ET-52 * SIMULTANEOUS BRAIN DELIVERY OF A THREE ANTI-CANCER DRUG COMBINATION VIA A PEPTIDE CARRIER-MEDIATED INTRAVENOUS INJECTION OF THE THREE-DRUG COCKTAIL

Abstract

BACKGROUND: Combinations of anti-cancer medications often yield better outcome than a single medication in the treatment of patients with cancer including patients with brain cancer. However, limitations imposed by the blood-brain barrier (BBB) create serious challenge to deliver even a single drug to the brain, let alone a combination of drugs. We have developed a peptide carrier K16ApoE, which apparently creates transient opening of the BBB. We investigated the ability of the carrier peptide to deliver a three-drug combination (cetuximab, cisplatin and methotrexate) to the brain injected via intravenous route. METHODS: Brain delivery of the drugs was achieved either by separate or combined administration of K16ApoE and a given drug(s) through femoral vein injection. A modification of the method comprised injection of K16ApoE pre-mixed with cetuximab, followed by injection of a drug. Brain uptake of cetuximab was assessed by micro single photon electron computed tomography (microSPECT). Quantification of brain uptake of cisplatin and methotrexate were achieved by atomic absorption spectrometry and LC-MS/MS, respectively. RESULTS: Experiments designed to deliver cetuximab, cisplatin and methotrexate separately show brain-uptake of the drugs was ∼3-fold, ∼40-fold and ∼51-fold greater with K16ApoE than without, amounting to brain uptake of ∼0.5% for cetuximab and ∼1.5% each for cisplatin and methotrexate, respectively, of the injected dose. Experiments designed to deliver cetuximab, cisplatin and methotrexate simultaneously (in a mixture) produced brain uptake of the three drugs at ∼3-fold, ∼18-fold and ∼41-fold greater with K16ApoE than without for cetuximab, cisplatin and methotrexate, respectively, which amounted to brain uptake of∼ 0.5% for cetuximab, ∼0.7% for cisplatin and ∼ 0.5% for methotrexate. SIGNIFICANCE: The results suggest that multiple anti-cancer agents can be simultaneously delivered to the brain via the synthetic carrier peptide K16ApoE. Thus, the method offers a novel therapeutic avenue for intervention against brain cancer.