Ultra-small micelles together with UTMD enhanced the therapeutic effect of docetaxel on Glioblastoma

Abstract

Owing to the difficult-to-penetrate blood-brain barrier (BBB), glioblastoma (GBM) doesn't respond well to the current chemical therapeutics. In this study, ultra-small micelles (NMs) self-assembled by RRR-a-tocopheryl succinate-grafted-ε-polylysine conjugate (VES-g-ε-PLL) as the delivery vehicle of chemical therapeutics in conjunction with ultrasound-targeted microbubble destruction (UTMD) to surmount BBB and treat GBM. Docetaxel (DTX) as a hydrophobic model drug was incorporated into NMs. DTX-loaded micelles (DTX-NMs) with 3.08% of drug loading exhibited a hydrodynamic diameter (33.2 nm) and positive Zeta potential (16.9 mV), having a remarkable tumor-permeating capacity. Furthermore, DTX-NMs presented good stability in physiologic condition. The sustained- release profile of DTX-NMs was also displayed by dynamic dialysis. Treatment of DTX-NMs together with UTMD led to more pronounced apoptosis of C6 tumor cells than DTX-NMs alone. Moreover, compared with the DTX solution or DTX-NMs alone, the combination of DTX-NMs with UTMD had a stronger inhibitory effect on tumor growth for GBM-bearing rats. The median survival period of GBM-bearing rats was extended to 75 days in the DTX-NMs+UTMD group from under 25 days in the control group. The invasive growth of glioblastoma was largely inhibited by the combination of DTX-NMs with UTMD, which was demonstrated by staining of Ki67, caspase-3, and CD31, together with TUNEL assay. In conclusion, the combination of ultra-small micelles (NMs) with UTMD may be a promising strategy to overcome the limitations of the first-line chemotherapeutics against GBM.