Co-delivery of sorafenib and metapristone encapsulated by CXCR4-targeted PLGA-PEG nanoparticles overcomes hepatocellular carcinoma resistance to sorafenib

Abstract

Background Sorafenib is approved as a standard therapy for advanced hepatocellular carcinoma (HCC), but its clinical application is limited due to moderate therapeutic efficacy and high incidence of acquired resistance resulted from elevated levels of SDF-1/CXCR4 axis induced by prolonged sorafenib treatment. We previously demonstrated metapristone (RU486 metabolite) as a cancer metastatic chemopreventive agent targeting SDF-1/CXCR4 axis. Therefore, we hypothesized that combining sorafenib with metapristone could synergistically suppress cell proliferation, enhance anti-cancer activity and repress potential drug resistance. Methods Changes in cellular CXCR4 expression by metapristone were analyzed by RT-PCR and western blotting. Effect of combining sorafenib with metapristone on cell viability was examined by MTT assay; combination index value was calculated to evaluate the synergistic effect of combined therapy. To overcome poor pharmacokinetics and reduce off-target toxicity, CXCR4-targeted nanoparticles (NPs) were developed to co-deliver sorafenib and metapristone into CXCR4-expressing HCC in vitro and in vivo; cell proliferation, colony formation and apoptosis assays were conducted; nude mice bearing HCC xenograft were used to examine effects of this therapeutic approach on HCC progression. Results Here we showed metapristone significantly reduced CXCR4 expression in HCC. Combinatory chemotherapy of sorafenib with metapristone synergistically suppressed HCC proliferation and resistance. CXCR4-targeted PEGylated poly (lactic-co-glycolic acid) NPs conjugated with LFC131 (a peptide inhibitor of CXCR4), could deliver more sorafenib and metapristone into HCC via specific recognition and binding with transmembrane CXCR4, and resulted in the enhanced cytotoxicity, colony inhibition and apoptosis by regulating more Akt/ERK/p38 MAPK/caspase signaling pathways. Co-delivery of sorafenib with metapristone by the LFC131-conjugated NPs showed prolonged circulation and target accumulation at tumor sites, and thus suppressed tumor growth in a tumor xenograft model. Conclusions In conclusion, co-delivery of sorafenib and metapristone via the CXCR4-targeted NPs displays a synergistic therapy against HCC. Our results suggest combinational treatment of chemotherapeutics offer an effective strategy for enhancing the therapeutic efficacy on carcinoma, and highlight the potential application of ligand-modified tumor-targeting nanocarriers in delivering drugs as a promising cancer therapeutic approach. Electronic supplementary material The online version of this article (10.1186/s13046-019-1216-x) contains supplementary material, which is available to authorized users.

Antimicrobial Peptides as New Combination Agents in Cancer Therapeutics: A Promising Protocol against HT-29 Tumoral Spheroids

“…Based on the results reported before, we decided to use only the two smallest concentrations of GA, together with different concentrations of Doxo. This type of protocol, where one of the drugs has a fixed concentration and the concentration of the second one is varied, has been applied successfully for different drug combinations, as reported in the literature [31][32][33][34]. Furthermore, in order to assess if the combination of the two drugs has a synergistic effect, we calculated the combination index (CI) and found that all conditions tested were synergistic (CI < 1).…”

Current status of sorafenib nanoparticle delivery systems in the treatment of hepatocellular carcinoma

“…At temperatures below the lower critical solution temperature, these materials are in a sol state with a low viscosity, but they enter a gel state at higher temperatures 53 . Thermosensitive hydrogels are promising drug carriers because of their biodegradability, low toxicity, high drug loading capacity, site specificity, sustained release, controlled release, and other advantages 54 . For example, Zheng et al synthesized a thermosensitive composite NP that was used as an effective drug carrier for SOR and was combined with radiotherapy for local and continuous treatment of liver cancer 55 .…”

“…Metapristone (RU486 metabolite) is a metastatic chemopreventive agent targeting the SDF-1/CXCR4 axis 106 . Zheng et al encapsulated SOR and metapristone in a hydrophobic nucleus through hydrophobic interactions between the drugs and PLGA-PEG-COOH (Figure 6 ) 54 . The LFC131 peptide was covalently bound to the surface of the NPs to target CXCR4, and SOR and metapristone were simultaneously delivered to CXCR4-expressing HCC cells.…”

<p>A Review of Biomimetic Nanoparticle Drug Delivery Systems Based on Cell Membranes</p>

“…10,13 Zheng et al verified co-delivery of sorafenib and metapristone by the LFC131-conjugated (a peptide inhibitor of CXCR4) PLGA NPs showed prolonged circulation and target accumulation at tumor sites, and thus suppressed tumor growth in HCC models. 14 Byeon et al developed HA-labeled PLGA NPs (HA-PLGA NPs) incorporating both PTX and FAK siRNA as a two-in one delivery system to increase the efficiency of targeted delivery against tumor-specific receptors and to enhance therapeutic efficacy in drug-resistant ovarian cancer. 15 In comparison to monotherapy, anticancer drugs encapsulated in PLGA nanoparticles show good biocompatibility, strong cytotoxicity, significant antitumor activity and minimal systemic toxicity.…”