediately below and above the thallium K-edge, and at 50 keV. Three control groups were given irradiation only, thallium only, or no treatment at all. For animals receiving thallium in combination with radiation to 15 Gy at 50 keV, the median survival time was 30 days, which was 67% longer than for the untreated controls (p = 0.0020) and 36% longer than for the group treated with radiation alone (not significant). Treatment with thallium and radiation at the higher energy levels were not effective at the given absorbed dose and thallium concentration. In the groups treated at 50 keV and above the K-edge, several animals exhibited extensive and sometimes contra-lateral edema, neuronal death and frank tissue necrosis. No such marked changes were seen in the other groups. The results were discussed with reference to Monte Carlo calculated electron energy spectra and dose enhancement factors.

Preparation, biodistribution and neurotoxicity of liposomal cisplatin following convection enhanced delivery in normal and F98 glioma bearing rats.

The purpose of this study was to evaluate two novel liposomal formulations of cisplatin as potential therapeutic agents for treatment of the F98 rat glioma. The first was a commercially produced agent, Lipoplatin™, which currently is in a Phase III clinical trial for treatment of non-small cell lung cancer (NSCLC). The second, produced in our laboratory, was based on the ability of cisplatin to form coordination complexes with lipid cholesteryl hemisuccinate (CHEMS). The in vitro tumoricidal activity of the former previously has been described in detail by other investigators. The CHEMS liposomal formulation had a Pt loading efficiency of 25% and showed more potent in vitro cytotoxicity against F98 glioma cells than free cisplatin at 24 h. In vivo CHEMS liposomes showed high retention at 24 h after intracerebral (i.c.) convection enhanced delivery (CED) to F98 glioma bearing rats. Neurotoxicologic studies were carried out in non-tumor bearing Fischer rats following i.c. CED of Lipoplatin™ or CHEMS liposomes or their "hollow" counterparts. Unexpectedly, Lipoplatin™ was highly neurotoxic when given i.c. by CED and resulted in death immediately following or within a few days after administration. Similarly "hollow" Lipoplatin™ liposomes showed similar neurotoxicity indicating that this was due to the liposomes themselves rather than the cisplatin. This was particularly surprising since Lipoplatin™ has been well tolerated when administered intravenously. In contrast, CHEMS liposomes and their "hollow" counterparts were clinically well tolerated. However, a variety of dose dependent neuropathologic changes from none to severe were seen at either 10 or 14 d following their administration. These findings suggest that further refinements in the design and formulation of cisplatin containing liposomes will be required before they can be administered i.c. by CED for the treatment of brain tumors and that a formulation that may be safe when given systemically may be highly neurotoxic when administered directly into the brain.

Intracerebral delivery of carboplatin in combination with either 6 MV photons or monoenergetic synchrotron X-rays are equally efficacious for treatment of the F98 rat glioma.

BACKGROUND: The purpose of the present study was to compare side-by-side the therapeutic efficacy of a 6-day infusion of carboplatin, followed by X-irradiation with either 6 MV photons or synchrotron X-rays, tuned above the K-edge of Pt, for treatment of F98 glioma bearing rats. METHODS: Carboplatin was administered intracerebrally (i.c.) to F98 glioma bearing rats over 6 days using AlzetTM osmotic pumps starting 7 days after tumor implantation. Radiotherapy was delivered in a single 15 Gy fraction on day 14 using a conventional 6 MV linear accelerator (LINAC) or 78.8 keV synchrotron X-rays. RESULTS: Untreated control animals had a median survival time (MeST) of 33 days. Animals that received either carboplatin alone or irradiation alone with either 78.8 keV or 6 MV had a MeSTs 38 and 33 days, respectively. Animals that received carboplatin in combination with X-irradiation had a MeST of > 180 days with a 55% cure rate, irrespective of whether they were irradiated with either 78.8 KeV synchrotron X-rays or 6MV photons. CONCLUSIONS: These studies have conclusively demonstrated the equivalency of i.c. delivery of carboplatin in combination with X-irradiation with either 6 MV photons or synchrotron X-rays.

Monochromatic minibeams radiotherapy: from healthy tissue-sparing effect studies toward first experimental glioma bearing rats therapy.

PURPOSE: The purpose of this study was to evaluate high-dose single fraction delivered with monochromatic X-rays minibeams for the radiotherapy of primary brain tumors in rats. METHODS AND MATERIALS: Two groups of healthy rats were irradiated with one anteroposterior minibeam incidence (four minibeams, 123 Gy prescribed dose at 1 cm depth in the brain) or two interleaved incidences (54 Gy prescribed dose in a 5 × 5 × 4.8 mm(3) volume centered in the right hemisphere), respectively. Magnetic resonance imaging (MRI) follow-up was performed over 1 year. T2-weighted (T2w) images, apparent diffusion coefficient (ADC), and blood vessel permeability maps were acquired. F98 tumor bearing rats were also irradiated with interleaved minibeams to achieve a homogeneous dose of 54 Gy delivered to an 8 × 8 × 7.8 mm(3) volume centered on the tumor. Anatomic and functional MRI follow-up was performed every 10 days after irradiation. T2w images, ADC, and perfusion maps were acquired. RESULTS: All healthy rats were euthanized 1 year after irradiation without any clinical alteration visible by simple examination. T2w and ADC measurements remain stable for the single incidence irradiation group. Localized Gd-DOTA permeability, however, was observed 9 months after irradiation for the interleaved incidences group. The survival time of irradiated glioma bearing rats was significantly longer than that of untreated animals (49 ± 12.5 days versus 23.3 ± 2 days, p < 0.001). The tumoral cerebral blood flow and blood volume tend to decrease after irradiation. CONCLUSIONS: This study demonstrates the sparing effect of minibeams on healthy tissue. The increased life span achieved for irradiated glioma bearing rats was similar to the one obtained with other radiotherapy techniques. This experimental tumor therapy study shows the feasibility of using X-ray minibeams with high doses in brain tumor radiotherapy.