Multi-b-value DWI to evaluate the synergistic antiproliferation and anti-heterogeneity effects of bufalin plus sorafenib in an orthotopic HCC model

Abstract Background Multi- b -value diffusion-weighted imaging (DWI) with different postprocessing models allows for evaluating hepatocellular carcinoma (HCC) proliferation, spatial heterogeneity, and feasibility of treatment strategies. We assessed synergistic effects of bufalin+sorafenib in orthotopic HCC-LM3 xenograft nude mice by using intravoxel incoherent motion (IVIM), diffusion kurtosis imaging (DKI), a stretched exponential model (SEM), and a fractional-order calculus (FROC) model. Methods Twenty-four orthotopic HCC-LM3 xenograft mice were divided into bufalin+sorafenib, bufalin, sorafenib treatment groups, and a control group. Multi- b -value DWI was performed using a 3-T scanner after 3 weeks’ treatment to obtain true diffusion coefficient D t , pseudo-diffusion coefficient D p , perfusion fraction f , mean diffusivity (MD), mean kurtosis (MK), distributed diffusion coefficient (DDC), heterogeneity index α , diffusion coefficient D, fractional order parameter β , and microstructural quantity μ . Necrotic fraction (NF), standard deviation (SD) of hematoxylin-eosin staining, and microvessel density (MVD) of anti-CD31 staining were evaluated. Correlations of DWI parameters with histopathological results were analyzed, and measurements were compared among four groups. Results In the final 22 mice, f positively correlated with MVD ( r = 0.679, p = 0.001). Significantly good correlations of MK ( r = 0.677), α ( r = -0.696), and β ( r = -0.639) with SD were observed (all p < 0.010). f , MK, MVD, and SD were much lower, while MD, α , β , and NF were higher in bufalin plus sorafenib group than control group (all p < 0.050). Conclusion Evaluated by IVIM, DKI, SEM, and FROC, bufalin+sorafenib was found to inhibit tumor proliferation and angiogenesis and reduce spatial heterogeneity in HCC-LM3 models. Relevance statement Multi- b- value DWI provides potential metrics for evaluating the efficacy of treatment in HCC. Key points • Bufalin plus sorafenib combination may increase the effectiveness of HCC therapy. • Multi- b -value DWI depicted HCC proliferation, angiogenesis, and spatial heterogeneity. • Multi- b -value DWI may be a noninvasive method to assess HCC therapeutic efficacy. Graphical Abstract