Liver-Targeted Combination Therapy Basing on Glycyrrhizic Acid-Modified DSPE-PEG-PEI Nanoparticles for Co-delivery of Doxorubicin and Bcl-2 siRNA.

Guixiang Tian,Ruiyan Pan,Bo Zhang,Meihua Qu,Hong Jiang,Jingliang Wu,Bo Lian,Zhiqin Gao

doi:10.3389/fphar.2019.00004

Guixiang Tian, Ruiyan Pan + Show 6 more

Open Access

https://doi.org/10.3389/fphar.2019.00004

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Abstract

Combination therapy based on nano-sized drug delivery system has been developed as a promising strategy by combining two or more anti-tumor mechanisms. Here, we prepared liver-targeted nanoparticles (GH-DPP) composed of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-polyetherimide (DSPE-PEG-PEI) with Glycyrrhetinic acid-modified hyaluronic acid (GA-HA) for co-delivery of doxorubicin (DOX) and Bcl-2 siRNA. Particles size, zeta potential and morphology were determined for the drug-loaded GH-DPP nanoparticles (siRNA/DOX/GH-DPP). Cellular uptake and in vitro cytotoxicity were analyzed against HepG2 cells. In vivo bio-distribution and anti-tumor therapeutic effects of siRNA/DOX/GH-DPP were evaluated in H22-bearing mice. The results showed that siRNA/DOX/GH-DPP nanoparticles were nearly spherical and showed dose-dependent cytotoxicity against HepG2 cells. Compared to Glycyrrhetinic acid-free co-delivery system (siRNA/DOX/DPP) and GH-DPP nanoparticles for delivery of DOX or Bcl-2 siRNA alone, siRNA/DOX/GH-DPP nanoparticles could induce more cellular apoptosis, and showed higher anti-tumor effect. Herein GH-DPP nanoparticles could simultaneously deliver both chemotherapy drugs and siRNA into the tumor region, exhibiting great potential in anti-tumor therapy.

Highlights

Liver cancer is one of prevalent cancers with high mortality rate around the world, and traditional chemotherapy is one effective approach used in anti-cancer therapy (Gravitz, 2014; Sia et al, 2017)
The nano-vehicles basing on phosphoethanolamine-polyethylene glycol polymers (PEG-PE) represent a promising nanoparticles delivery system owing to biocompatibility, prolonged circulation, and accumulation in tumors by the enhanced permeability and retention (EPR) effect (Perche et al, 2012; Kohay et al, 2017)
The results suggested that DPP and GA-HA conjugate (GH)-DPP nanoparticles could be used in drug delivery materials due to their negligible toxicity

Summary

Introduction

Liver cancer is one of prevalent cancers with high mortality rate around the world, and traditional chemotherapy is one effective approach used in anti-cancer therapy (Gravitz, 2014; Sia et al, 2017). To improve selectivity toward liver cancer cells, an effective strategy is to design nano-sized carrier to realize liver-targeted delivery (Shamay et al, 2018). The nano-vehicles basing on phosphoethanolamine-polyethylene glycol polymers (PEG-PE) represent a promising nanoparticles delivery system owing to biocompatibility, prolonged circulation, and accumulation in tumors by the enhanced permeability and retention (EPR) effect (Perche et al, 2012; Kohay et al, 2017). It has been reported that GA-modified nano-carriers could significantly improve liver-targeting efficiency and inhibit liver cancer development

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