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

Abstract

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 r 1 and r 2 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.

Protein MRI Contrast Agents as an Effective Approach for Precision Molecular Imaging

“…We have shown that ProCA32 agents exhibit both high r 1 (30 mM −1 s −1 at 1.4 T) and r 2 (42 mM −1 s −1 at 1.4 T) values that were 6-to 10-fold higher than clinically approved CAs at medical field strengths 1.5 T 50,52,59,116 (Fig. 2D).…”

“…It is also important for the agent to reach the molecular biomarkers quickly to facilitate temporal imaging of dynamic molecular contrast enhancement that can provide important data related to disease vessel structure and subtle structural changes. 52,115,116 Fifth, rapid, quick, and complete clearance of the CA can reduce any potential toxicity. The agent should accumulate quickly in the organ/tissue of interest to reduce the waiting period for MRI scanning, followed by fast washout of unbound agent to improve targeted imaging.…”

“…Using O 17 NMR and various biophysical methods, we have also shown that water is at the fast exchange region and τ m is not rate limited. 132 This high relaxivity enabled molecular imaging for early detection of HER2 and GRPR in ovarian cancer, breast cancer, and prostate cancer, in several animal models 52,59,62,115,116,159,162 (Fig. 5).…”

“…1C). 116 The EF-hand 2 Gd(III)-binding site was composed of 5 negatively charged oxygen ligands from carboxy groups of D91, D93, D95, and bidentate E102, as well as carbonyl of K97. A single water molecule bridges the gap between the Gd(III) ion and the oxygen atom from G99 and is shared between the 2 coupled Gd EF-hand-binding sites in each first shell (0.5 each), as determined by Tb(III) luminescence lifetime decay.…”

Construction of Targeting-Peptide-Based Imaging Reagents and Their Application in Bioimaging

“…Magnetic resonance imaging (MRI) has been widely used in clinical diagnostics . MRI is a noninvasive technique with the advantages of having extremely high spatial resolution and the absence of radiation exposure. − This feature allows early detection of even tumors as small as a few hundred cells and hundreds of micrometers in size . However, MRI has low sensitivity and usually requires a contrast agent to increase its sensitivity.…”