The upregulation of low-density lipoprotein (LDL) transporters in tumour cells has been exploited to deliver a sufficient amount of gadolinium/boron/ligand (Gd/B/L) probes for neutron capture therapy, a binary chemio-radiotherapy for cancer treatment. The Gd/B/L probe consists of a carborane unit (ten B atoms) bearing an aliphatic chain on one side (to bind LDL particles), and a Gd(III)/1,4,7,10-tetraazacyclododecane monoamide complex on the other (for detection by magnetic resonance imaging (MRI)). Up to 190 Gd/B/L probes were loaded per LDL particle. The uptake from tumour cells was initially assessed on cell cultures of human hepatoma (HepG2), murine melanoma (B16), and human glioblastoma (U87). The MRI assessment of the amount of Gd/B/L taken up by tumour cells was validated by inductively coupled plasma-mass-spectrometric measurements of the Gd and B content. Measurements were undertaken in vivo on mice bearing tumours in which B16 tumour cells were inoculated at the base of the neck. From the acquisition of magnetic resonance images, it was established that after 4-6 hours from the administration of the Gd/B/L-LDL particles (0.1 and 1 mmol kg(-1) of Gd and (10)B, respectively) the amount of boron taken up in the tumour region is above the threshold required for successful NCT treatment. After neutron irradiation, tumour growth was followed for 20 days by MRI. The group of treated mice showed markedly lower tumour growth with respect to the control group.

Purpose: The aim of our study was to assess if the sodium salt of cobaltabis(dicarbollide) and its di-iodinated derivative (Na[o-COSAN] and Na[8,8′-I2-o-COSAN]) could be promising agents for dual anti-cancer treatment (chemotherapy + BNCT) for GBM. Methods: The biological activities of the small molecules were evaluated in vitro with glioblastoma cells lines U87 and T98G in 2D and 3D cell models and in vivo in the small model animal Caenorhabditis elegans (C. elegans) at the L4-stage and using the eggs. Results: Our studies indicated that only spheroids from the U87 cell line have impaired growth after treatment with both compounds, suggesting an increased resistance from T98G spheroids, contrary to what was observed in the monolayer culture, which highlights the need to employ 3D models for future GBM studies. In vitro tests in U87 and T98G cells conclude that the amount of 10B inside the cells is enough for BNCT irradiation. BNCT becomes more effective on T98G after their incubation with Na[8,8′-I2-o-COSAN], whereas no apparent cell-killing effect was observed for untreated cells. Conclusions: These small molecules, particularly [8,8′-I2-o-COSAN]−, are serious candidates for BNCT now that the facilities of accelerator-based neutron sources are more accessible, providing an alternative treatment for resistant glioblastoma.

Abstract.In this study the synthesis and characterization of a new dual, imaging and therapeutic, agent is proposed with the aim of improving the efficacy of Boron Neutron Capture Therapy (BNCT) in cancer treatment. The agent (Gd-B-AC01) consists of a carborane unit (ten boron atoms) bearing a cholesterol unit on one side (to pursue the incorporation into the liposome bi-layer), and a Gd(III)/1,4,7,10-tetraazacyclododecane monoamide complex on the other side (as MRI reporter to attain the quantification of B/Gd concentration). In order to endow the BNCT agent with specific delivery properties, the liposome embedded with the MRI/BNCT dual probes has been functionalized with a peghilated phospholipid containing a folic acid residue at the end of the PEG

Gadolinium neutron capture therapy (Gd-NCT) is currently under development as an alternative approach for cancer therapy. All of the clinical experience to date with NCT is done with 10 B, known as BNCT, a binary treatment combining neutron irradiation with the delivery of boron-containing compounds to tumors. Currently, the use of gadolinium for NCT has been getting more attention because of its highest neutron cross-section. Although Gd-NCT was first proposed many years ago, its development has suffered due to lack of appropriate tumor-selective Gd-agents. This review aims to highlight the recent advances for the design, synthesis and biological testing of new Gd-and B-Gd-containing compounds with the task of finding the best systems able to improve the NCT clinical outcome. Keywords:Gadolinium Neutron Capture Therapy, Boron Neutron Capture Therapy, MRI, Gd contrast agents, Tumor Treatment, Nanosized Gd agents. 3 General introduction on NCT: rationale and applicationNeutron Capture Therapy (NCT) is a non-conventional radiotherapy that combines low energy neutron irradiation with the presence of a neutron-absorbing substance at the targeted cells [1][2].Two isotopes are of major interest because of their large capture cross section: head and neck recurrent cancer [6][7], melanoma [8] and adenocarcinoma liver metastases [9]; ii) sodium mercaptoundecahydro-closo-dodecaborate (BSH) that has been investigated for the treatment of malignant glioma [10]. Despite their clinical use and the safe and effective BNCT, trials performed with these two drugs until now, both BPA and BSH show low selectivity and great efforts have been made by several research groups to develop new and more selective boron delivery agents [11][12].The use of BNCT to destroy malignant cells was proposed long time ago [13]. In spite of huge promises, it has not attained an established position in the mainstream medicine.However, the methodology has never been discarded and it remains in an intermediate state with a small group of enthusiast supporters and many critical spectators. The reasons why BNCT has not maintained the original promises rely mainly in the lack of properly designed agents. The conditions for an effective therapeutic output are well established: the BNCT agent must reach selectively a given concentration inside cells and the not-attainment of this task makes the therapy less effective. Only a proper NCT agent design (based on an improved knowledge on how molecules enter healthy and diseased cells) allows to reach selectively the needed threshold of intracellular concentration required to drive the breakthrough of BNCT in the field of conventional and diffused treatments for cancer. Moreover, the in vivo assessment of the amount of NCT agent can now be tackled by its conjugation to a suitable imaging-reporter. [14][15] To date there is no non-invasive means to evaluate boron concentration in tumor and healthy tissues of the subject undergoing the irradiation. Thus, dose calculations are based on boron content values in...

This paper presents a biophysical model of radiation-induced cell death, implemented as a Monte Carlo code called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA), based on the assumption that some chromosome aberrations (dicentrics, rings, and large deletions, called ‘‘lethal aberrations’’) lead to clonogenic inactivation. In turn, chromosome aberrations are assumed to derive from clustered, and thus severe, DNA lesions (called ‘‘cluster lesions,’’ or CL) interacting at the micrometer scale; the CL yield and the threshold distance governing CL interaction are the only model parameters. After a pilot study on V79 hamster cells exposed to protons and carbon ions, in the present work the model was extended and applied to AG1522 human cells exposed to photons, He ions, and heavier ions including carbon and neon. The agreement with experimental survival data taken from the literature supported the assumptions. In particular, the inactivation of AG1522 cells was explained by lethal aberrations not only for X-rays, as already reported by others, but also for the aforementioned radiation types. Furthermore, the results are consistent with the hypothesis that the critical initial lesions leading to cell death are DNA cluster lesions having yields in the order of *2 CL Gy-1 cell-1 at low LET and*20 CL Gy-1 cell-1 at high LET, and that the processing of these lesions is modulated by proximity effects at the micrometer scale related to interphase chromatin organization. The model was then applied to calculate the fraction of inactivated cells, as well as the yields of lethal aberrations and cluster lesions, as a function of LET; the results showed a maximum around 130 keV/lm, and such maximum was much higher for cluster lesions and lethal aberrations than for cell inactivation.

The potential biomedical applications of the MNPs nanohybrids coated with mcarboranylphosphinate (1-MNPs) as a theranostic biomaterial for cancer therapy were tested. The cellular uptake and toxicity profile of 1-MNPs from culture media by human brain endothelial cells (hCMEC/D3) and glioblastoma multiform A172 cell line was demonstrated. Prior to testing 1-MNPs' in vitro toxicity, studies of colloidal stability of the 1-MNPs' suspension in different culture media and temperatures were carried out. TEM images and chemical titration confirmed that 1-MNPs penetrate into cells. Additionally, to explore 1-MNPs' potential use in Boron Neutron Capture Therapy (BNCT) for treating cancer locally, the presence of the mcarboranyl coordinated with the MNPs core after uptake was proven by XPS and EELS. Importantly, thermal neutrons irradiation in BNCT reduced by 2.5 the number of cultured glioblastoma cells after 1-MNP treatment, and the systemic administration of 1-MNPs in mice was well tolerated with no major signs of toxicity.

Some open questions on the mechanisms underlying radiation-induced cell death were addressed by a biophysical model, focusing on DNA damage clustering and its consequences. DNA "cluster lesions" (CLs) were assumed to produce independent chromosome fragments that, if created within a micrometer-scale threshold distance (d), can lead to chromosome aberrations following mis-rejoining; in turn, certain aberrations (dicentrics, rings and large deletions) were assumed to lead to clonogenic cell death. The CL yield and d were the only adjustable parameters. The model, implemented as a Monte Carlo code called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA), provided simulated survival curves that were directly compared with experimental data on human and hamster cells exposed to photons, protons, α-particles and heavier ions including carbon and iron. d = 5 μm, independent of radiation quality, and CL yields in the range ~2-20 CLs Gy(-1) cell(-1), depending on particle type and energy, led to good agreement between simulations and data. This supports the hypothesis of a pivotal role of DNA cluster damage at sub-micrometric scale, modulated by chromosome fragment mis-rejoining at micrometric scale. To investigate the features of such critical damage, the CL yields were compared with experimental or theoretical yields of DNA fragments of different sizes, focusing on the base-pair scale (related to the so-called local clustering), the kbp scale ("regional clustering") and the Mbp scale, corresponding to chromatin loops. Interestingly, the CL yields showed better agreement with kbp fragments rather than bp fragments or Mbp fragments; this suggests that also regional clustering, in addition to other clustering levels, may play an important role, possibly due to its relationship with nucleosome organization in the chromatin fiber.

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