L-Boronphenylalanine Biodistribution Dynamics in the Organs of Mice with Subcutaneous Tumor Xenograft is a Model to Assess Neuron Sources Efficiency in Boron Neutron Capture Therapy
Boron neutron capture therapy (BNCT), due to its high biological efficiency, is one of the most promising methods of radiation therapy for malignant tumors. Currently, research in this area has received momentum due to the emergence of fundamentally new compact neutron sources suitable for clinical use.
The aim of the investigation was to study L-boronphenylalanine (L-BPA) biodistribution in the organs of experimental animals with subcutaneous tumor xenografts, and evaluate the application of the experimental model to assess the effectiveness of new neutron sources.
Materials and Methods. The experiments were carried out on BALB/c mice with subcutaneous xenograft of mouse adenocarcinoma CT26. L-boronphenylalanine in a molar excess of fructose was administered intravenously at a dose of 350 mg/kg, the organs under study were taken 1.5, 3, 6, and 24 h after drug administration. The content of the 10B isotope was analyzed using inductively coupled plasma mass spectroscopy (ICP-MS). The absence of toxic effects was verified pathomorphologically.
Results. The maximum L-BPA content in the tumor was 142.0±4.41 µg/g 1.5 h after drug administration. The minimum therapeutic concentration of L-BPA in the tumor persists up to 5.4 h after drug administration. Among normal organs, the maximum content was observed in the kidneys, it is most likely being associated with the structural and functional features of the organ rather than the true content of L-BPA in the tissues. Histological studies revealed no structural disorders and dystrophic changes in tissues against the background of L-BPA introduction.
Conclusion. The results of the study demonstrate the feasibility of the studied tumor model to evaluate the efficiency of new neutron sources for BNCT. The L-borophenylalanine content in the tumor and the time of maintaining the minimum therapeutic concentration appeared to be sufficient for effective BNCT. The high contrast of 10B accumulation relative to non-pathological tissues minimizes the possible side effects of BNCT.
- Barth R.F., Zhang Z., Liu T. A realistic appraisal of boron neutron capture therapy as a cancer treatment modality. Cancer Commun (Lond) 2018; 38(1): 36, https://doi.org/10.1186/s40880-018-0280-5.
- Nedunchezhian K., Aswath N., Thiruppathy M., Thirugnanamurthy S. Boron neutron capture therapy — a literature review. J Clin Diagn Res 2016; 10(12): ZE01–ZE04, https://doi.org/10.7860/jcdr/2016/19890.9024.
- Belchenko Y., Savkin V. Direct current H− source for the medicine accelerator (invited). Rev Sci Instrum 2004; 75(5): 1704–1708, https://doi.org/10.1063/1.1699457.
- Belchenko Y.I., Grigoryev E. Surface–plasma negative ion source for the medicine accelerator. Rev Sci Instrum 2002; 73(2): 939–939, https://doi.org/10.1063/1.1432463.
- Akhmetov T.D., Davydenko V.I., Ivanov A.A., Kobets V.V., Medvedko A.S., Skorobogatov D.N., Tiunov M.A. Radially uniform circular sweep of ion beam. Rev Sci Instrum 2006; 77(3): 03C106, https://doi.org/10.1063/1.2162854.
- Tahara Y., Abe S., Akiyama Y., Kamei Y., Tsutsui T., Yokobori H., Unno Y., Baba M. A BNCT neutron generator using a 30 MeV proton beam. In: Proc 12th 101 Int Cong Neutron Capture Therapy. Takamatsu, Japan; 2006; p. 327–330.
- Tanaka H., Sakurai Y., Suzuki M., Masunaga S., Mitsumoto T., Fujita K., Kashino G., Kinashi Y., Liu Y., Takada M., Ono K., Maruhashi A. Experimental verification of beam characteristics for cyclotron-based epithermal neutron source (C-BENS). Appl Radiat Isot 2011; 69(12): 1642–1645, https://doi.org/10.1016/j.apradiso.2011.03.020.
- Taskaev S.Y. Accelerator based epithermal neutron source. Phys Part Nucl 2015; 46: 956–990.
- Taskaev S.Y. Development of an accelerator-based epithermal neutron source for boron neutron capture therapy. Phys Part Nucl 2019; 50: 569–575.
- Skalyga V., Izotov I., Golubev S., Razin S., Sidorov A., Maslennikova A., Volovecky A., Kalvas T., Koivisto H., Tarvainen O. Neutron generator for BNCT based on high current ECR ion source with gyrotron plasma heating. Appl Radiat Isot 2015; 106: 29–33, https://doi.org/10.1016/j.apradiso.2015.08.015.
- Skalyga V., Izotov I., Golubev S., Sidorov A., Razin S., Strelkov A., Tarvainen O., Koivisto H., Kalvas T. High yield neutron generator based on a high-current gasdynamic electron cyclotron resonance ion source. J Appl Phys 2015; 118(9): 093301, https://doi.org/10.1063/1.4929955.
- Hattori Y., Kusaka S., Mukumoto M., Uehara K., Asano T., Suzuki M., Masunaga S., Ono K., Tanimori S., Kirihata M. Biological evaluation of dodecaborate-containing L-amino acids for boron neutron capture therapy. J Med Chem 2012; 55(15): 6980–6984, https://doi.org/10.1021/jm300749q.
- Lin Y.C., Hwang J.J., Wang S.J., Yang B.H., Chang C.W., Hsiao M.C., Chou F.I. Macro- and microdistributions of boron drug for boron neutron capture therapy in an animal model. Anticancer Res 2012; 32(7): 2657–2664.
- Garabalino M.A., Heber E.M., Monti Hughes A., González S.J., Molinari A.J., Pozzi E.C., Nievas S., Itoiz M.E., Aromando R.F., Nigg D.W., Bauer W., Trivillin V.A., Schwint A.E. Biodistribution of sodium borocaptate (BSH) for boron neutron capture therapy (BNCT) in an oral cancer model. Radiat Environ Biophys 2013; 52(3): 351–361, https://doi.org/10.1007/s00411-013-0467-8.
- Sauerwein W.A.G. Principles and roots of neutron capture therapy. In: Neutron capture therapy: principles and applications. Moss R., Nakagawa Y. (editors). Springer; 2012; p. 1–16.
- Matsumoto T., Aoki M., Aizawa O. Phantom experiment and calculation for in vivo 10boron analysis by prompt gamma ray spectroscopy. Phys Med Biol 1991; 36(3): 329–338, https://doi.org/10.1088/0031-9155/36/3/002.
- Mukai K., Nakagawa Y., Matsumoto K. Prompt gamma ray spectrometry for in vivo measurement of boron-10 concentration in rabbit brain tissue. Neurol Med Chir (Tokyo) 1995; 35(12): 855–860, https://doi.org/10.2176/nmc.35.855.
- Wittig A., Huiskamp R., Moss R.L., Bet P., Kriegeskotte C., Scherag A., Hilken G., Sauerwein W.A. Biodistribution of 10B for boron neutron capture therapy (BNCT) in a mouse model after injection of sodium mercaptoundecahydro-closo-dodecaborate and l-para-boronophenylalanine. Radiat Res 2009; 172(4): 493–499, https://doi.org/10.1667/rr1700.1.
- Smith F.G., Wiederin D.R., Houk R.S., Egan C.B., Serfass R.E. Measurement of boron concentration and isotope ratios in biological samples by inductivey coupled plasma mass spectrometry with direct injection nebulization. Anal Chim Acta 1991; 248(1): 229–234, https://doi.org/10.1016/s0003-2670(00)80889-2.
- Evans E.H., Giglio J.J. Interferences in inductively coupled plasma mass spectrometry. A review. J Anal At Spectrom 1993; 8(1): 1–18, https://doi.org/10.1039/ja9930800001.
- Solares G.R., Zamenhof R.G. A novel approach to the microdosimetry of neutron capture therapy. Part I. High-resolution quantitative autoradiography applied to microdosimetry in neutron capture therapy. Radiat Res 1995; 144(1): 50–58.
- Alfassi Z.B., Probst T.U. On the calibration curve for determination of boron in tissue by quantitative neutron capture radiography. Nucl Instrum Methods Phys Res A: Accel Spectrom Detect Assoc Equip 1999; 428(2–3): 502–507, https://doi.org/10.1016/s0168-9002(99)00145-x.
- Yokoyama K., Miyatake S., Kajimoto Y., Kawabata S., Doi A., Yoshida T., Okabe M., Kirihata M., Ono K., Kuroiwa T. Analysis of boron distribution in vivo for boron neutron capture therapy using two different boron compounds by secondary ion mass spectrometry. Radiat Res 2007; 167(1): 102–109, https://doi.org/10.1667/rr0501.1.
- Michel J., Sauerwein W., Wittig A., Balossier G., Zierold K. Subcellular localization of boron in cultured melanoma cells by electron energy-loss spectroscopy of freeze-dried cryosections. J Microsc 2003; 210(Pt 1): 25–34, https://doi.org/10.1046/j.1365-2818.2003.01172.x.
- March R.E. An introduction to quadrupole ion trap mass spectrometry. J Mass Spectrom 1997; 32(4): 351–369.
- Coderre J.A., Chanana A.D., Joel D.D., Elowitz E.H., Micca P.L., Nawrocky M.M., Chadha M., Gebbers J.O., Shady M., Peress N.S., Slatkin D.N. Biodistribution of boronophenylalanine in patients with glioblastoma multiforme: boron concentration correlates with tumor cellularity. Radiat Res 1998; 149(2): 163–170.
- Seo I.H., Lee J., Na D., Kyung H., Yang J., Lee S., Jeon S.J., Choi J.W., Lee K.Y., Yi J., Han J., Yoo M., Kim S.H. The anti-tumor effect of boron neutron capture therapy in glioblastoma subcutaneous xenograft model using the proton linear accelerator-based BNCT system in Korea. Life (Basel) 2022; 12(8): 1264, https://doi.org/10.3390/life12081264.
- Arima J., Taniguchi K., Yamamoto M., Watanabe T., Suzuki Y., Hamamoto H., Inomata Y., Kashiwagi H., Kawabata S., Tanaka K., Uchiyama K., Suzuki M., Lee S.W. Anti-tumor effect of boron neutron capture therapy in pelvic human colorectal cancer in a mouse model. Biomed Pharmacother 2022; 154: 113632, https://doi.org/10.1016/j.biopha.2022.113632.
- Yoshimura K., Kawabata S., Kashiwagi H., Fukuo Y., Takeuchi K., Futamura G., Hiramatsu R., Takata T., Tanaka H., Watanabe T., Suzuki M., Hu N., Miyatake S.I., Wanibuchi M. Efficacy of boron neutron capture therapy in primary central nervous system lymphoma: in vitro and in vivo evaluation. Cells 2021; 10(12): 3398, https://doi.org/10.3390/cells10123398.
- Tsygankova A.R., Kanygin V.V., Kasatova A.I., Zav’yalov E.L., Gusel’nikova T.Y., Kichigin A.I., Mukhamadiyarov R.A. Determination of boron by inductively coupled plasma atomic emission spectroscopy. biodistribution of 10B in tumor-bearing mice. Izvestia Akademii nauk. Seria himiceskaa 2020; 3: 601–607.
- Lee W., Kim K.W., Lim J.E., Sarkar S., Kim J.Y., Chang Y., Yoo J. In vivo evaluation of the effects of combined boron and gadolinium neutron capture therapy in mouse models. Sci Rep 2022; 12(1): 13360, https://doi.org/10.1038/s41598-022-17610-4.
- Andoh T., Fujimoto T., Sudo T., Fujita I., Imabori M., Moritake H., Sugimoto T., Sakuma Y., Takeuchi T., Kawabata S., Kirihata M., Akisue T., Yayama K., Kurosaka M., Miyatake S., Fukumori Y., Ichikawa H. Boron neutron capture therapy for clear cell sarcoma (CCS): biodistribution study of p-borono-L-phenylalanine in CCS-bearing animal models. Appl Radiat Isot 2011; 69(12): 1721–1724, https://doi.org/10.1016/j.apradiso.2011.02.005.