Dual-Responsive Core Crosslinking Glycopolymer-Drug Conjugates Nanoparticles for Precise Hepatocarcinoma Therapy

Abstract

Nanoparticles (NPs) have demonstrated a potential for hepatocarcinoma therapy. However, the effective and safe NP-mediated drug transportation is still challenging due to premature leakage and inaccurate release of the drug. Herein, we designed a series of core cross-linking galactose-based glycopolymer-drug conjugates (GPDs) NPs with both redox-responsive and pH-sensitive characteristics to target and program drug release. Glycopolymer is comprised of galactose-containing units, which gather on the surface of GPD NPs and exhibit specific recognition to hepatocarcinoma cells, which over-express the asialoglycoprotein receptor. GPD NPs are stable in a normal physiological environment and can rapidly release the drug in hepatocarcinoma cells, which are reductive and acidic, by combining disulfide bond cross-linked core, as well as boronate ester-linked hydrophilic glycopolymer chain and the hydrophobic drug.

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

“…Interestingly, the cytotoxicity of siRNA/DOX/GH-DPP against A549 cells (no GA-receptor) was lower than that of siRNA/DOX/DPP. The possible explanation was that the introduction of GA-HA conjugate promotes the cellular uptake of drug-loaded GH-DPP nanoparticles by HepG2 cells via GA-receptor-mediated endocytosis, leading to higher cytotoxicity (Wu J. et al, 2018). However, there was no GA receptor on A549 cells, and drug-loaded DPP nanoparticles (positive charged) were easily taken up by tumor cells, resulting in higher cytotoxicity than drug-loaded GH-DPP nanoparticles (negative charged).…”

“…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). In the past decade, many efforts have been made to prepare liver-targeting nano-carriers, which were modified by sugars, antibodies, and other ligands (Singh et al, 2016; Zhu et al, 2016; Yan et al, 2017; Wu J. et al, 2018). Glycyrrhetinic acid (GA), a metabolite of glycyrrhizin, has attracted growing interest in anti-hepatoma therapy (Wu J. et al, 2018).…”

“…In the past decade, many efforts have been made to prepare liver-targeting nano-carriers, which were modified by sugars, antibodies, and other ligands (Singh et al, 2016; Zhu et al, 2016; Yan et al, 2017; Wu J. et al, 2018). Glycyrrhetinic acid (GA), a metabolite of glycyrrhizin, has attracted growing interest in anti-hepatoma therapy (Wu J. et al, 2018). It has been reported that GA-modified nano-carriers could significantly improve liver-targeting efficiency and inhibit liver cancer development.…”

Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope

“…However, it is worth mentioning that the release performance of these DDSs should be carefully investigated, and the NCs' design possibly optimized. Especially for long-circulating NCs, minimizing the premature drug release is fundamental to improve its therapeutic outcome [65].…”

Fabrication of pH/Reduction Sensitive Polyethylene Glycol-Based Micelles for Enhanced Intracellular Drug Release

“…Low pH and reduction conditions, as the characteristics of tumor microenvironment, can be integrated to achieve a variety of effects, such as enhancement of the targeting of drug release in lysosomes and other internal chambers of tumor cells, the realization of rapid drug release into cytoplasm and nucleus, etc. [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].…”