Gadolinium-free extracellular MR contrast agent for tumor imaging.

PURPOSE: To evaluate a new formulation of manganese porphyrin as a potential gadolinium (Gd)-free extracellular magnetic resonance imaging (MRI) contrast agent for dynamic contrast-enhanced (DCE) MRI of tumors. MATERIALS AND METHODS: A previously reported new contrast agent, MnTCP, was evaluated in six female tumor-bearing nude rats. MRI was performed on a 3 T clinical scanner 3 to 4 weeks after inoculation of breast tumor cells in the mammary fat pads. Gd-DTPA was injected intravenously, followed by injection of MnTCP at least 2 hours later (both at 0.05 mmol/kg). T1 relaxation time measurements and DCE-MRI were performed. RESULTS: Enhancement and clearance patterns were visually similar between MnTCP and Gd-DTPA. However, relative R1 increases in all 11 tumors were larger for MnTCP over 60 minutes postcontrast, the difference being significant as late as 20 minutes (R1post /R1pre = 1.42 ± 0.15 for MnTCP vs. 1.20 ± 0.08 for Gd-DTPA, P < 0.05). R1 -related effects for MnTCP were largely reduced after 60 minutes (R1post /R1pre = 1.13 ± 0.07) and completely gone within 24 hours (R1post /R1pre = 0.97 ± 0.06). DCE-MRI revealed a consistently larger (1.5 to over 2-fold) peak enhancement and higher values of the steepest slope, time-to-peak, and AUC60 in all tumors with MnTCP (P < 0.01). CONCLUSION: MnTCP is an alternative to extracellular Gd agents for tumor imaging, offering sensitive detection and rapid renal clearance.

Establishment of a lung metastatic breast tumor xenograft model in nude rats.

OBJECTIVE: Larger animal models provide relevant tumor burden in the development of advanced clinical imaging methods for non-invasive cancer detection and diagnosis, and are especially valuable for studying metastatic disease. Most available experimental models, however, are based on immune-compromised mice. To lay the foundation for studying spontaneous metastasis using non-invasive magnetic resonance imaging (MRI), this study aims to establish a highly metastatic breast cancer xenograft model in nude rats. MATERIALS AND METHODS: A highly metastatic variant of human adenocarcinoma MDA-MB-231 known as LM2 was inoculated into nude rats. Orthotopic and subcutaneous (flank) sites were compared, with half of the orthotopic injections guided by ultrasound imaging. MRI with gadolinium contrast administration was performed weekly beginning on Day 6 and ending on Day 104. Excised tumors were assessed on histology using hematoxylin and eosin and CD34. Fisher's exact test was used to compare successful tumor induction amongst different inoculation methods. RESULTS: Primary LM2 tumors were established orthotopically in all cases under ultrasound-guided injection, and none otherwise (p = 0.0028). Contrast-enhanced MRI revealed rapidly progressing tumors that reached critical size (15 mm diameter) in 2 to 3 weeks after inoculation. MRI and histology findings were consistent: LM2 tumors were characterized by low vascularity confined to the tumor rim and large necrotic cores with increasing interstitial fluid pressure. CONCLUSIONS: The metastatic LM2 breast tumor model was successfully established in the mammary fat pads of nude rats, using ultrasound needle guidance as a non-invasive alternative to surgery. This platform lays the foundation for future development and application of MRI to study spontaneous metastasis and different stages throughout the metastatic cascade.

Noninvasive manganese-enhanced magnetic resonance imaging for early detection of breast cancer metastatic potential.

Cancer cells with a high metastatic potential will more likely escape and form distant tumors. Once the cancer has spread, a cure is rarely possible. Unfortunately, metastasis often proceeds unnoticed until a secondary tumor has formed. The culprit is that current imaging-based cancer screening and diagnosis are limited to assessing gross physical changes, not the earliest cellular changes that drive cancer progression. The purpose of this study is to develop a novel noninvasive magnetic resonance (MR) cellular imaging capability for characterizing the metastatic potential of breast cancer and enable early cancer detection. This MR method relies on imaging cell uptake of manganese, an endogenous calcium analogue and an MR contrast agent, to detect aggressive cancer cells. Studies on normal breast epithelial cells and three breast cancer cell lines, from nonmetastatic to highly metastatic, demonstrated that aggressive cancer cells appeared significantly brighter on MR as a result of altered cell uptake of manganese. In vivo results in nude rats showed that aggressive tumors that are otherwise unseen on conventional gadolinium-enhanced MR imaging are detected after manganese injection. This cellular MR imaging technology brings a critically needed, unique dimension to cancer imaging by enabling us to identify and characterize metastatic cancer cells at their earliest appearance.

Ultrashort echo time for improved positive-contrast manganese-enhanced MRI of cancer.

OBJECTIVE: Manganese (Mn) is a positive magnetic resonance imaging (MRI) contrast agent that has been used to obtain physiological, biochemical, and molecular biological information. There is great interest to broaden its applications, but a major challenge is to increase detection sensitivity. Another challenge is distinguishing regions of Mn-related signal enhancement from background tissue with inherently similar contrast. To overcome these limitations, this study investigates the use of ultrashort echo time (UTE) and subtraction UTE (SubUTE) imaging for more sensitive and specific determination of Mn accumulation. MATERIALS AND METHODS: Simulations were performed to investigate the feasibility of UTE and SubUTE for Mn-enhanced MRI and to optimize imaging parameters. Phantoms containing aqueous Mn solutions were imaged on a MRI scanner to validate simulations predictions. Breast cancer cells that are very aggressive (MDA-MB-231 and a more aggressive variant LM2) and a less aggressive cell line (MCF7) were labeled with Mn and imaged on MRI. All imaging was performed on a 3 Tesla scanner and compared UTE and SubUTE against conventional T1-weighted spoiled gradient echo (SPGR) imaging. RESULTS: Simulations and phantom imaging demonstrated that UTE and SubUTE provided sustained and linearly increasing positive contrast over a wide range of Mn concentrations, whereas conventional SPGR displayed signal plateau and eventual decrease. Higher flip angles are optimal for imaging higher Mn concentrations. Breast cancer cell imaging demonstrated that UTE and SubUTE provided high sensitivity, with SubUTE providing background suppression for improved specificity and eliminating the need for a pre-contrast baseline image. The SubUTE sequence allowed the best distinction of aggressive breast cancer cells. CONCLUSIONS: UTE and SubUTE allow more sensitive and specific positive-contrast detection of Mn enhancement. This imaging capability can potentially open many new doors for Mn-enhanced MRI in vascular, cellular, and molecular imaging.