Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging

Abstract

With available MRI techniques, primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents without Gd 3+ toxicity. We have developed a protein contrast agent (ProCA32) that exhibits high stability for Gd 3+ and a 10 11 -fold greater selectivity for Gd 3+ over Zn 2+ compared with existing contrast agents. ProCA32, modified from parvalbumin, possesses high relaxivities (r 1 /r 2 : 66.8 mmol −1 ·s −1 / 89.2 mmol −1 ·s −1 per particle). Using T 1 -and T 2 -weighted, as well as T 2 /T 1 ratio imaging, we have achieved, for the first time (to our knowledge), robust MRI detection of early liver metastases as small as ∼0.24 mm in diameter, much smaller than the current detection limit of 10-20 mm. Furthermore, ProCA32 exhibits appropriate in vivo preference for liver sinusoidal spaces and pharmacokinetics for high-quality imaging. ProCA32 will be invaluable for noninvasive early detection of primary and metastatic liver cancers as well as for monitoring treatment and guiding therapeutic interventions, including drug delivery.MRI | uveal melanoma | metastasis | contrast agents | T 2 /T 1 ratio imaging T umor metastasis is the main cause of nearly all human cancerrelated deaths. Liver is a common site for metastases of a variety of cancers, including melanoma, breast, pancreatic, and colon cancers (1, 2). For example, uveal melanoma, the most common primary intraocular tumor, has a 40% risk of metastasizing to the liver within 10 y of diagnosis of the primary tumor. Hepatic metastases, which occur in 95% of patients with uveal melanoma metastasis, result in death in almost all cases. This high death rate is related to the recognition of liver metastasis at a late clinical stage (at stage II or later in the TNM system) in which the metastatic uveal melanoma is resistant to currently available systemic chemotherapies (3, 4). The liver may also give rise to primary tumors such as hepatocellular carcinoma (HCC), which is the most common primary malignancy worldwide (5). However, currently there is no reliable way to detect primary liver cancer and hepatic metastases at early stages with high sensitivity and specificity.MRI is a widely used clinical imaging modality that provides exquisite soft-tissue contrast without using ionizing radiation (6, 7). More than 35% of MRI scans use MRI contrast agents, particularly paramagnetic gadolinium (Gd 3+ )-based contrast agents, which shorten T 1 and lead to an increase in MRI intensity (8). All clinically approved Gd 3+ -containing contrast agents are based on small chelators with relaxivity (r 1 and r 2 ) values around 4-6 mM −1 ·s −1 . Their low relaxivities severely limit the sensitivity of current MR imaging methods with respect to detection of lesions and treatment planning and monitoring. Repeat MRI scans are frequently requested for patients with ambiguous small lesions and are used as a routine follow-up modality for highrisk patients, but t...

Reduction of Nodular Growth Pattern of Metastatic Uveal Melanoma after Radioembolization of Hepatic Metastases

“…Through determination of the tumor doubling time, investigators have hypothesized that the seeding of liver micrometastases likely precedes recognition of the primary uveal tumor [10]. Recently, histological work demonstrating quiescent, avascular micrometastases in liver specimens has offered credence to this theory; however, at this early stage, these tiny metastases are undetectable on MRI using conventional contrast agents [11,12]. …”

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“…Efforts to improve relaxivity have focused on identifying proteins with higher-spin metals, including Mn 2+ [10], and exchanging natural metals with higher-spin alternatives including Mn 2+ and Gd 3+ [14, 15]. In theory, if appropriate proteins can be engineered, and issues with metal bioavailability can be solved, the molecular sensitivity could improve, especially for imaging conducted at lower field strengths [16].…”

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“…Some of the Gd(III) protein complexes possess high T 1 relaxivities in the range of 25 - 50 mM −1 s −1 per Gd at 1.4T [23–25]. Targeted contrast agents based on the Gd(III) protein complexes are able to generate significant signal enhancement for tumor detection with a dose as low as 25 μmol/kg.…”