Polypeptide nanomicelles co-deliver PLK1 and BCL-2/xL inhibitors for synergetic therapy of brain tumor

Abstract

Molecular targeted therapy has revolutionized the clinical practice for various cancer patients. The therapeutic benefits vary greatly due to low bioavailability, insufficient accessibility on targets, and presence of intrinsic and acquired resistance. Restrained by additional blood-brain barrier (BBB), treatments of small molecule inhibitors in brain tumors have made less progress. Here, we find that ApoE peptide-decorated nanomicelles (ApoE-PM) based on phenylboronic acid-functionalized polypeptide mediate efficient co-delivery of polo-like kinase 1 (PLK1) and B-cell lymphoma-2/xL (BCL-2/xL) inhibitors to brain tumor. Nanomicelles exhibit exceptional stability, proportional co-loading and responsive release of small molecule inhibitors with diverse properties and molecular targets, by exploiting the B-N coordination and π-π stacking between phenylboronic acid groups and drugs. Notably, micelles decorated with ApoE peptide on the surface and loaded with volasertib and navitoclax at a weight ratio of 1/1 (ApoE-PMVN) reveals proficient BBB crossing, efficient internalization and strong synergistic antiproliferation effect in GL261 cells. In mice bearing orthotopic GL261 glioblastoma (GBM) model, ApoE-PMVN affords significant growth inhibition and markedly improved survival time via synergistic inhibition of PLK1, BCL-2/xL and myeloid cell leukemia 1 (MCL-1) targets. PM provides a versatile strategy for co-delivery of small molecule inhibitors, offering a potential for synergistic therapy of brain tumors.