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.
Highlights
Hepatocellular carcinoma (HCC) is the third most deadly type of cancer worldwide (Chiang & Villanueva, 2017; Nakamura et al, 2018)
Hydrazine hydrate (50%), Pluronic P123 (Mw 1⁄4 5800), N-succinimidyl 3-maleimidopropionate (SMMP), stannous octoate (Sn(Oct)2), 4-toluene sulfochloride, Traut's reagent (2-iminothiolane), phthalimide potassium salt, and trimethylamine were purchased from Alfa Aesar (Ward Hill, MA)
Primary antibodies for Bad and X-linked inhibitor of apoptosis protein (XIAP) were purchased from BD Biosciences (Bedford, MA); anti-VEGF, anti-PARP, and antiBak antibodies were obtained from ALEXIS Corporation (San Diego, CA)
Summary
Hepatocellular carcinoma (HCC) is the third most deadly type of cancer worldwide (Chiang & Villanueva, 2017; Nakamura et al, 2018). There has not been a major advance in the systematic treatment of liver cancer for many years. There is no second-line treatment for advanced HCC. SFB is a multi-kinase inhibitor with both anti-tumor cell and anti-tumor vascular effects, and it has been shown to improve the survival times of HCC patients (Parikh et al, 2017; Pinter et al, 2017; Won et al, 2017). Some cases of HCC are refractory to SFB (Won et al, 2017; Zhu et al, 2017), so it is important to develop new methods for overcoming this problem. Due to its unique properties, polycaprolactone (PCL) is one of the most widely used polymers. While copolymerization of PCL with TPGS makes PCL more hemocompatible, PCL still retains its high degree of hydrophobicity and slow degradation and drug release properties, which limit its applications.
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