PEGylated Nanoliposomal Doxorubicin Conjugated with Specific TREM2 Peptides for Glioma‐Targeting Therapy

Abstract

PEGylated liposomes can deliver anti‐cancer drugs to brain tumors, and achieve enhanced permeability and retention effects. Triggering receptor expressed on myeloid cells 2 (TREM2) is an excellent biomarker for precise therapy of glioma. The present study is aimed at designing PEGylated nanoliposomal doxorubicin (PLD) conjugated with peptides targeting TREM2 for glioma‐targeting therapy. The specific peptides are designed with the Rosetta Peptiderive Protocol. Schrodinger's peptide‐specific version of Glide is used for molecular docking. PLD modified with peptides (peptide‐PLD) are engineered and prepared. Cell cycle, apoptosis, cell invasion and migration, cell viability, and colony‐formation assays are performed to analyze glioma cell functions. The anti‐tumor effects of peptide‐PLD are validated in an intracranial U87‐MG cells orthotopic glioma model. The targeting peptides HLRKLRKR and LRKLRLRL showed specific affinity for TREM2 and better cellular uptake in U87‐MG cells. PLD with peptide modification demonstrated stable doxorubicin loading, small sizes (<60 nm), and enrichment in the mouse brain. Peptide‐PLD treatment inhibited the Akt/GSK3β/β‐catenin pathway, thereby inhibiting cell invasion and migration, and colony‐forming ability in U87‐MG cells. The peptide modification of PLD achieved better suppression of glioma development than PLD. Overall, TREM2‐targeting peptides are successfully designed, and peptide‐PLD served as a potent drug delivery carrier for glioma‐targeting therapy.