Abstract
Early diagnosis and noninvasive detection of liver fibrosis and its heterogeneity remain as major unmet medical needs for stopping further disease progression toward severe clinical consequences. Here we report a collagen type I targeting protein-based contrast agent (ProCA32.collagen1) with strong collagen I affinity. ProCA32.collagen1 possesses high relaxivities per particle (r1 and r2) at both 1.4 and 7.0 T, which enables the robust detection of early-stage (Ishak stage 3 of 6) liver fibrosis and nonalcoholic steatohepatitis (Ishak stage 1 of 6 or 1 A Mild) in animal models via dual contrast modes. ProCA32.collagen1 also demonstrates vasculature changes associated with intrahepatic angiogenesis and portal hypertension during late-stage fibrosis, and heterogeneity via serial molecular imaging. ProCA32.collagen1 mitigates metal toxicity due to lower dosage and strong resistance to transmetallation and unprecedented metal selectivity for Gd3+ over physiological metal ions with strong translational potential in facilitating effective treatment to halt further chronic liver disease progression.
Highlights
Diagnosis and noninvasive detection of liver fibrosis and its heterogeneity remain as major unmet medical needs for stopping further disease progression toward severe clinical consequences
Nonalcoholic steatohepatitis (NASH) and hepatic fibrosis can develop in patients with any type of chronic liver disease (CLD), including alcoholic liver disease, hepatitis C, hepatitis B, Nonalcoholic fatty liver disease (NAFLD) and autoimmune hepatitis
We report the development of a protein Magnetic resonance imaging (MRI) contrast agent (ProCA) based on rat α-parvalbumin expressed in Escherichia coli for molecular imaging of collagen I levels (ProCA32.collagen1) in three models of CLDs23
Summary
Diagnosis and noninvasive detection of liver fibrosis and its heterogeneity remain as major unmet medical needs for stopping further disease progression toward severe clinical consequences. Tremendous effort has been devoted to the development of noninvasive imaging techniques associated with fibrosis and NASH, such as ultrasound; MR apparent diffusion coefficient (ADC); magnetic resonance elastography (MRE); T1, T2, relaxation in the rotating frame (T1ƿ)[13]; magnetization transfer[14]; and proton density fat fraction. These techniques cannot provide accurate detection of early stage liver fibrosis and NASH
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