Early Detection and Staging of Lung Fibrosis Enabled by Collagen-Targeted MRI Protein Contrast Agent.

Chronic lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), are major leading causes of death worldwide and are generally associated with poor prognoses. The heterogeneous distribution of collagen, mainly type I collagen associated with excessive collagen deposition, plays a pivotal role in the progressive remodeling of the lung parenchyma to chronic exertional dyspnea for both IPF and COPD. To address the pressing need for noninvasive early diagnosis and drug treatment monitoring of pulmonary fibrosis, we report the development of human collagen-targeted protein MRI contrast agent (hProCA32.collagen) to specifically bind to collagen I overexpressed in multiple lung diseases. When compared to clinically approved Gd3+ contrast agents, hProCA32.collagen exhibits significantly better r1 and r2 relaxivity values, strong metal binding affinity and selectivity, and transmetalation resistance. Here, we report the robust detection of early and late-stage lung fibrosis with stage-dependent MRI signal-to-noise ratio (SNR) increase, with good sensitivity and specificity, using a progressive bleomycin-induced IPF mouse model. Spatial heterogeneous mapping of usual interstitial pneumonia (UIP) patterns with key features closely mimicking human IPF, including cystic clustering, honeycombing, and traction bronchiectasis, were noninvasively detected by multiple MR imaging techniques and verified by histological correlation. We further report the detection of fibrosis in the lung airway of an electronic cigarette-induced COPD mouse model, using hProCA32.collagen-enabled precision MRI (pMRI), and validated by histological analysis. The developed hProCA32.collagen is expected to have strong translational potential for the noninvasive detection and staging of lung diseases, and facilitating effective treatment to halt further chronic lung disease progression.

Non-invasive detection and complementary diagnosis of liver metastases via chemokine receptor 4 imaging.

Noninvasive detection of early-stage liver metastases from different primary cancers is a pressing unmet medical need. The lack of both molecular biomarkers and the sensitive imaging methodology makes the detection challenging. In this study, we observed the elevated expression of chemokine receptor 4 (CXCR4) in uveal melanoma (UM) patient liver tissues, and high CXCR4 expression in liver metastases of UM murine models, regardless of the expression levels in the primary tumors. Based on these findings, we identified CXCR4 as an imaging biomarker and exploited a CXCR4-targeted MRI contrast agent ProCA32.CXCR4 for molecular MRI imaging. ProCA32.CXCR4 has strong CXCR4 binding affinity, high metal selectivity, and r1 and r2 relaxivities, which enables the sensitive detection of liver micrometastases. The MRI imaging capacity for detecting liver metastases was demonstrated in three UM models and one ovarian cancer model. The imaging results were validated by histological and immunohistochemical analysis. ProCA32.CXCR4 has strong potential clinical application for non-invasive diagnosis of liver metastases.

Visions by Women in Molecular Imaging Network: Antiracism and Allyship in Action.

Recent events in America in 2020 have stimulated a worldwide movement to dismantle anti-Black racism in all facets of our lives. Anti-Black racism is, as defined by the Movement for Black Lives, a "term used to specifically describe the unique discrimination, violence, and harm imposed on and impacting Black people specifically." In science, technology, engineering, and mathematics (STEM), we have yet to achieve the goal and responsibility to ensure that the field reflects the diversity of our lived experiences. Members of the Women in Molecular Imaging Network (WIMIN) have come together to take a stand on diversity, equity, and inclusion in the field of molecular imaging. We strongly condemn oppression in all its forms and strive to identify and dismantle barriers that lead to inequities in the molecular imaging community and STEM as a whole. In this series coined "Visions" (Antiracism and Allyship in Action), we identify and discuss specific actionable items for improving diversity and representation in molecular imaging and ensuring inclusion of all members of the community, inclusive of race, disability, ethnicity, religion, or LGBTQ+ identity. Although the issues highlighted here extend to other under-recruited and equity-seeking groups, for this first article, we are focusing on one egregious and persistent form of discrimination: anti-Black racism. In this special article, Black women residing in America present their lived experiences in the molecular imaging field and give candid insights into the challenges, frustrations, and hopes of our Black friends and colleagues. While this special article focuses on the experiences of Black women, we would like the readers to reflect on their anti-Blackness toward men, transgender, nonbinary, and gender non-conforming people. From the vulnerability we have asked of all our participants, these stories are meant to inspire and invoke active antiracist work among the readership. We present strategies for dismantling systemic racism that research centers and universities can implement in the recruitment, retention, mentorship, and development of Black trainees and professionals. We would like to specifically acknowledge the Black women who took the time to be interviewed, write perspectives, and share their lived experiences in hopes that it will inspire genuine and lasting change.

Molecular imaging of extracellular matrix proteins with targeted probes using magnetic resonance imaging.

The extracellular matrix (ECM) consists of proteins and carbohydrates that supports different biological structures and processes such as tissue development, elasticity, and preservation of organ structure. Diseases involving inflammation, fibrosis, tumor invasion, and injury are all attributed to the transition of the ECM from homeostasis to remodeling, which can significantly change the biochemical and biomechanical features of ECM components. While contrast agents have played an indispensable role in facilitating clinical diagnosis of diseases using magnetic resonance imaging (MRI), there is a strong need to develop novel biomarker-targeted imaging probes for in vivo visualization of biological processes and pathological alterations at a cellular and molecular level, for both early diagnosis and monitoring drug treatment. Herein, we will first review the pathological accumulation and characterization of ECM proteins recognized as important molecular features of diseases. Developments in MRI probes targeting ECM proteins such as collagen, fibronectin, and elastin via conjugation of existing contrast agents to targeting moieties and their applications to various diseases, are also reviewed. We have also reviewed our progress in the development of collagen-targeted protein MRI contrast agent with significant improvement in relaxivity and metal binding specificity, and their applications in early detection of fibrosis and metastatic cancer. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Biology-Inspired Nanomaterials > Peptide-Based Structures Biology-Inspired Nanomaterials > Protein and Virus-Based Structures.

Early detection and staging of chronic liver diseases with a protein MRI contrast agent.

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.

Designing Calcium-Binding Proteins for Molecular MR Imaging.

Early diagnosis, noninvasive detection, and staging of various diseases, remain one of the major clinical barriers to effective medical treatment and prevention of disease progression toward major clinical consequences. Molecular imaging technologies play an indispensable role in the clinical field in overcoming these major barriers. The increasing application of imaging techniques and agents in early detection of different diseases such as cancer has resulted in improved treatment response and clinical patient management. In this chapter we will first introduce criteria for the design and engineering of calcium-binding protein (CaBP) parvalbumin as a protein Gd-MRI contrast agent (ProCA) with unprecedented metal selectivity for Gd3+ over physiological metal ions. We will then discuss the further development of targeted MRI contrast agent for molecular imaging of PSMA biomarker for early detection of prostate cancer.