Chemotherapies for brain diseases have been hampered due to the inability of transport of drug across the blood-brain barrier (BBB). In order to overcome the barrier, p-hydroxybenzoic acid (p-HA), a small molecule of benzamide analogue, was used as a ligand for brain-targeted drug delivery. The p-HA was conjugated to PEG-DSPE to form p-HA-PEG-DSPE. Docetaxel-loaded polymeric micelles were prepared by a thin-film hydration method using methoxy-poly(ethylene glycol)-distearoylphosphatidyl- ethanolamine (mPEG 2000 -DSPE) as a carrier and the p-HA-PEG-DSPE as a brain targeted material. The prepared micelles showed spherical with a mean diameter of (18±3) nm. Encapsulation efficiency and drug loading were (83.49±1.3)%, (7.7±1.2)% for un- modified micelles and (80.65±1.6)%, (7.47±1.8)% for p-HA-modified micelles, respectively. In vitro cellular uptake experiments showed that the p-HA-modified micelles increased BCECs cellular uptake by 1.2 times compared to the unmodified micelles. Ex vivo near-infrared fluorescence imaging showed that brain uptake of the p-HA-modified micelles was 1.3-1.8 times higher than that of the unmodified micelles. In vitro cytotoxicity assay against glioblastoma cell U87 MG showed that inhibition rate of the p-HA-modified micelles increased by 1.2 times compared to that of the unmodified micelles and 1.7 times compared to that of DTX. Survival time of nude mice bearing intracranial glioblastoma showed that the lifetime of saline group, Taxotere group, mPEG-DSPE/DTX micelles group and p-HA-PEG-DSPE/DTX micelles group was 22, 27, 32 and 45.8 d, representively, which indicated that anti-glioblastoma activity of DTX could be significantly enhanced by the p-HA-modified polymeric micelles. These results demonstrated that the p-HA-modified micelles could be a promising brain-targeted drug delivery system for hydrophobic drugs against glioblastoma.
