PET imaging of intra-arterial 89 Zr bevacizumab in mice with and without osmotic opening of the blood-brain barrier: distinct advantage of intra-arterial delivery.

Glioblastoma multiforme (GBM) is the most aggressive and common type of brain cancer. Five-year survival rates are below 12%, even with the most aggressive tri-modal therapies. Poor blood-brain barrier (BBB) permeability of therapeutics is a major obstacle limiting efficacy. Intravenous (IV) administration of bevacizumab (BV) is the standard treatment for GBM. It has been recently demonstrated that single intra-arterial (IA) infusion of BV provides superior therapeutic outcomes in patients with recurrent GBM. Further GBM treatment benefits can be achieved upon BBB opening (BBBO) prior to IA infusion of BV. However, rationale for IA delivery and BBBO when delivering antibodies is lacking. A method facilitating quantification of intra-arterially delivery of BV is needed for more effective and personalized GBM treatment. Here, we demonstrate such a method using positron emission tomography (PET) of radiolabeled BV. Methods: BV was conjugated with deferoxamine (DFO) and subsequently radiolabeled with 89 Zr. 89 ZrBVDFO was prepared with a specific radioactivity of 81.4 ± 7.4 MBq/mg (2.2 ±0.2 µCi/mg). Brain uptake of 89 ZrBVDFO upon carotid artery and tail vein infusion with intact BBB (BBBI) or BBBO with mannitol was initially monitored by dynamic positron emission tomography (PET), followed by whole body PET-CT imaging at 1 h and 24 h post-infusion (pi). Ex vivo biodistribution of 89 ZrBVDFO was also carried out. Results: IA administration of 89 ZrBVDFO resulted in gradual accumulation of radioactivity in the ipsilateral hemisphere with 9.16 ±2.13 %ID/cc at the end of infusion. There was negligible signal observed in the contralateral hemisphere. BBBO with mannitol prior to IA infusion of 89 ZrBVDFO resulted in faster and higher accumulation of radioactivity in the ipsilateral hemisphere (23.58 ± 4.46 %ID/cc) with negligible uptake in the contralateral hemisphere. In contrast, IV infusion of 89 ZrBVDFO and subsequent BBBO did not lead to uptake of radiotracer in the brain. Ex vivo biodistribution validated PET-CT studies. Conclusion: Our findings demonstrate that IA delivery of BV into the brain across an osmotically opened BBB is effective in contrast to the IV route.