Abstract and keywords
Abstract (English):
Purpose: Evaluating the possibilities to increase proton radiotherapy therapeutic efficacy by means of combined (binary) technologies: simultaneous application of proton radiation and special drugs. Material and methods: Published studies assessing antitumor efficacy of proton radiation together with simultaneous tumor radiosensitizing chemical compounds administration in treating cancer are being reviewed and analyzed. Results: Two approaches to increase therapeutic efficacy of proton radiotherapy using drugs, which have abnormally large value of proton interaction cross section comparing to soft tissues, can be outlined recently. They are: 1) utilization of proton induced nuclear reactions producing high LET secondary radiation to increase absorbed dose in tumor; 2) utilization of protons and proton track’s secondary electrons interaction with high-Z nanoparticles (Z>52), that leads to redistribution of released proton energy in soft tissues and its localization in tumor volume. Limited number of the studies devoted to application of 11B(p,3a) nuclear reaction in proton therapy and contradictoriness of the obtained result do not allow to judge so far about the future prospects of the boron containing drugs utilization in proton therapy to increase its antitumor efficacy. However, this approach looks very attractive because of the already existing boron drugs successfully being applied in boron neutron capture therapy. Analysis of the metal nanoparticle application in radiotherapy showed that despite of the promising results showing impressive tumor suppression increase represented in many scientific papers only three pharmaceuticals based on nanoparticles reached Phase I/II Clinical Trials. Radiosensitizing mechanism of metal nanoparticles in radiotherapy is still unrevealed, unstudied and not formalized thus interfering nanoparticle based pharmaceuticals to be approved for Clinical Trials. Quantitative relationship between nanoparticles’ properties (i.e. chemical composition, shape, surface coating etc.), irradiation parameters and final biological effect (therapeutic efficacy) is still undetermined. Conclusion: Fundamental and applied studies should be carried out to determine and describe the processes underlying in the basis of combined methods of proton radiotherapy. That would allow to perform both proper treatment planning, similar to conventional radiotherapy, as well as the prognosis of the therapy final outcomes in curing malignant tumors.

proton therapy, radiosensitization, radioenhancement, boron-11, nanomedicine , nanoparticles

1. Brahme A. Development of radiation therapy optimization. Acta Oncologica. 2000;39:479-595.

2. Van Dyk J. Advances in Modern Radiation Therapy. In: The Modern Technology of Radiation Oncology Vol.2. Madison: Medical Physics Pub Corp. 2005. 514 p.

3. Fryback DG, Craig BM. Measuring economic outcomes of cancer. J Nat Cancer Inst. Monog. 2004;33:134-41.

4. Lipscomb J, Donaldson MS, Arora NK, Brown ML, Clauser SB, Potosky AL, et al. Cancer outcomes research. Journal of the National Cancer Institute. Monographs. 2004;(33):178-97.

5. Mohan R, Grosshans D. Proton therapy – present and future. Adv Drug Deliv Rev. 2017;109:26-44. DOI: 10.1016/j.addr.2016.11.006.

6. Hu M, Jiang L, Cui X, Zhang J, Yu J. Proton beam therapy for cancer in the era of precision medicine. J Hematol Oncol. 2008;11(1):136. DOI: 10.1186/s13045-018-0683-4.

7. Connell PP, Hellman S. Advances in radiotherapy and implications for the next century: a historical perspective. Cancer Res. 2009 Jan 15;69(2):383-92. DOI: 10.1158/0008-5472.CAN-07-6871.

8. Lehnert S. Radiosensitizers and radiochemotherapy in the treatment of cancer. Boca Raton: CRC Press, Taylor&Francis Gr., 2015, 548 p.

9. Sheino IN, Izhevskij PV, Lipengolts AA, Kulakov VN, Wagner AA, Sukhikh ES, et al. Development of binary technologies of radiotherapy of malignant neoplasms: condition and problems. Bulletin of Siberian Medicine. 2017;16(3):192-209. DOI: 10.20538/1682-0363-2017-3-192-209. (Russian).

10. Kulakov VN, Lipengol’ts AA, Grigor’eva EYu, Shimanovskii NL. Pharmaceuticals for binary radiotherapy and their use for treatment of malignancies (a review). Pharm Chem J Sep. 2016;50(6):388-93. DOI: 10.1007/s11094-016-1457-3. (Russian).

11. Seiwert TY, Salama JK, Vokes EE. The concurrent chemoradiation paradigm–general principles. Nat Clin Pract Oncol. 2007;4:86-100.

12. Connell PP, Hellman S, Advances in radiotherapy and implications for the next century: a historical perspective. Cancer Res. 2009;69:383-92.

13. Sauerwein W, Wittig A, Moss R, Nakagawa Y (eds). Neutron Capture Therapy: Principles and Applications. Berlin: Springer; 2012. 553 p. DOI: 10.1007/978-3-642-31334-9.

14. Sheino IN. Dose-supplementary therapy of malignant tumors. In: Advances in Neutron Capture Therapy 2006. Proc. 12th Intern. Congress on Neutron Capture Therapy. “From the Past to the Future”, October 9–13, 2006; Takamatsu, Kagawa. Ed.: Nakagawa Y, Kobayashi T, Fukuda H. Japan, 2006:531-4.

15. Lipengolts AA, Cherepanov AA, Kulakov VN, Grigor’eva EYu, Merkulova IB, Sheino IN. Comparison of the antitumor efficacy of bismuth and gadolinium as dose-enhancing agents in formulations for photon capture therapy. Pharm Chem J. Sep 2017;51(9):783-6. DOI: 10.1007/s11094-017-1693-1. (Russian).

16. Bergs JW, Wacker MG, Hehlgans S, Piiper A, Multhoff G, Rödel C, et al. The role of recent nanotechnology in enhancing the efficacy of radiation therapy. Biochim Biophys Acta. 2015 Aug;1856(1):130-43. DOI: 10.1016/j.bbcan.2015.06.008.

17. King R, McMahon S, Hyland W, Jain S, Butterworth K, Prise K, et al. An overview of current practice in external beam radiation oncology with consideration to potential benefits and challenges for nanotechnology. Cancer Nanotechnology. 2017;8:3. DOI: 10.1186/s12645-017-0027-z.

18. Brun E, Sicard-Roselli C. Actual questions raised by nanoparticle radiosensitization. Radiat Phys Chem. 2016;128:134-42.

19. Yoon D, Jung J, Suh T. Application of proton boron fusion reaction to radiation therapy: A Monte Carlo simulation study. Appl Phys Lett. 2014;105:223507.

20. Jung JY, Yoon DK, Barraclough B, Lee HC, Suh TS, Lu B. Comparison between proton boron fusion therapy (PBFT) and boron neutron capture therapy (BNCT): a Monte Carlo study. Oncotarget. 2017 Jun 13;8(24):39774-39781. DOI: 10.18632/oncotarget.15700.

21. Cirrone GAP, Manti L, Margarone D, Petringa G, Giuffrida L, Minopoli A, et al. First experimental proof of Proton Boron Capture Therapy (PBCT) to enhance protontherapy effectiveness . Sci Rep. 2018 Jan 18;8(1):1141. DOI: 10.1038/s41598-018-19258-5.

22. Willers H, Allen A, Grosshans D, McMahon SJ, Neubeck C, Wiese C, et al Toward a variable RBE for proton beam therapy. Radiother Oncol. 2018 Jul;128(1):68-75. DOI: 10.1016/j.radonc.2018.05.019.

23. Koldaeva EYu, Grigorieva EYu, Kulakov VN, Sauerwein W. BSH for BNCT of B-16 Melanoma in a Murine Model. In: “New Challenges in neutron capture therapy 2010” Proc. 14th Intern. Congress on Neutron Capture Therapy. October 25–29, 2010, Buenos Aires:CNEA:144-6.

24. Mazzone A, Finocchiaro P, Lo Meo S, Colonna N. On the (un)effectiveness of Proton Boron Capture in Proton Therapy. arXiv:1802.09482v2 [].

25. Kim JK, Seo SJ, Kim KH, Kim TJ, Chung MH, Kim KR, et al. Therapeutic application of metallic nanoparticles combined with particle-induced X-ray emission effect. Nanotechnology. 2010 Oct 22;21(42):425102. DOI: 10.1088/0957-4484/21/42/425102.

26. Kim JK, Seo SJ, Kim HT, Kim KH, Chung MH, Kim KR, et al. Enhanced proton treatment in mouse tumors through proton irradiated nanoradiator effects on metallic nanoparticles. Phys Med Biol. 2012;57(24):8309-23. DOI: 10.1088/0031-9155/57/24/8309.

27. Dollinger G. Comment on ‘Therapeutic application of metallic nanoparticles combined with particle-induced x-ray emission effect. Nanotechnology. 2011 Jun 17;22(24):248001; discussion 248002. DOI: 10.1088/0957-4484/22/24/248001.

28. Polf JC, Bronk LF, Driessen WHP, Arap W, Pasqualini R, Gillin M. Enhanced relative biological effectiveness of proton radiotherapy in tumor cells with internalized gold nanoparticles. Appl Phys Lett. 2011;98:193702. DOI: 10.1063/1.3589914.

29. Li S, Penninckx S, Karmani L, Heuskin AC, Watillon K, Marega R, et al. LET-dependent radiosensitization effects of gold nanoparticles for proton irradiation. Nanotechnology. 2016 Nov 11;27(45):455101.

30. Jeynes JCG, Merchant MJ, Spindler A, Wera A-C, et al. Investigation of gold nanoparticle radiosensitization mechanisms using a free radical scavenger and protons of different energies. Phys Med Biol. 2014;59:6431-43.

31. Wälzlein C, Scifoni E, Krämer M, Durante M. Simulations of dose enhancement for heavy atom nanoparticles irradiated by protons. Phys Med Biol. 2014;59:1441-58. DOI: 10.1088/0031-9155/59/6/1441.

32. Lacombe S, Porcel E, Scifoni E. Particle therapy and nanomedicine: state of art and research perspectives. Cancer Nano. 2017;8:9. DOI 10.1186/s12645-017-0029-x.

33. Ahmad R, Royle G, Lourenço A, Schwarz M, Fracchiolla F, Ricketts K. Investigation into the effects of high-Z nano materials in proton therapy. Phys Med Biol. 2016 Jun 21;61(12):4537-50. DOI: 10.1088/0031-9155/61/12/4537.

34. Cho J, Gonzalez-Lepera C, Manohar N, Kerr M, Krishnan S, Cho SH. Quantitative investigation of physical factors contributing to gold nanoparticle-mediated proton dose enhancement Phys Med Biol. 2016 Mar 21;61(6):2562-81. DOI: 10.1088/0031-9155/61/6/2562.

35. Verkhovtsev AV, Korol AV, Solov’yov AV. Electron production by sensitizing gold nanoparticles irradiated by fast ions. J Phys Chem C. 2015;119:11000-13. DOI: 10.1021/jp511419n.

36. Tran HN, Karamitros M, Ivanchenko VN, Guatelli S, McKinnon S, Murakami K, et al. Geant4 Monte Carlo simulation of absorbed dose and radiolysis yields enhancement from a gold nanoparticle under MeV proton irradiation. Nucl Instrum Methods Phys Res Sect B Beam Interact with Mater Atoms. 2016;373:126-39. DOI: 10.1016/j.nimb.2016.01.017.

37. Martínez-Rovira I, Prezado Y. Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles. Med Phys. 2015;42(11):6703-10. DOI: 10.1118/1.4934370.

38. Lin Y, McMahon SJ, Paganetti H, Schuemann J. Biological modeling of gold nanoparticle enhanced radiotherapy for proton therapy. Phys Med Biol. 2015;60(10):4149-68. DOI: 10.1088/0031-9155/60/10/4149.

39. Haume K, Rosa S, Grellet S, Śmiałek MA, Butterworth KT, Solov’yov AV, et al. Gold nanoparticles for cancer radiotherapy: a review. Cancer Nanotechnol. 2016;7:8. DOI: 10.1186/s12645-016-0021-x.

40. Schlathölter T, Eustache P, Porcel E, Salado D, Stefancikova L, Tillement O, et al. Improving proton therapy by metal-containing nanoparticles: nanoscale insights. Int J Nanomed. 2016;11:1549-56.

41. Her S, Jaffray DA, Allen C. Gold nanoparticles for applications in cancer radiotherapy: Mechanisms and recent advancements. Adv Drug Deliver Rev. 2017;109:84-101.

42. Durante M, Orecchia R, Loeffler JS. Charged-particle therapy in cancer: clinical uses and future perspectives. Nat Rev Clin Oncol. 2017 Aug;14(8):483-95. DOI: 10.1038/nrclinonc.2017.30.

43. Liu Y, Zhang P, Li F, Jin X, Li J, Chen W, Li Q. Metal-based NanoEnhancers for future radiotherapy: radiosensitizing and synergistic effects on tumor cells. Theranostics. 2018;8(7):1824-49. DOI: 10.7150/thno.22172.

44. Yang C, Bromma K, Di Ciano-Oliveira C, Zafarana G, van Prooijen M. Chithrani DB. Gold nanoparticle mediated combined cancer therapy. Cancer Nano. Dec 2018. 9:4. DOI: 10.1186/s12645-018-0039-3.

45. Falk M. Nanodiamonds and nanoparticles as tumor cell radiosensitizers-promising results but an obscure mechanism of action. Ann Transl Med. 2017;5:18.

46. Dimitriou NM, Tsekenis G, Balanikas EC, Pavlopoulou A, Mitsiogianni M, Mantso T, et al. Gold nanoparticles, radiations and the immune system: Current insights into the physical mechanisms and the biological interactions of this new alliance towards cancer therapy. Pharmacol Therapeut. 2017;178:1-17.

47. Ricketts K, Ahmad R, Beaton L, Cousins B, Critchley K, Davies M, et al. Recommendations for clinical translation of nanoparticle-enhanced radiotherapy. Br J Radiol. 2018;91:20180325. DOI: org/10.1259/bjr.20180325.

48. Libutti SK, Paciotti GF, Byrnes AA, Alexander HR, Gannon WE, Walker M, et al. Phase I and pharmacokinetic studies of Cyt-6091, a novel PEGylated colloidal gold-RhTNF nanomedicine. Clin Cancer Res. 2010 Dec 15;16(24):6139-49. DOI: 10.1158/1078-0432.CCR-10-0978.

49. Lux F, Tran VL, Thomas E, Dufort S, Rossetti F, Martini M, et al. AGuIX® from bench to bedside—Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine. Br J Radiol. 2018;91:20180365.

50. Bonvalot S, Le Pechoux C, De Baere T, Kantor G, Buy X, Stoeckle E, et al. First-in human study testing a new radioenhancer using nanoparticles (NBTXR3) activated by radiation therapy in patients with locally advanced soft tissue sarcomas. Clin Cancer Res. 2017;23:908-17. DOI: 10. 1158/1078-0432.CCR-16-1297.

51. Rodallec A, Benzekry S, Lacarelle B, Ciccolini J, Fanciullino R. Pharmacokinetics variability: Why nanoparticles are not just magic-bullets in oncology. Crit Rev Oncol Hematol Sep. 2018;129:1-12.

Login or Create
* Forgot password?