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

Xue, Shenghui, Yang, Hua, Qiao, Jingjuan, Pu, Fan, Jiang, Jie, Hubbard, Kendra, Hekmatyar, Khan, Langley, Jason, Salarian, Mani, Long, Robert C., Bryant, Robert G., Hu, Xiaoping Philip, Grossniklaus, Hans E., Liu, Zhi-Ren, Yang, Jenny J.
Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.21 pp. 6607-6612
engineering, humans, image analysis, liver, liver neoplasms, magnetic resonance imaging, metastasis, mortality, rats
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.