MRI-guided neutron capture therapy by use of a dual gadolinium/boron agent targeted at tumour cells through upregulated low-density lipoprotein transporters.

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.

Dynamical Detection of Boundaries and Cavities in Biophysical Cell-Based Simulations of Growing Tumor Tissues.

Cell-based lattice-free simulations of the growth of tumor tissues require the definition of geometrical and topological relations among cells and the other basic elements of the simulation (most notably the local and the global environments). This is necessary for the correct description of the biochemistry of tumor tissues, and to implement the biomechanical interactions among cells. Weak cell-cell forces and the necrosis of tumor tissues due to poor vascularization can lead to the formation of cavities - i.e., regions without viable cells and filled with cellular debris and fluids. It is important to give an accurate geometrical/topological description of the resulting microenvironment that plays an important role in the pathology of cancer. In this paper, we concentrate on simulations of the growth of avascular solid tumors and we describe the STAR (Shape of Tumors from Algorithmic Reconstruction) algorithm that defines the shape of clusters of cells and searches for the boundary and cavities in a 3D environment. The algorithm is GPU-based and exploits the high degree of parallelism of GPUs. The final implementation achieves a 30-fold speedup with respect to a previous CPU-based version.

Collective radioresistance of T47D breast carcinoma cells is mediated by a Syncytin-1 homologous protein.

It is generally accepted that radiotherapy must target clonogenic cells, i.e., those cells in a tumour that have self-renewing potential. Focussing on isolated clonogenic cells, however, may lead to an underestimate or even to an outright neglect of the importance of biological mechanisms that regulate tumour cell sensitivity to radiation. We develop a new statistical and experimental approach to quantify the effects of radiation on cell populations as a whole. In our experiments, we change the proximity relationships of the cells by culturing them in wells with different shapes, and we find that the radiosensitivity of T47D human breast carcinoma cells in tight clusters is different from that of isolated cells. Molecular analyses show that T47D cells express a Syncytin-1 homologous protein (SyHP). We observe that SyHP translocates to the external surface of the plasma membrane of cells killed by radiation treatment. The data support the fundamental role of SyHP in the formation of intercellular cytoplasmic bridges and in the enhanced radioresistance of surviving cells. We conclude that complex and unexpected biological mechanisms of tumour radioresistance take place at the cell population level. These mechanisms may significantly bias our estimates of the radiosensitivity of breast carcinomas in vivo and thereby affect treatment plans, and they call for further investigations.

Pulsation-limited oxygen diffusion in the tumour microenvironment.

Hypoxia is central to tumour evolution, growth, invasion and metastasis. Mathematical models of hypoxia based on reaction-diffusion equations provide seemingly incomplete descriptions as they fail to predict the measured oxygen concentrations in the tumour microenvironment. In an attempt to explain the discrepancies, we consider both the inhomogeneous distribution of oxygen-consuming cells in solid tumours and the dynamics of blood flow in the tumour microcirculation. We find that the low-frequency oscillations play an important role in the establishment of tumour hypoxia. The oscillations interact with consumption to inhibit oxygen diffusion in the microenvironment. This suggests that alpha-blockers-a class of drugs used to treat hypertension and stress disorders, and known to lower or even abolish low-frequency oscillations of arterial blood flow -may act as adjuvant drugs in the radiotherapy of solid tumours by enhancing the oxygen effect.

Computer-aided biophysical modeling: a quantitative approach to complex biological systems.

When dealing with the biophysics of tumors, analytical and numerical modeling tools have long been regarded as potentially useful but practically immature tools. Further developments could not just overturn this predicament, but lead to completely new perspectives in biology. Here, we give an account of our own computational tool and how we have put it to good use, and we discuss a paradigmatic example to outline a path to making cell biology more quantitative and predictive.