Focussed transcranial ultrasounds: application to the delivery of glycosylated oleic acid/vitamin d-binding protein to brain tumours and metastases

Glycosylated oleic acid/vitamin D-binding protein, also known as oleic acid/Gc protein-derived macrophage activating factor (OA-GcMAF), has proven effective in the immunotherapy of solid neoplasms and haematological malignancies. The limited permeability of the blood brain barrier (BBB), however, is an obstacle to its widespread use in primary brain tumours, as well as in brain metastases. In order to overcome this limitation, we developed a procedure involving the use of focussed ultrasounds that allow selective permeabilisation of the BBB and targeted delivery of OA-GcMAF. One day before the procedure, OA-GcMAF is injected in the proximity of inguinal nodes; it is administered orally as a fermented milk product and with suppositories or enemas. The following day, OA-GcMAF is administered by nebulisation. Measurement of blood pressure variations and assessment of splenic blood flow after nebulisation are used to determine the individual response (1). Five minutes after nebulisation, transcranial ultrasounds are applied through the temporal acoustic window on the same side where the lesion is located. With proper setting, the cerebral cortex can be visualised, thus indicating that the ultrasound waves reach the gray matter (2). The ultrasound could then be directed toward the anatomical regions where the lesion is located. Most regions of the brain can be accessed through the temporal acoustic window, with the exception of distal areas of the frontal and occipital lobes. Focussed ultrasounds are known to transiently increase the permeability of the BBB (3) and, therefore, allow passage of OA-GcMAF that is a relatively lipophilic molecule thanks to the presence of oleic acid. The procedure lasts 5-15 min, causes no discomfort or side effects and can be repeated continuously or in cycles. The procedure can be safely performed before, during or after other anti-neoplastic treatments. 1.Ruggiero M et al: Oleic Acid, deglycosylated vitamin dbinding protein, nitric oxide: a molecular triad made lethal to cancer. Anticancer Res 34(7): 3569-3578, 2014. 2.Bradstreet JJ et al: A new methodology of viewing extraaxial fluid and cortical abnormalities in children with autism via transcranial ultrasonography. Front Hum Neurosci 7: 934, 2014. 3.Burgess A et al: Drug delivery across the blood-brain barrier using focused ultrasound. Expert Opin Drug Deliv1 1(5): 711-721, 2014.