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MRI detection of breast cancer micrometastases with a fibronectin-targeting contrast agent.

Zhou Z, Qutaish M, Han Z, Schur RM, Liu Y, Wilson DL, Lu ZR - Nat Commun (2015)

Bottom Line: Early detection of high-risk breast cancer, including micrometastasis, is critical in tailoring appropriate and effective interventional therapies.We find that CREKA-Tris(Gd-DOTA)3 provides robust contrast enhancement in the metastatic tumours and enables the detection of micrometastases of size <0.5 mm, extending the detection limit of the current clinical imaging modalities.These results demonstrate that molecular MRI with CREKA-Tris(Gd-DOTA)3 may facilitate early detection of high-risk breast cancer and micrometastasis in the clinic.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA [2] Center for Bionanoengineering and State Key Laboratory of Chemical Engineering, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027 China.

ABSTRACT
Metastasis is the primary cause of death in breast cancer patients. Early detection of high-risk breast cancer, including micrometastasis, is critical in tailoring appropriate and effective interventional therapies. Increased fibronectin expression, a hallmark of epithelial-to-mesenchymal transition, is associated with high-risk breast cancer and metastasis. We have previously developed a penta-peptide CREKA (Cys-Arg-Glu-Lys-Ala)-targeted gadolinium-based magnetic resonance imaging (MRI) contrast agent, CREKA-Tris(Gd-DOTA)3 (Gd-DOTA (4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecyl gadolinium), which binds to fibrin-fibronectin complexes that are abundant in the tumour microenvironment of fast-growing breast cancer. Here we assess the capability of CREKA-Tris(Gd-DOTA)3 to detect micrometastasis with MRI in co-registration with high-resolution fluorescence cryo-imaging in female mice bearing metastatic 4T1 breast tumours. We find that CREKA-Tris(Gd-DOTA)3 provides robust contrast enhancement in the metastatic tumours and enables the detection of micrometastases of size <0.5 mm, extending the detection limit of the current clinical imaging modalities. These results demonstrate that molecular MRI with CREKA-Tris(Gd-DOTA)3 may facilitate early detection of high-risk breast cancer and micrometastasis in the clinic.

No MeSH data available.


Related in: MedlinePlus

MRI of spontaneous metastases in mice with orthotopic implant of 4T1–GFP-Luc2 breast cancer cells.(a) MRI and fluorescence cryo-imaging of cancer metastasis in mouse bearing metastasis, 40 days after cell inoculation in the mammary fat pad. (b) Representative sections showing whole-body co-registration of MRI and fluorescence cryo-images (arrows indicate metastases, auto-fluorescence from intestine and stomach is masked; Scale bars, 10 mm). (c) The co-registration quality of MRI and cryo-images. (d) Representative co-registered MRI (post-injected with the targeted contrast agent) and cryo-images of micrometastases in different organs or tissues (Scale bars, 1 mm).
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f6: MRI of spontaneous metastases in mice with orthotopic implant of 4T1–GFP-Luc2 breast cancer cells.(a) MRI and fluorescence cryo-imaging of cancer metastasis in mouse bearing metastasis, 40 days after cell inoculation in the mammary fat pad. (b) Representative sections showing whole-body co-registration of MRI and fluorescence cryo-images (arrows indicate metastases, auto-fluorescence from intestine and stomach is masked; Scale bars, 10 mm). (c) The co-registration quality of MRI and cryo-images. (d) Representative co-registered MRI (post-injected with the targeted contrast agent) and cryo-images of micrometastases in different organs or tissues (Scale bars, 1 mm).

Mentions: We next evaluated the ability of molecular MRI with CREKA-Tris(Gd-DOTA)3 in imaging micrometastases spontaneously developed in mice bearing orthotopic 4T1–GFP-Luc2 breast cancer xenografts in the mammary fat pad in co-registration with high-resolution fluorescence cryo-imaging (Fig. 6a). This metastatic tumour model closely mimics the physiological symptoms of naturally developed breast cancer metastases23738. Metastatic tumours formed in the mice after the primary tumors were surgically excised39. High-resolution 3D MR images, which were contrast-enhanced by CREKA-Tris(Gd-DOTA)3, were acquired and co-registered with fluorescence cryo-images of both GFP and CREKA-Cy5.0. Representative co-registration of the contrast-enhanced MR images and cryo-images of bright-field and fluorescent channels are shown in Fig. 6b. A high quality of co-registration was achieved, because there was <100 μm difference between the MRI and cryo-images (Fig. 6c). The targeted contrast agent provided strong contrast enhancement in the metastases (Fig. 6b). Most of the micrometastases labelled with GFP were detected by MRI with CREKA-Tris(Gd-DOTA)3. Fluorescence cryo-imaging had the resolution and sensitivity to detect a single GFP-labelled metastatic cancer cell and was able to detect all micrometastases expressing GFP, while molecular MRI was limited by its resolution in detecting the smallest metastases. These metastases were also recognized by CREKA-Cy5.0, as shown in red in the cryo-images, further validating the effectiveness of molecular MRI. Figure 6d shows contrast-enhanced MR images of micrometastases validated by the whole-body image co-registration with both GFP and Cy5.0 fluorescence cryo-imaging. CREKA-Tris(Gd-DOTA)3 was able to produce robust contrast enhancement in the MR images of micrometastases as small as 0.125 mm3, which enabled the detection of micrometastases in the lung, liver, bone marrow, lymph nodes and other distant organs (Fig. 6d).


MRI detection of breast cancer micrometastases with a fibronectin-targeting contrast agent.

Zhou Z, Qutaish M, Han Z, Schur RM, Liu Y, Wilson DL, Lu ZR - Nat Commun (2015)

MRI of spontaneous metastases in mice with orthotopic implant of 4T1–GFP-Luc2 breast cancer cells.(a) MRI and fluorescence cryo-imaging of cancer metastasis in mouse bearing metastasis, 40 days after cell inoculation in the mammary fat pad. (b) Representative sections showing whole-body co-registration of MRI and fluorescence cryo-images (arrows indicate metastases, auto-fluorescence from intestine and stomach is masked; Scale bars, 10 mm). (c) The co-registration quality of MRI and cryo-images. (d) Representative co-registered MRI (post-injected with the targeted contrast agent) and cryo-images of micrometastases in different organs or tissues (Scale bars, 1 mm).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557274&req=5

f6: MRI of spontaneous metastases in mice with orthotopic implant of 4T1–GFP-Luc2 breast cancer cells.(a) MRI and fluorescence cryo-imaging of cancer metastasis in mouse bearing metastasis, 40 days after cell inoculation in the mammary fat pad. (b) Representative sections showing whole-body co-registration of MRI and fluorescence cryo-images (arrows indicate metastases, auto-fluorescence from intestine and stomach is masked; Scale bars, 10 mm). (c) The co-registration quality of MRI and cryo-images. (d) Representative co-registered MRI (post-injected with the targeted contrast agent) and cryo-images of micrometastases in different organs or tissues (Scale bars, 1 mm).
Mentions: We next evaluated the ability of molecular MRI with CREKA-Tris(Gd-DOTA)3 in imaging micrometastases spontaneously developed in mice bearing orthotopic 4T1–GFP-Luc2 breast cancer xenografts in the mammary fat pad in co-registration with high-resolution fluorescence cryo-imaging (Fig. 6a). This metastatic tumour model closely mimics the physiological symptoms of naturally developed breast cancer metastases23738. Metastatic tumours formed in the mice after the primary tumors were surgically excised39. High-resolution 3D MR images, which were contrast-enhanced by CREKA-Tris(Gd-DOTA)3, were acquired and co-registered with fluorescence cryo-images of both GFP and CREKA-Cy5.0. Representative co-registration of the contrast-enhanced MR images and cryo-images of bright-field and fluorescent channels are shown in Fig. 6b. A high quality of co-registration was achieved, because there was <100 μm difference between the MRI and cryo-images (Fig. 6c). The targeted contrast agent provided strong contrast enhancement in the metastases (Fig. 6b). Most of the micrometastases labelled with GFP were detected by MRI with CREKA-Tris(Gd-DOTA)3. Fluorescence cryo-imaging had the resolution and sensitivity to detect a single GFP-labelled metastatic cancer cell and was able to detect all micrometastases expressing GFP, while molecular MRI was limited by its resolution in detecting the smallest metastases. These metastases were also recognized by CREKA-Cy5.0, as shown in red in the cryo-images, further validating the effectiveness of molecular MRI. Figure 6d shows contrast-enhanced MR images of micrometastases validated by the whole-body image co-registration with both GFP and Cy5.0 fluorescence cryo-imaging. CREKA-Tris(Gd-DOTA)3 was able to produce robust contrast enhancement in the MR images of micrometastases as small as 0.125 mm3, which enabled the detection of micrometastases in the lung, liver, bone marrow, lymph nodes and other distant organs (Fig. 6d).

Bottom Line: Early detection of high-risk breast cancer, including micrometastasis, is critical in tailoring appropriate and effective interventional therapies.We find that CREKA-Tris(Gd-DOTA)3 provides robust contrast enhancement in the metastatic tumours and enables the detection of micrometastases of size <0.5 mm, extending the detection limit of the current clinical imaging modalities.These results demonstrate that molecular MRI with CREKA-Tris(Gd-DOTA)3 may facilitate early detection of high-risk breast cancer and micrometastasis in the clinic.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA [2] Center for Bionanoengineering and State Key Laboratory of Chemical Engineering, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027 China.

ABSTRACT
Metastasis is the primary cause of death in breast cancer patients. Early detection of high-risk breast cancer, including micrometastasis, is critical in tailoring appropriate and effective interventional therapies. Increased fibronectin expression, a hallmark of epithelial-to-mesenchymal transition, is associated with high-risk breast cancer and metastasis. We have previously developed a penta-peptide CREKA (Cys-Arg-Glu-Lys-Ala)-targeted gadolinium-based magnetic resonance imaging (MRI) contrast agent, CREKA-Tris(Gd-DOTA)3 (Gd-DOTA (4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecyl gadolinium), which binds to fibrin-fibronectin complexes that are abundant in the tumour microenvironment of fast-growing breast cancer. Here we assess the capability of CREKA-Tris(Gd-DOTA)3 to detect micrometastasis with MRI in co-registration with high-resolution fluorescence cryo-imaging in female mice bearing metastatic 4T1 breast tumours. We find that CREKA-Tris(Gd-DOTA)3 provides robust contrast enhancement in the metastatic tumours and enables the detection of micrometastases of size <0.5 mm, extending the detection limit of the current clinical imaging modalities. These results demonstrate that molecular MRI with CREKA-Tris(Gd-DOTA)3 may facilitate early detection of high-risk breast cancer and micrometastasis in the clinic.

No MeSH data available.


Related in: MedlinePlus