Identification of novel medulloblastoma cell-targeting peptides for use in selective chemotherapy drug delivery.

Abstract

Medulloblastoma is a malignant brain tumor diagnosed in children. Chemotherapy has improved survival rates to approximately 70%, however, children are often left with long-term treatment side-effects. New therapies which maintain a high cure rate while reducing off-target toxicity are required. We describe for the first time the use of a bacteriophage-peptide display library to identify heptapeptides which bind to medulloblastoma cells. Two heptapeptides which demonstrated high [E1-3(1)] or low [E1-7(2)] medulloblastoma cell binding affinity were synthesized. The potential of the peptides to deliver a therapeutic drug to medulloblastoma cells with specificity was investigated by conjugating E1-3(1) or E1-7(2) to doxorubicin (5). Both peptide-drug conjugates were cytotoxic to medulloblastoma cells. E1-3-doxorubicin (1) could permeabilize an in vitro blood-brain barrier and showed a marked reduction in cytotoxicity compared to free doxorubicin (5) in non-tumor cells. This study provides proof-of-concept for developing peptide-drug conjugates to inhibit medulloblastoma cell growth while minimizing off-target toxicity.