Anti-GPC3 antibody-modified sorafenib-loaded nanoparticles significantly inhibited HepG2 hepatocellular carcinoma

Abstract

Sorafenib (SFB) has improved the treatment of hepatocellular carcinoma (HCC) and has fewer severe side effects than other agents used for that purpose. However, due to a lack of tumor-specific targeting, the concentration of the drug in tumor tissue cannot be permanently maintained at a level that inhibits tumor growth. To overcome this problem, we developed a novel SFB-loaded polymer nanoparticle (NP). The NP (a TPGS-b-PCL copolymer that was synthesized from ε-caprolactone and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) via ring-opening polymerization) contains Pluronic P123 and SFB, and its surface is modified with anti-GPC3 antibody to produce the polymer nanoparticle (NP-SFB-Ab). The Ab-conjugated NPs had higher cellular uptake by HepG2 cells than did non-antibody-conjugated SPD-containing nanoparticles (NP-SFB). The NP-SFB-Ab also displayed better stability characteristics, released higher levels of SFB into cell culture medium, and was more cytotoxic to tumor cells than was non-targeted NP-SFB and free SFB. The NP-SFB-Ab downregulated expression of the anti-apoptosis molecule MCL-1, which led to polymerization of Bax and Bak in mitochondrial cytosol. The NP-SFB-AB also promoted the mitochondrial release of cytochrome C, resulting in cellular apoptosis. Moreover, the NP-SFB-Ab significantly inhibited the growth of HepG2 xenograft tumors in nude mice without producing obvious side effects. These findings suggest that NP-SFB-Ab is a promising new method for achieving targeted therapy of HCC.

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“…Polyester materials, such as poly (d,llactide-co-glycolic acid, PLGA), d-α-tocopheryl polyethylene glycol 1000 succinate(TPGS), and poly(ethylene glycol) (PEG), yield favorable biodegradation products that do not cause sexual or organ damage and have been widely used in controlled release drug-loaded microspheres [16,17]. PLA and PLGA drug-loaded microspheres and NPs protect the drugs, aid their solubilization, and improve their bioavailability and targeted release [18]. However, the hydrophobicity of these two materials limits their use as pharmaceutical carriers.…”

Drug targeting strategies for liver cancer and other liver diseases

“…In this conditions, required some new strategy to treat or manage advanced liver cancer. This review concluded that there are some new strategies available such as ligand mediated active targeting, nano carrier based RES uptake and some molecular conjugates of targeting ligands and active drugs that applicable to target effectively and killed the actively proliferating cancer cells, 68,69 and the available targeting ligands such as asialoglycoprotein, lactose and mannose, liver cancer cell specific antibodies, aptamers, avimers, bile acid conjugation, Collagen Type VI Receptor, Collagen Type VI Receptor and others ligands were successfully used for targeting liver cancer and further can be used for targeting and deliver anticancer drug or drug which are used to treatment of liver diseases. 70…”

The Dual Role of the Liver in Nanomedicine as an Actor in the Elimination of Nanostructures or a Therapeutic Target

“…In vitro and in vivo experiments showed that the use of anti-GPC3 polymeric NPs loaded with sorafenib inhibited HepG2 cell proliferation. erefore, this drug delivery system could be a potential tool for the targeted treatment of liver cancer [104].…”