Combined treatment of sorafenib and doxorubicin-loaded microbubble-albumin nanoparticle complex for hepatocellular carcinoma: A feasibility study.

Seunghyun Lee,Hyungwon Moon,Hak Jong Lee,Joon Koo Han,Jung Hoon Kim,Gianfranco D Alpini

doi:10.1371/journal.pone.0243815

Abstract

PurposeTo assess the feasibility of the combined sorafenib (SOR) and doxorubicin-loaded microbubble-albumin nanoparticle complex (DOX-MAC) treatment effect in an orthotopic rat model of hepatocellular carcinoma (HCC).Materials and methodsSixty-two rats with N1-S1 hepatoma were divided into four groups according to the treatment methods, i.e. G1 (SOR and DOX-MAC; n = 12), G2 (SOR; n = 15), G3 (DOX-MAC; n = 12), G4 (DOX; n = 11), and G5 (normal saline; n = 12). We performed the theragnostic, contrast-enhanced ultrasound examination and treatment at the baseline, one-week, and two-weeks. Tumor volume and perfusion parameters were compared at each time point and the differences between all of the groups over time were analyzed using repeated measures ANOVA. We also analyzed the apoptotic index and microvessel density (MVD) per each tumor specimen in all of the groups.ResultsThe tumors increased from the beginning in all of the groups to the final follow-up, whereas the tumor growth in the G1 group and the G2 group was inhibited during the treatment period compared to the baseline tumor volume (P = 0.016 and P = 0.031). The G1 group resulted in tumor growth inhibition compared to the control group (P = 0.008). The G1 group showed that the peak enhancement and wash-in area under the curve were lower than that of the G4 group (P = 0.010 and 0.022). However, there was no difference in perfusion parameters in the other treated group compared to control group. The MVD of the G1 group tumor was lower than that of the G4 group (P = .016).ConclusionOur results suggest that the combination therapy of SOR and DOX-MAC can cause inhibition of tumor growth after treatment and that this therapy can be adequately monitored using the theragnostic DOX-MAC agent.

Highlights

Systemic chemotherapy has been proposed as a treatment option for patients with advanced hepatocellular carcinoma (HCC) [1]
Our results suggest that the combination therapy of SOR and DOX-Microbubble-albumin nanoparticle complex (MAC) can cause inhibition of tumor growth after treatment and that this therapy can be adequately monitored using the theragnostic DOX-MAC agent
For the delivery of a chemotherapeutic agent, doxorubicin-loaded, microbubble-albumin nanoparticle complex (DOX-MAC) can be burst by applying high ultrasonic acoustic pressure which leads to the release of DOX from DOX-MAC

Summary

Introduction

Systemic chemotherapy has been proposed as a treatment option for patients with advanced hepatocellular carcinoma (HCC) [1]. Doxorubicin (DOX) is a commonly used cytotoxic agent for the treatment of HCC [2]. Sorafenib (SOR) is one of the molecular-targeted agents with antiangiogenic effects for the treatment of advanced HCC [1]. The combination of SOR and DOX is feasible and effective in enhancing the effects of SOR, but the previous reports have reported shorter overall patient survival and higher toxicity than single-agent therapy [2,3]. For the delivery of a chemotherapeutic agent, doxorubicin-loaded, microbubble-albumin nanoparticle complex (DOX-MAC) can be burst by applying high ultrasonic acoustic pressure which leads to the release of DOX from DOX-MAC. DOXMAC has a potential for in vivo uses for contrast-enhanced ultrasound (CEUS) imaging with MB, which was one of a component, and local delivery of DOX to minimize the toxicity of the chemotherapeutic agent [5]. We evaluated the feasibility of CEUS for the monitoring tool using DOX-MAC or MAC as theragnostic agents

Methods

Results

Conclusion