Chemokine receptor 4 targeted protein MRI contrast agent for early detection of liver metastases

Abstract

Liver metastases often progress from primary cancers including uveal melanoma (UM), breast, and colon cancer. Molecular biomarker imaging is a new non-invasive approach for detecting early stage tumors. Here, we report the elevated expression of chemokine receptor 4 (CXCR4) in liver metastases in UM patients and metastatic UM mouse models, and development of a CXCR4-targeted MRI contrast agent, ProCA32.CXCR4, for sensitive MRI detection of UM liver metastases. ProCA32.CXCR4 exhibits high relaxivities (r1 = 30.9 mM−1 s−1, r2 = 43.2 mM−1 s−1, 1.5 T; r1 = 23.5 mM−1 s−1, r2 = 98.6 mM−1 s−1, 7.0 T), strong CXCR4 binding (Kd = 1.10 ± 0.18 μM), CXCR4 molecular imaging capability in metastatic and intrahepatic xenotransplantation UM mouse models. ProCA32.CXCR4 enables detecting UM liver metastases as small as 0.1 mm3. Further development of the CXCR4-targeted imaging agent should have strong translation potential for early detection, surveillance, and treatment stratification of liver metastases patients.

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

“…We have developed a platform technique to achieve molecular imaging of different biomarkers such as collagen 1 [ 27 , 28 ], prostate-specific membrane antigen (PSMA) [ 29 ] etc. To achieve CXCR4 targeted molecular MRI imaging, we incorporated a CXCR4 targeting moiety into a protein scaffold ProCA32 [ 30 ], and ProCA32.CXCR4 [ 31 ] (Fig. 4A ).…”

Recent advances in development of dendritic polymer‐based nanomedicines for cancer diagnosis

“…Dendritic polymers, including dendrons, dendrimers, hyperbranched polymers, dendrigraft polymers and other dendritic hybrid polymers (Cook & Perrier, 2020), have emerged to deliver imaging probes or function as imaging reporters (El‐Betany et al, 2020; Jin et al, 2018; Y. Zeng, Li, et al, 2020), as well as capture cancer markers, such as circulating tumor cells (CTCs), cell‐free tumor DNA (ctDNA), and tumor derived exosomes (Bu et al, 2020; J. Dong et al, 2020; Poellmann et al, 2020). The intrinsic physiochemical properties endow the dendritic polymers with unique advantages in cancer diagnosis, and the use of dendritic polymer‐based nanomedicines is of great help in effectively diagnosing early stage tumors and tracking the information on tumor characterization, invasiveness, metastasis, and prognosis (C. Li, Wang, et al, 2020; Tan et al, 2020).…”

“…Dong et al, 2020;Poellmann et al, 2020). The intrinsic physiochemical properties endow the dendritic polymers with unique advantages in cancer diagnosis, and the use of dendritic polymer-based nanomedicines is of great help in effectively diagnosing early stage tumors and tracking the information on tumor characterization, invasiveness, metastasis, and prognosis (C. Tan et al, 2020).…”

Microenvironment-Triggered Degradable Hydrogel for Imaging Diagnosis and Combined Treatment of Intraocular Choroidal Melanoma

“…Human choroidal melanoma (HCM) is a frequently occurring intraocular tumor with a poor therapeutic outcome . Although multimodal therapeutic approaches including chemotherapy and radiotherapy can manipulate localized tumors, there are many patients with HCM that manifest liver metastasis, which leads to primary disease deterioration and delay in treatment. , The main obstacles facing clinical medicine in HCM management are the lack of sensitive and noninvasive imaging modalities for liver metastases and the resistance to broad-spectrum chemotherapies. , Nanotechnology may make more novel avenues for targeted and controlled drug delivery on the enhancement in diagnosis and therapy against HCM. − Optical imaging based on nanomaterials is a convenient method for identifying the tumor position in the therapeutic process by many reports. − Especially, the second near-infrared window (NIR-II) imaging has recently been explored for biological diagnosis in multiple cancer cell lines, − owing to its outstanding characteristics, such as excellent penetration depth and the absence of autofluorescence from biosomes. − Therefore, noninvasive NIR-II imaging diagnosis could be of great value for the search for ophthalmic pathobiology. , …”

“…1 Although multimodal therapeutic approaches including chemotherapy and radiotherapy can manipulate localized tumors, 2 there are many patients with HCM that manifest liver metastasis, which leads to primary disease deterioration and delay in treatment. 3,4 The main obstacles facing clinical medicine in HCM management are the lack of sensitive and noninvasive imaging modalities for liver metastases and the resistance to broad-spectrum chemotherapies. 5,6 Nanotechnology may make more novel avenues for targeted and controlled drug delivery on the enhancement in diagnosis and therapy against HCM.…”