IMPROVING DRUG-DELIVERY TO INTRACEREBRAL TUMOR AND SURROUNDING BRAIN IN A RODENT MODEL - A COMPARISON OF OSMOTIC VERSUS BRADYKININ MODIFICATION OF THE BLOOD-BRAIN AND OR BLOOD-TUMOR BARRIERS/

OBJECTIVE: To compare transient blood-brain barrier disruption (BBBD) by hypertonic mannitol with pharmacological modification of the blood- tumor barrier by the vasoactive peptide bradykinin for delivery of sma ll and large agents to nude rat intracerebral xenografts. METHODS: Fem ale nude rats (n = 104) with 6-day intracerebral human small cell lung carcinoma tumors were treated using BBBD (n = 24), intracarotid brady kinin (n = 38), or saline (controls, n = 32) administered intra-arteri ally. During or immediately after infusion, the rats were given radiol abeled agent (methotrexate or dextran 70; Dupont NEN, Boston, MA). The rats were killed 10 minutes later, and samples of tumor and brain reg ions were obtained for scintillation counting. Twenty-two additional r ats were examined using magnetic resonance imaging after administering one of two contrast agents (gadoteridol or iron oxide nanoparticles) or saline (controls) in conjunction with BBBD or bradykinin.RESULTS: A fter BBBD, the delivery of both small (methotrexate) and large (dextra n 70) radiolabeled tracers was increased 2- to 6-fold in the tumor and 3- to 20-fold in surrounding brain, as compared with saline controls. After bradykinin treatment, there was minimal change in delivery of m ethotrexate or dextran 70 to tumor and brain around tumor, with the gr eatest increase less than 60% over controls. Magnetic resonance imagin g demonstrated increased delivery of both small and large contrast age nts to the treated hemisphere after BBBD. In comparison, no increased tumor enhancement could be detected after bradykinin treatment. CONCLU SION: BBBD resulted in global delivery of a variety of agents in a wid e range of sizes. In this human brain tumor xenograft model, bradykini n was not effective at increasing delivery to the tumor of any agent t ested.