2014 Fiscal Year Research-status Report
Novel adjuvant method of malignant brain tumor diagnosis and therapy with targeted nanoparticles made of high-Z elements
| Project/Area Number |
26860393
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| Research Institution | University of Tsukuba |
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Principal Investigator |
ザボロノク アレクサンドル 筑波大学, 附属病院, 病院講師 (20723117)
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| Project Period (FY) |
2014-04-01 – 2016-03-31
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| Keywords | glioma / gold nanoparticles / boron-hyaluronic acid / neutron capture therapy / photon capture therapy |
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| Outline of Annual Research Achievements |
In 2014 fiscal year several stages of the main study plan were performed. Hyaluronic acid-melanin-gold nanoparticles (HAMG-NPs) were synthesized. Optical characteristics were analyzed by the light absorption and dynamic light scattering, showing particle size distribution, zeta-potential and the plasmon resonance. The particles were examined under light and electronic microscopy, showing sufficient penetration into the tumor cells. Boron-hyaluronic acid (BHA) compound was produced using solid-state synthesis. Nuclear magnetic resonance characteristics were analyzed, showing the stable connection of boron to hyaluronic acid (HA) and probable cites in the HA molecule for boron connection. MTS-assay showed relatively low time-dependent toxicity of BHA, being similar for both normal V79 and C6 malignant cells. The accumulation of boron in tumor and normal cells was performed using ICP-AES. The accumulation turned to be insufficient in both normal and tumor cells using current compound concentrations and experiment conditions, and further measures for accumulation improvement were analyzed, and their implementation was planned. The results of the study were presented at the 16th International Congress on Neutron Capture Therapy (ICNCT), June 14-19, 2014, Helsinki, Finland. Study results were summarized in the manuscript, which was submitted to the Applied Radiation and Isotopes special issue (ARI-D-15-00103, Hyaluronic acid as a potential boron carrier for BNCT: preliminary evaluation of feasibility for preclinical use. Zaboronok A, et al).
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| Current Status of Research Progress |
Current Status of Research Progress
3: Progress in research has been slightly delayed.
Reason
The study according to the main plan was slightly delayed due to the peculiarities of gold nanoparticles (GNPs) production process and reevaluation of the necessity of progression in the photon capture therapy experiments. Though GNPs showed radiation enhancement in glioma radiotherapy with x-rays in vitro, further development of the method for in vivo might have difficulties due to the potential toxicity of GNPs in laboratory animals after intravenous injections with further accumulation in such organs as liver and spleen. In this regard alternative methods of administration of GNPs are being analyzed. According to the alternative plan mentioned in the grant application it had been decided to direct more efforts towards the development of compounds for boron neutron capture therapy based on hyaluronic acid (HA), as a carries for boron. HA is a non-allergenic compound with the similar chemical composition among living organisms. HA can selectively bind to specific receptors on the surface of glioma cells and provide selective accumulation. Boron-hyaluronic acid compound showed relatively low cytotoxicity both for normal and tumor cells at prelimnary pilot experiments.
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| Strategy for Future Research Activity |
According to the study stages performed and preliminary conclusions made, GNPs might have a potential to enhance radiotherapy mainly in vitro with different contraindications for further in vivo experiments. Therefor it has been decided to direct efforts to the development and evaluation of chemical compounds for boron-neutron capture therapy, the method being developed for malignant glioma treatment using boron-10 containing compound and a neutron course. In the next 2015 fiscal year it is planned to continue experiments with GNPs, analyzing their toxicity, accumulation in vitro and administration methods and accumulation in vivo. Modification of GNPs using hyaluronic acid of high molecular weight is planned to develop a gel-like compound for local administration into the tumor bed after tumor excision. For BNCT compound development, it is planned to lower the HA molecular weight by using 2kDa HA for boron delivery, increasing the motility of the compound in the cell medium solution and the velocity in blood after an intravenous injection. Further it is planned modify BHA into HA-boron phenyl alanine (HA-BPA). BPA is used as an experimental compound for BNCT. Additional connection with low molecular HA might increase the compound attachment to glioma cells, leading to better boron accumulation, as well as potentially lowering the toxicity. Experiments on neutron irradiation of the samples containing newly developed boron compound at the accelerator-based neutron source are planned as the final stage of the method feasibility and efficacy evaluation.
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| Causes of Carryover |
The study according to the main plan was slightly delayed due to thegold nanoparticles (GNPs) production process and reevaluation of the of the progress in photon capture therapy experiments. The alternative plan described in the grant application was followed. At the initial stage of the development of compounds for boron neutron capture therapy based on hyaluronic acid (HA), as a carries for boron, less funds were spent on the articles. The manuscript preparation did not require the funds to be used. Publishing and further manuscript-related costs are to be covered in the next fiscal year.
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| Expenditure Plan for Carryover Budget |
The funds will be used according to the main plan of the study and for the alternative study for boron neutron capture therapy, according to the alternative plan described in the grant application, with additional costs for publications, transfered to the next fiscal year.
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