THE NEW TRENDS IN ENHANCING EFFICACY AND SAFETY OF PROTON THERAPY: IN VITRO CYTOTOXICITY STUDY

Abstract

Some of the background of this research was presented in the form of a poster presentation at the scientific conference PTCO61 in Madrid in June 2023. The submitted paper is the next step of the research significantly expanding and deepening the subject and scope of previous research and providing significant progress towards achieving the ultimate goal - the development of highly effective and safe adjuvant cancer treatments that enhance proton and ion therapy. As is known, proton therapy is the most advanced type of particle therapy of malignant neoplasms. Despite its noticeably lower relative biological effectiveness (RBE) in comparison to the C-ion, the latter is much less demanded due to its high cost, very high research intensity and very high requirements for medical and engineering staff. According to PTCOG data its outspread is currently several times lower than of the heavy ion therapy. In our opinion, this could be explained by a much higher cost, very high research intensity and very high requirements for medical and engineering staff in case of ion therapy. The literary data clearly show that the overall spread of hadron therapy has also slowed down drastically: in 2021 there were 107 operating proton therapy facilities, 26 were under construction and only 11 were in the planning stage. At the same time, there were only 13 operating C-ion therapy centers, while 6 were under construction and only 1 was in the planning stage. Therefore, in our opinion significant increase of the biological effectiveness and safety of proton therapy is an acute and urgent need of the current time. One of the most prospective pathways to enhance the efficacy and safety of cancer therapy is the concept of the multi-component whole body treatment of cancer by combining hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery, which was first reported by Y. Yagawa, et al. Independently, the concept of the strongly localized multi-component synergistic treatment of cancer involving nano-based super-paramagnetic liquids and requiring a possibly full concentration of all applied therapeutic effects in the tumor area was developed and reported by A. Chirakadze et al. The advantages of this model compared to the whole body treatment are the sharp reduction in the required total treatment doses and minimization of the harmful effects on healthy tissues and vital systems of patients. The rapid developments of nanotechnologies and the obvious successes of additional methods helped to establish a new approach based on the simultaneous or time-separated synergistic use of combinations of the so-called basic, supporting, adjuvant and alternative methods both in a whole body or strongly localized mode. A revolutionary contribution to the success of the concept was made by adding of boron nanoparticle provided boron-neutron capture and boron-proton capture nuclear reactions which can substantially expand and greatly enhance the effectiveness of the combined modalities developed within the framework of the concept, serving as effective and safe adjuncts to proton therapy. The use of boron-neutron and boron-proton reactions can fundamentally increase the efficiency and reduce many important limitations of proton therapy due to greater efficiency and shorter mean free path in tissues compared to protons; due to the suppression of secondary neutron radiation arising in equipment components and irradiated tissues and, in part, due to the anti-cancer activity of nuclear reaction products (for example, lithium). Vast varieties of nanoparticles have been developed and proposed for the local hyperthermia of cancer during the last decades, but only a few of them correspond to the mandatory requirements of having therapeutic range Curie temperature (T_C=41-43⁰ C), high-rate crystallinity and “strong” magnetic properties, strictly controlled homogeneity and dispersion of the anoparticles, good biocompatibility and harmless decomposition products. Among them are the nickel-copper (Ni-Cu) and silver doped lanthanum manganite (Ag_xLa_1-xMnO₃) nanoparticles. The developed research showed that the materials obtained at lower than usual temperatures using microwave enhanced synthesizes and annealing can be successfully used for local hyperthermia revealing high magnetic properties and . Behavioral toxicity testing of the developed nanoparticles was enhanced by blood oxygen saturation measurements using noninvasive oximetry in white rats. Both of the developed nanomaterials revealed a lower toxicity level than the commercially available Fe₂O₃ and Fe₃O₄ nanoparticles, and the ability to maintain a given temperature range with high accuracy (about 0,1-0.3^OC) over a whole area of the tumor.