Transient And Efficient Vascular Permeability Window For Adjuvant Drug Delivery Triggered By Microbeam Radiation

Simple SummaryOne of the major challenges in the pharmacological treatment of solid tumours is ensuring that therapeutic concentrations of the agent reach and penetrate the tumour tissue. This is hampered by physiological barriers imposed by the aberrant and abnormal vessel structures of the tumours and high intratumoural pressure. We show that compound penetration into tumour tissue can be greatly enhanced by irradiating the tumour with an arrangement of discrete, synchrotron generated parallel X-rays in a range of 25-50 mu m in width. This irradiation geometry induces a transient increase in vessel permeability in a time-dependent manner with a maximum between 45 min and 2 h after irradiation. The latter phenomenon was fully characterized in a vascular model of the developing chick embryo and termed "permeability window". The reported methodology could be considered as a potent and unique drug delivery system for combined tumour treatment. This will help to create new, more efficient treatment strategies against cancer and other vascular diseases.Background: Microbeam Radiation Therapy (MRT) induces a transient vascular permeability window, which offers a novel drug-delivery system for the preferential accumulation of therapeutic compounds in tumors. MRT is a preclinical cancer treatment modality that spatially fractionates synchrotron X-rays into micrometer-wide planar microbeams which can induce transient vascular permeability, especially in the immature tumor vessels, without compromising vascular perfusion. Here, we characterized this phenomenon using Chicken Chorioallantoic Membrane (CAM) and demonstrated its therapeutic potential in human glioblastoma xenografts in mice. Methods: the developing CAM was exposed to planar-microbeams of 75 Gy peak dose with Synchrotron X-rays. Similarly, mice harboring human glioblastoma xenografts were exposed to peak microbeam doses of 150 Gy, followed by treatment with Cisplatin. Tumor progression was documented by Magnetic Resonance Imaging (MRI) and caliper measurements. Results: CAM exposed to MRT exhibited vascular permeability, beginning 15 min post-irradiation, reaching its peak from 45 min to 2 h, and ending by 4 h. We have deemed this period the "permeability window". Morphological analysis showed partially fragmented endothelial walls as the cause of the increased transport of FITC-Dextran into the surrounding tissue and the extravasation of 100 nm microspheres (representing the upper range of nanoparticles). In the human glioblastoma xenografts, MRI measurements showed that the combined treatment dramatically reduced the tumor size by 2.75-fold and 5.25-fold, respectively, compared to MRT or Cisplatin alone. Conclusions: MRT provides a novel mechanism for drug delivery by increasing vascular transpermeability while preserving vessel integrity. This permeability window increases the therapeutic index of currently available chemotherapeutics and could be combined with other therapeutic agents such as Nanoparticles/Antibodies/etc.