Angiopep-2-Conjugated "Core-Shell" Hybrid Nanovehicles for Targeted and pH-Triggered Delivery of Arsenic Trioxide into Glioma.

Abstract

The poor capability of drugs to permeate through the blood-brain barrier (BBB) and further release inside glioma greatly limits the curative effects of glioma chemotherapies. In this study, we prepared angiopep-2-conjugated liposome-silica hybrid nanovehicles for targeted delivery and increased the permeation of arsenic trioxide (ATO) in glioma. Polyacrylic acid (PAA) was grafted on mesoporous silica nanoparticles (MSN) for pH-sensitive release and supporting the lipid membrane. The prepared "core-shell" nanovehicles (ANG-LP-PAA-MSN) were characterized with uniform size, high drug loading efficiency (8.19 ± 0.51%), and superior pH-sensitive release feature. From the experiments, the enhanced targeted delivery of ATO by ANG-LP-PAA-MSN (ANG-LP-PAA-MSN@ATO) was evidenced by the improvement of transport, enhanced cellular uptake, and apoptosis in vitro. In addition, the pharmacokinetic study was creatively carried out through the blood-glioma synchronous microdialysis and revealed that the half-life ( t1/2) of blood and glioma tissue in the ANG-LP-PAA-MSN@ATO treatment group was extended by 1.65 and 2.34 times compared with the ATO solution group (ATO-Sol). The targeting efficiency of ANG-LP-PAA-MSN@ATO (24.96%) was dramatically stronger than that of the ATO-Sol (5.94%). Importantly, ANG-LP-PAA-MSN@ATO had a higher accumulation (4.6 ± 2.6% ID per g) in tumor tissues and showed a better therapeutic efficacy in intracranial C6 glioma bearing rats. Taken together, the blood-glioma synchronous microdialysis was successful used for the pharmacokinetic study and real-time monitoring of drug concentrations in blood and glioma; ANG-LP-PAA-MSN could be a promising targeted drug delivery system for glioma therapy.