Reprint of Application of BNCT to the treatment of HER2+ breast cancer recurrences: Research and developments in Argentina.

In the frame of the Argentine BNCT Project a new research line has been started to study the application of BNCT to the treatment of locoregional recurrences of HER2+ breast cancer subtype. Based on former studies, the strategy considers the use of immunoliposomes as boron carriers nanovehicles to target HER2 overexpressing cells. The essential concerns of the current stage of this proposal are the development of carriers that can improve the efficiency of delivery of boron compounds and the dosimetric assessment of treatment feasibility. For this purpose, an specific pool of clinical cases that can benefit from this application was determined. In this work, we present the proposal and the advances related to the different stages of current research.

Application of BNCT to the treatment of HER2+ breast cancer recurrences: Research and developments in Argentina.

In the frame of the Argentine BNCT Project a new research line has been started to study the application of BNCT to the treatment of locoregional recurrences of HER2+ breast cancer subtype. Based on former studies, the strategy considers the use of immunoliposomes as boron carriers nanovehicles to target HER2 overexpressing cells. The essential concerns of the current stage of this proposal are the development of carriers that can improve the efficiency of delivery of boron compounds and the dosimetric assessment of treatment feasibility. For this purpose, an specific pool of clinical cases that can benefit from this application was determined. In this work, we present the proposal and the advances related to the different stages of current research.

Simulation of the neutron flux in the irradiation facility at RA-3 reactor.

A facility for the irradiation of a section of patients' explanted liver and lung was constructed at RA-3 reactor, Comisión Nacional de Energía Atómica, Argentina. The facility, located in the thermal column, is characterized by the possibility to insert and extract samples without the need to shutdown the reactor. In order to reach the best levels of security and efficacy of the treatment, it is necessary to perform an accurate dosimetry. The possibility to simulate neutron flux and absorbed dose in the explanted organs, together with the experimental dosimetry, allows setting more precise and effective treatment plans. To this end, a computational model of the entire reactor was set-up, and the simulations were validated with the experimental measurements performed in the facility.

Boron uptake measurements in a rat model for Boron Neutron Capture Therapy of lung tumours.

Lung carcinoma is the leading cause of cancer mortality in the Western countries. Despite the introduction over the last few years of new therapeutic agents, survival from lung cancer has shown no discernible improvement in the last 20 years. For these reasons any efforts to find and validate new effective therapeutic procedures for lung cancer are very timely. The selective boron uptake in the tumour with respect to healthy tissues makes Boron Neutron Capture Therapy a potentially advantageous option in the treatment of tumours that affect whole vital organs, and that are surgically inoperable. To study the possibility of applying BNCT to the treatment of diffuse pulmonary tumours, an animal model for boron uptake measurements in lung metastases was developed. Both healthy and tumour-bearing rats were infused with Boronophenylalanine (BPA) and sacrificed at different time intervals after drug administration. The lungs were extracted, and prepared for boron analysis by neutron autoradiography and α-spectroscopy. The boron concentrations in tumour and normal lung were plotted as a function of the time elapsed after BPA administration. The concentration in tumour is almost constant within the error bars for all the time intervals of the experiment (1-8 h), while the curve in normal lung decreases after 4 h from BPA infusion. At 4 h, the ratio of boron concentration in tumour to boron concentration in healthy lung is higher than 3, and it stays above this level up to 8 h. Also the images of boron distribution in the samples, obtained by neutron autoradiography, show a selective absorption in the metastases.

Carborane derivatives loaded into liposomes as efficient delivery systems for boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is an anticancer therapy based on the incorporation of (10)B in tumors, followed by neutron irradiation. Recently, the synthesis and delivery of new boronated compounds have been recognized as some of the main challenges in BNCT application. Here, we report on the use of liposomes as carriers for BNCT active compounds. Two carborane derivatives, i.e., o-closocarboranyl beta-lactoside (LCOB) and 1-methyl-o-closocarboranyl-2-hexylthioporphyrazine (H(2)PzCOB), were loaded into liposomes bearing different surface charges. The efficacy of these formulations was tested on model cell cultures, that is, DHD/K12/TRb rat colon carcinoma and B16-F10 murine melanoma. These induce liver and lung metastases, respectively, and are used to study the uptake of standard BNCT drugs, including borophenylalanine (BPA). Boron concentration in treated cells was measured by alpha spectrometry at the TRIGA mark II reactor (University of Pavia). Results showed high performance of the proposed formulations. In particular, the use of cationic liposomes increased the cellular concentration of (10)B by at least 30 times more than that achieved by BPA.

Calculations of dose distributions in the lungs of a rat model irradiated in the thermal column of the TRIGA reactor in Pavia.

To test the possibility to apply boron neutron capture therapy (BNCT) to lung tumors, some rats are planned to be irradiated in the thermal column of the TRIGA reactor of the University of Pavia. Before the irradiation, lung metastases will be induced in BDIX rats, which will be subsequently infused with boronophenylalanine (BPA). During the irradiation, the rats will be positioned in a box designed to shield the whole animal except the thorax area. In order to optimize the irradiation set-up and to design a suitable shielding box, a set of calculations were performed with the MCNP Monte Carlo transport code. A rat model was constructed using the MCNP geometry capabilities and was positioned in a box with walls filled with lithium carbonate. A window was opened in front of the lung region. Different shapes of the holder and of the window were tested and analyzed in terms of the dose distribution obtained in the lungs and of the dose absorbed by the radiosensitive organs in the rat. The best configuration of the holder ensures an almost uniform thermal neutron flux inside the lungs (Phi(max)/Phi(min)=1.5), an irradiation time about 10 min long, to deliver at least 40 Gy(w) to the tumor, a mean lung dose of 5.9+/-0.4 Gy(w), and doses absorbed by all the other healthy tissues below the tolerance limits.

Preliminary liver dose estimation in the new facility for biomedical applications at the RA-3 reactor.

As a part of the project concerning the irradiation of a section of the human liver left lobe, a preliminary estimation of the expected dose was performed. To obtain proper input values for the calculation, neutron flux and gamma dose rate characterization were carried out using adequate portions of cow or pig liver covered with demineralized water simulating the preservation solution. Irradiations were done inside a container specially designed to fulfill temperature preservation of the organ and a reproducible irradiation position (which will be of importance for future planification purposes). Implantable rhodium based self-powered neutron detectors were developed to obtain neutron flux profiles both external and internal. Implantation of SPND was done along the central longitudinal axis of the samples, where lowest flux is expected. Gamma dose rate was obtained using a neutron shielded graphite ionization chamber moved along external surfaces of the samples. The internal neutron profile resulted uniform enough to allow for a single and static irradiation of the liver. For dose estimation, irradiation condition was set in order to obtain a maximum of 15 Gy-eq in healthy tissue. Additionally, literature reported boron concentrations of 47 ppm in tumor and 8 ppm in healthy tissue and a more conservative relationship (30/10 ppm) were used. To make a conservative estimation of the dose the following considerations were done: i). Minimum measured neutron flux inside the sample (approximately 5 x 10(9) n cm-2 s-1) was considered to calculate dose in tumor. (ii). Maximum measured neutron flux (considering both internal as external profiles) was used to calculate dose in healthy tissue (approximately 8.7 x 10(9) n cm-2 s-1). (iii). Maximum measured gamma dose rate (approximately 13.5 Gy h-1) was considered for both tumor and healthy tissue. Tumor tissue dose was approximately 69 Gy-eq for 47 ppm of (10)B and approximately 42 Gy-eq for 30 ppm, for a maximum dose of 15 Gy-eq in healthy tissue. As can be seen from these results, even for the most conservative case, minimum tumor dose will be acceptable from the treatment point of view, which shows that the irradiation conditions at this facility have quite good characteristics for the proposed irradiation.