LAUSR

BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a highly lethal malignancy that occurs predominantly in children. DIPG is inoperable and post-diagnosis survival is less than 1 year, as conventional chemotherapy is ineffective. The intact blood brain barrier (BBB) blocks drugs from entering the brain. Convection-enhanced delivery (CED) is a direct infusion technique delivering drugs to the brain, but it suffers from rapid drug clearance. Our goal is to overcome the delivery barrier via CED and maintain a therapeutic concentration at the glioma site with a payload-adjustable peptide nanofiber precursor (NFP) that displays a prolonged retention property as a drug carrier. METHODS The post-CED retention of 89Zr-NFP was determined in real time using positron emission tomography/computed tomography (PET/CT) imaging. Emtansine (DM1), a microtubule inhibitor, was conjugated to NFP. The cytotoxicity of resulting DM1-NFP was tested against patient-derived DIPG cell lines. The therapeutic efficacy was evaluated in animals bearing orthotopic DIPG, according to glioma growth (measured using bioluminescence imaging) and the long-term survival. RESULTS NFP remained at the infusion site (pons) for weeks, with the clearance half-life of 60 days. DM1-NFP demonstrated potency against multiple glioma cell lines. The IC50 values were in the nanomolar range. DM1-NFP inhibited glioma progression in animals, and offered a survival benefit (median survival of 62 days) compared to the untreated controls (28 days) and DM1-treated animal group (26 days). CONCLUSIONS CED, in combination with DM1-NFP, complementarily functions to bypass the BBB, prolong drug retention at the fusion site, and maintain an effective therapeutic effect against DIPG to improve treatment outcome.