Abstract
Objective: A molecular dynamics approach to understanding fundamental mechanisms of combined thermal and osmotic stress induced by thermochemical ablation (TCA) is presented.Methods: Structural models of fibronectin and fibronectin bound to its integrin receptor provide idealized models for the effects of thermal and osmotic stress in the extracellular matrix. Fibronectin binding to integrin is known to facilitate cell survival. The extracellular environment produced by TCA at the lesion boundary was modelled at 37 °C and 43 °C with added sodium chloride (NaCl) concentrations (0, 40, 80, 160, and 320 mM). Atomistic simulations of solvated proteins were performed using the GROMOS96 force field and TIP3P water model. Computational results were compared with the results of viability studies of human hepatocellular carcinoma (HCC) cell lines HepG2 and Hep3B under matching thermal and osmotic experimental conditions.Results: Cell viability was inversely correlated with hyperthermal and hyperosmotic stresses. Added NaCl concentrations were correlated with a root mean square fluctuation increase of the fibronectin arginylglycylaspartic acid (RGD) binding domain. Computed interaction coefficients demonstrate preferential hydration of the protein model and are correlated with salt-induced strengthening of hydrophobic interactions. Under the combined hyperthermal and hyperosmotic stress conditions (43 °C and 320 mM added NaCl), the free energy change required for fibronectin binding to integrin was less favorable than that for binding under control conditions (37 °C and 0 mM added NaCl).Conclusion: Results quantify multiple measures of structural changes as a function of temperature increase and addition of NaCl to the solution. Correlations between cell viability and stability measures suggest that protein aggregates, non-functional proteins, and less favorable cell attachment conditions have a role in TCA-induced cell stress.
Highlights
Ablation and embolization are the two most common minimally invasive methods of treating unresectable hepatocellular carcinoma (HCC)
We focus on the extracellular matrix (ECM) protein fibronectin and integrin, the cell surface receptor for fibronectin, which is known to facilitate cell spreading, survival, and proliferation
Cell viability was correlated with salt concentration for each cell line
Summary
Ablation and embolization are the two most common minimally invasive methods of treating unresectable hepatocellular carcinoma (HCC). Residual tumor is present for 90% of nodules treated with embolization [3]. Thermochemical ablation (TCA) provides a novel conceptual platform for minimally invasive therapy of HCC. An acid and base are mixed immediately prior to injection into the target tissue. Heat is released as the solutions react exothermally after mixing directly prior to entering the targeted tissue as a hot salt solution [9]. TCA using a 10 M combination of acid and base has been shown sufficient to coagulate a 18.9-ml volume of blood perfused tissue in vivo animal models [10]. By-products of the reaction create a locally toxic high salt concentration environment that may synergistically increase the diameter of the lethal zone of this therapy as well as serve as a local diffusion reservoir to decrease the risk of local recurrence
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