Glioblastoma multiforme is the most devastating malignant
brain tumor in adults. Even with the standard care of
therapy, the prognosis remains dismal due to
tumor heterogeneity,
tumor infiltration, and, more importantly, the restrictive nature of the blood-brain barrier (BBB). To overcome the challenge of effectively delivering therapeutic cargo into the brain, herein a "smart", multifunctional polymeric
micelle was developed using a
cholesterol-conjugated
polyoxyethylene sorbitol oleate. A
cell-penetrating peptide,
arginine-
glycine repeats (RG)5, was incorporated into the
micelles to improve cellular uptake, while a pH-sensitive masking sequence,
histidine-
glutamic acid repeats (HE)5, was introduced for charge shielding to minimize nonspecific binding and uptake at physiological pH. Results demonstrated that (RG)5- and (HE)5-modified mixed
micelles were optimized using this strategy to effectively mask the cationic charges of the activated
cell-penetrating peptide (RG)5 at physiological pH, i.e., limiting internalization, and were selectively triggered in response to a mildly acidic microenvironment in vitro based on a charge reversal mechanism. In vivo results further confirmed that such
micelles preferentially accumulated in both brain and
tumor tissues in both xenograft and orthotropic
glioma mouse models. Furthermore,
micelles significantly inhibited
tumor growth with limited toxicity to peripheral tissues. The combination of BBB penetration,
tumor targeting, potent efficacy, and high tolerance of these
micelles strongly suggests that they could be a promising candidate for safe and effective drug delivery to the brain.