In this study, a dual-
ligand polymer-
lipid hybrid nanoparticle
drug delivery vehicle comprised of an anti-HER2/neu
peptide (AHNP) mimic with a modified HIV-1 Tat (
mTAT) was established for the targeted treatment of Her2/neu-overexpressing cells. The resultant dual-
ligand hybrid nanoparticles (NPs) consisted of a
poly(lactide-co-glycolide) core, a near 90% surface coverage of the
lipid monolayer, and a 5.7 nm hydrated
polyethylene glycol shell.
Ligand density optimization study revealed that cellular uptake efficiency of the hybrid NPs could be manipulated by controlling the surface-
ligand densities. Furthermore, the cell uptake kinetics and mechanism studies showed that the dual-
ligand modifications of hybrid NPs altered the cellular uptake pathway from caveolae-mediated endocytosis (CvME) to the multiple endocytic pathways, which would significantly enhance the NP internalization. Upon the systemic investigation of the cellular uptake behavior of dual-
ligand hybrid NPs,
docetaxel (
DTX), a hydrophobic anticancer
drug, was successfully encapsulated into dual-
ligand hybrid NPs with high
drug loading for Her2/neu-overexpressing SK-BR-3
breast cancer cell treatment. The DTX-loaded dual-
ligand hybrid NPs showed a decreased burst release and a more gradual sustained drug release property. Because of the synergistic effect of dual-
ligand modification, DTX-loaded dual-
ligand hybrid NPs exerted substantially better therapeutic potency against SK-BR-3
cancer cells than other NP formulations and free DTX drugs. These results demonstrate that the dual-
ligand hybrid NPs could be a promising vehicle for targeted
drug delivery to treat
breast cancer.