Chemical engineering of zein with polyethylene glycol and Angiopep-2 to manufacture a brain-targeted docetaxel nanomedicine for glioblastoma treatment

Abstract

AbstractGlioblastoma (GBM) is the deadliest adult brain cancer. The current standard-of-care chemotherapy using orally administered temozolomide (TMZ) presents poor improvement in patient survival, emphasizing the compelling need for new therapies. A possible chemotherapeutic alternative is docetaxel (DTX), which possesses higher tumoricidal potency against GBM cells. However, its limited blood-brain barrier (BBB) permeability poses a constraint on its application. Nonetheless, nanomedicine offers promising avenues for overcoming this challenge. Angiopep-2 (ANG2) is a peptide that targets the BBB-overexpressed low-density lipoprotein receptor (LDLR). In this work, we managed, for the first time, to employ a pioneering approach of covalently linking zein protein with polyethylene glycol (PEG) and ANG2 prior to its formulation into nanoparticles (ZNPs) with enhanced stability and LDLR-mediated brain targetability, respectively. Carbodiimide and click chemistry approaches were optimized, resulting in functional modification of zein with around 25% PEG, followed by functional modification of PEG with nearly 100% ANG2. DTX-loaded ZNPs presented 100 nm average size, indicating high suitability for BBB crossing through receptor-mediated transcytosis. ZNPs maintained the cytotoxic effect of the loaded DTX against GBM cells, while demonstrating a safe matrix against BBB cells. Importantly, these brain-targeted ZNPs showcased up to fourfold enhancement in blood-to-brain permeability in a BBB in vitro model, highlighting the potential of this novel approach of BBB targeting in significantly improving therapeutic outcomes for GBM patients. The versatility of the system and the possibility of significantly increasing drug concentration in the brain open the door to its future application in a wide range of other brain-related diseases. Graphical abstract