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Treating Brain Tumor with Microbeam Radiation Generated by a Compact Carbon-Nanotube-Based Irradiator: Initial Radiation Efficacy Study.

ABSTRACT: Microbeam radiation treatment (MRT) using synchrotron radiation has shown great promise in the treatment of brain tumors, with a demonstrated ability to eradicate the tumor while sparing normal tissue in small animal models. With the goal of expediting the advancement of MRT research beyond the limited number of synchrotron facilities in the world, we recently developed a compact laboratory-scale microbeam irradiator using carbon nanotube (CNT) field emission-based X-ray source array technology. The focus of this study is to evaluate the effects of the microbeam radiation generated by this compact irradiator in terms of tumor control and normal tissue damage in a mouse brain tumor model. Mice with U87MG human glioblastoma were treated with sham irradiation, low-dose MRT, high-dose MRT or 10 Gy broad-beam radiation treatment (BRT). The microbeams were 280 ?m wide and spaced at 900 ?m center-to-center with peak dose at either 48 Gy (low-dose MRT) or 72 Gy (high-dose MRT). Survival studies showed that the mice treated with both MRT protocols had a significantly extended life span compared to the untreated control group (31.4 and 48.5% of life extension for low- and high-dose MRT, respectively) and had similar survival to the BRT group. Immunostaining on MRT mice demonstrated much higher DNA damage and apoptosis level in tumor tissue compared to the normal brain tissue. Apoptosis in normal tissue was significantly lower in the low-dose MRT group compared to that in the BRT group at 48 h postirradiation. Interestingly, there was a significantly higher level of cell proliferation in the MRT-treated normal tissue compared to that in the BRT-treated mice, indicating rapid normal tissue repairing process after MRT. Microbeam radiation exposure on normal brain tissue causes little apoptosis and no macrophage infiltration at 30 days after exposure. This study is the first biological assessment on MRT effects using the compact CNT-based irradiator. It provides an alternative technology that can enable widespread MRT research on mechanistic studies using a preclinical model, as well as further translational research towards clinical applications.

SUBMITTER: Yuan H

PROVIDER: S-EPMC4600606 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Treating Brain Tumor with Microbeam Radiation Generated by a Compact Carbon-Nanotube-Based Irradiator: Initial Radiation Efficacy Study.

Yuan Hong H Zhang Lei L Frank Jonathan E JE Inscoe Christina R CR Burk Laurel M LM Hadsell Mike M Lee Yueh Z YZ Lu Jianping J Chang Sha S Zhou Otto O

Radiation research 20150825 3

Microbeam radiation treatment (MRT) using synchrotron radiation has shown great promise in the treatment of brain tumors, with a demonstrated ability to eradicate the tumor while sparing normal tissue in small animal models. With the goal of expediting the advancement of MRT research beyond the limited number of synchrotron facilities in the world, we recently developed a compact laboratory-scale microbeam irradiator using carbon nanotube (CNT) field emission-based X-ray source array technology. ...[more]

PMID: 26305294

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Project description:Microbeam radiation therapy (MRT) is defined as the use of parallel, microplanar x-ray beams with an energy spectrum between 50 and 300 keV for cancer treatment and brain radiosurgery. Up until now, the possibilities of MRT have mainly been studied using synchrotron sources due to their high flux (100s Gy/s) and approximately parallel x-ray paths. The authors have proposed a compact x-ray based MRT system capable of delivering MRT dose distributions at a high dose rate. This system would employ carbon nanotube (CNT) field emission technology to create an x-ray source array that surrounds the target of irradiation. Using such a geometry, multiple collimators would shape the irradiation from this array into multiple microbeams that would then overlap or interlace in the target region. This pilot study demonstrates the feasibility of attaining a high dose rate and parallel microbeam beams using such a system.The microbeam dose distribution was generated by our CNT micro-CT scanner (100 μm focal spot) and a custom-made microbeam collimator. An alignment assembly was fabricated and attached to the scanner in order to collimate and superimpose beams coming from different gantry positions. The MRT dose distribution was measured using two orthogonal radiochromic films embedded inside a cylindrical phantom. This target was irradiated with microbeams incident from 44 different gantry angles to simulate an array of x-ray sources as in the proposed compact CNT-based MRT system. Finally, phantom translation in a direction perpendicular to the microplanar beams was used to simulate the use of multiple parallel microbeams.Microbeams delivered from 44 gantry angles were superimposed to form a single microbeam dose distribution in the phantom with a FWHM of 300 μm (calculated value was 290 μm). Also, during the multiple beam simulation, a peak to valley dose ratio of ~10 was found when the phantom translation distance was roughly 4x the beam width. The first prototype CNT-based x-ray tube dedicated to the development of compact MRT technology development was proposed and planned based on the preliminary experimental results presented here and the previous corresponding Monte Carlo simulations.The authors have demonstrated the feasibility of creating microbeam dose distributions at a high dose rate using a proposed compact MRT system. The flexibility of CNT field emission x-ray sources could possibly bring compact and low cost MRT devices to the larger research community and assist in the translational research of this promising new approach to radiation therapy.

Project description:Microbeam radiation therapy (MRT) is an experimental radiotherapy technique that has shown potent antitumor effects with minimal damage to normal tissue in animal studies. This unique form of radiation is currently only produced in a few large synchrotron accelerator research facilities in the world. To promote widespread translational research on this promising treatment technology we have proposed and are in the initial development stages of a compact MRT system that is based on carbon nanotube field emission x-ray technology. We report on a Monte Carlo based feasibility study of the compact MRT system design.Monte Carlo calculations were performed using EGSnrc-based codes. The proposed small animal research MRT device design includes carbon nanotube cathodes shaped to match the corresponding MRT collimator apertures, a common reflection anode with filter, and a MRT collimator. Each collimator aperture is sized to deliver a beam width ranging from 30 to 200 μm at 18.6 cm source-to-axis distance. Design parameters studied with Monte Carlo include electron energy, cathode design, anode angle, filtration, and collimator design. Calculations were performed for single and multibeam configurations.Increasing the energy from 100 kVp to 160 kVp increased the photon fluence through the collimator by a factor of 1.7. Both energies produced a largely uniform fluence along the long dimension of the microbeam, with 5% decreases in intensity near the edges. The isocentric dose rate for 160 kVp was calculated to be 700 Gy∕min∕A in the center of a 3 cm diameter target. Scatter contributions resulting from collimator size were found to produce only small (<7%) changes in the dose rate for field widths greater than 50 μm. Dose vs depth was weakly dependent on filtration material. The peak-to-valley ratio varied from 10 to 100 as the separation between adjacent microbeams varies from 150 to 1000 μm.Monte Carlo simulations demonstrate that the proposed compact MRT system design is capable of delivering a sufficient dose rate and peak-to-valley ratio for small animal MRT studies.

Project description:Over the past few years, numerous nanotechnology-based drug delivery systems have been developed in an effort to maximize therapeutic effectiveness of conventional drug delivery, while limiting undesirable side effects. Among these, carbon nanotubes (CNTs) are of special interest as potential drug delivery agents due to their numerous unique and advantageous physical and chemical properties. Here, we show in vivo favorable biodistribution and enhanced therapeutic efficacy of cisplatin (CDDP) encapsulated within ultra-short single-walled carbon nanotube capsules (CDDP@US-tubes) using three different human breast cancer xenograft models. In general, the CDDP@US-tubes demonstrated greater efficacy in suppressing tumor growth than free CDDP in both MCF-7 cell line xenograft and BCM-4272 patient-derived xenograft (PDX) models. The CDDP@US-tubes also demonstrated a prolonged circulation time compared to free CDDP which enhanced permeability and retention (EPR) effects resulting in significantly more CDDP accumulation in tumors, as determined by platinum (Pt) analysis via inductively-coupled plasma mass spectrometry (ICP-MS). STATEMENT OF SIGNIFICANCE:Over the past decade, drug-loaded nanocarriers have been widely fabricated and studied to enhance tumor specific delivery. Among the diverse classes of nanomaterials, carbon nanotubes (CNTs), or more specifically ultra-short single-walled carbon nanocapsules (US-tubes), have been shown to be a popular, new platform for the delivery of various medical agents for both imaging and therapeutic purposes. Here, for the first time, we have shown that US-tubes can be utilized as a drug delivery platform in vivo to deliver the chemotherapeutic drug, cisplatin (CDDP) as CDDP@US-tubes. The studies have demonstrated the ability of the US-tube platform to promote the delivery of encapsulated CDDP by increasing the accumulation of drug in breast cancer resistance cells, which reveals how CDDP@US-tubes help overcome CDDP resistance.

Dataset Information

Treating Brain Tumor with Microbeam Radiation Generated by a Compact Carbon-Nanotube-Based Irradiator: Initial Radiation Efficacy Study.

Publications

Treating Brain Tumor with Microbeam Radiation Generated by a Compact Carbon-Nanotube-Based Irradiator: Initial Radiation Efficacy Study.

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