RGD conjugated liposome-hollow silica hybrid nanovehicles for targeted and controlled delivery of arsenic trioxide against hepatic carcinoma

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Abstract

Graphical abstract

To construct a targeted and controlled arsenic trioxide (ATO, a poor pharmacokinetic drug with dose-limited toxicity) delivery core-shell nanovehicle which combined the features of hollow mesoporous silica nanoparticles (HMSN) and functional liposome (named as RGD-LP-CHMSN-ATO). The chlorodimethyloctadecylsilane was modified on the surface of HMSN for supporting phospholipid bilayer which enhanced the stability of nanoparticles and increased the affinity between nanoparticles and cell membrane. Improved PK features and significant hepatic tumor-specific distribution of ATO were achieved by RGD-LP-CHMSN-ATO. The antitumor efficacy in vitro (HepG2 cell line) and in vivo (H22 xenografts) was remarkably improved by RGD-LP-CHMSN-ATO. All the findings proved this favorable drug delivery system may significantly expand the potential use of arsenic compounds in treating solid tumor.

The aim of our study was to construct an Arg-Gly-Asp (RGD)-conjugated liposome-hollow silica hybrid nanovehicle for targeted delivery and controlled release of arsenic trioxide (ATO), whose anti-solid tumor effect was hampered by poor pharmacokinetics and dose-limited toxicity. Hydrophobic interactions were used to attach intact lipid membrane to the surface of chlorodimethyloctadecylsilane-modified hollow mesoporous silica nanoparticles. The prepared nanovehicles (RGD-LP-CHMSN) were characterized for uniform structure (silica core of ˜140 nm in diameter and liposomal shell of ˜6 nm), comparable drug loading efficiency (6.76%), desirable stability and strengthened controlled release. In vitro, RGD-LP-CHMSN showed good biocompatibility and low toxicity on HepG2, MCF-7 and LO2 cells. The targeted delivery of ATO by nanocarriers (RGD-LP-CHMSN-ATO) was demonstrated by an enhanced cellular uptake and a reduced half maximal inhibitory concentration (IC50) value. In pharmacokinetic studies, the RGD-LP-CHMSN-ATO group, compared to the free ATO group, prolonged the half time (t1/2β) by 1.7 times and increased the area under curve (AUC) by 2.4 times. In addition, in a H22 tumor-xenograft mouse model, nanovehicles improved the targeting efficiency and anticancer potential of ATO. In conclusion, the strategy of constructing a nanocarrier with targeted delivery and controlled release characteristics is prospective to enhance the antitumor effect of ATO.

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