Glioblastoma is one of the most challenging and intractable
tumors with the difficult treatment and poor prognosis. Unsatisfactory traditional systemic
chemotherapies for
glioblastoma are mainly attributed to the insufficient and nonspecific drug delivery into the
brain tumors as well as the incomplete drug release at the
tumor sites. Inspired by the facts that
angiopep-2 peptide is an acknowledged dual-targeting moiety for
brain tumor-targeting delivery and high-intensity focused ultrasound (HIFU) is an ideal trigger for drug release with an ultrahigh energy and millimeter-sized focus ability, in the present study, a novel HIFU-responsive angiopep-2-modified small
poly(lactic-co-glycolic acid) (PLGA) hybrid nanoparticle (NP) drug delivery system holding
doxorubicin/
perfluorooctyl bromide (
ANP-D/P) was designed to increase the intratumoral drug accumulation, further trigger on-demand drug release at the
glioblastoma sites, and enhance
glioblastoma therapy. It was shown that the
ANP-D/P was stable and had a small size of 41 nm. The
angiopep-2 modification endowed the
ANP-D/P with improved blood-brain barrier transportation and specific accumulation in
glioblastoma tissues by 17 folds and 13.4 folds compared with unmodified NPs, respectively. Under HIFU irradiation, the
ANP-D/P could release 47% of the drug within 2 min and induce the apoptosis of most
tumor cells. HIFU-triggered instantaneous drug release at the
glioblastoma sites eventually enabled the
ANP-D/P to achieve the strongest antiglioblastoma efficacy with the longest median survival time (56 days) of
glioblastoma-bearing mice and the minimum vestiges of
tumor cells in the pathological slices among all groups. In conclusion, the HIFU-responsive
ANP-D/P in this study provided a new way for
glioblastoma therapy with a great potential for clinical applications.