The effective treatment of
glioblastoma (GBM) is a great challenge because of the blood-brain barrier (BBB) and the growing resistance to single-agent
therapeutics. Targeted combined co-delivery of drugs could circumvent these challenges; however, the absence of more effective
combination drug delivery strategies presents a potent barrier. Here, a unique combination
ApoE-functionalized liposomal nanoplatform based on
artesunate-
phosphatidylcholine (ARTPC) encapsulated with
temozolomide (
ApoE-ARTPC@TMZ) was presented that can successfully co-deliver dual therapeutic agents to TMZ-resistant U251-TR GBM in vivo. Examination in vitro showed ART-mediated inhibition of DNA repair through the Wnt/β-
catenin signaling cascade, which also improved GBM sensitivity to TMZ, resulting in enhanced synergistic DNA damage and induction of apoptosis. In assessing BBB permeation, the targeted
liposomes were able to effectively traverse the BBB through
low-density lipoprotein family receptors (LDLRs)-mediated transcytosis and achieved deep intracranial
tumor penetration. More importantly, the targeted combination
liposomes resulted in a significant decrease of U251-TR
glioma burden in vivo that, in concert, substantially improved the survival of mice. Additionally, by lowering the effective dosage of TMZ, the combination
liposomes reduced systemic TMZ-induced toxicity, highlighting the preclinical potential of this novel integrative strategy to deliver combination
therapies to
brain tumors.