Article

Current limitations of molecular magnetic resonance imaging for tumors as evaluated with high-relaxivity CD105-specific iron oxide nanoparticles.

CT and MR Contrast Media Research, Bayer Pharma AG, Berlin, Germany.
Investigative radiology (Impact Factor: 4.85). 05/2012; 47(7):383-91. DOI:10.1097/RLI.0b013e31824c5a57
Source: PubMed

ABSTRACT Tumor imaging via molecular magnetic resonance imaging (MRI) that uses specific superparamagnetic iron oxide particles (SPIOs) has been addressed in the literature several times in the last 20 years. To our knowledge, none of the reported approaches is currently used for routine clinical diagnostic evaluation, nor are any in clinical development. This raises questions as to whether SPIO-enhanced molecular MRI is sensitive and specific enough for use in clinical practice. The aim of our preclinical study was to investigate the minimum requirements for obtaining sensitive molecular MRI for use in tumor evaluations under optimal conditions. The well-vascularized F9 teratocarcinoma tumor model, which exhibits high levels of the highly accessible target CD105 (endoglin), was used to compare the accumulation and visualization of target-specific SPIOs by MRI.
Superparamagnetic iron oxide particles were optimized in the following ways: (a) proton relaxivity was increased for higher imaging sensitivity, (b) a coating material was used for optimal loading density of the αCD105 antibody, and (c) binding activity to the target CD105 was increased. Binding activity and specificity were confirmed in vitro using enzyme-linked immunosorbent assay and in vivo using pharmacokinetic and biodistribution studies of 11 F9 teratoma-bearing mice together with micro-autoradiography. CD105 target expression was determined using immunohistochemistry and quantitative enzyme-linked immunosorbent assay. The transverse relaxation rate R2* was quantified by 3.0-T MRI in the tumors, kidneys, and muscles before and up to 60 minutes after injection in 11 mice. The use of [Fe]-labeled SPIOs for all in vivo experiments allowed for the direct correlation of the imaging results with SPIO accumulation.
High-relaxivity αCD105-polyacrylic acid-SPIOs (r2 up to 440 L mmol Fe s) with strong binding activity accumulated specifically in tumors (1.4% injected dose/g) and kidneys (4.1% injected dose/g) in a manner dependent on the target concentration. The accumulation occurred within the first 3 minutes after injection. Visualization of specific SPIOs was accomplished with MRI. In contrast to the successful use of MRI in all examined kidneys (mean ± SEM ΔR2*, 61 ± 11 s), only 6 of 11 tumors (mean ± SEM ΔR2*, 15 ± 7 s) showed a clear signal when compared with the control even though optimal conditions were used.
The accumulation of CD105-specific SPIOs in F9 mouse teratomas was robust. However, visualization of the specifically accumulated SPIOs by MRI was not reliable because of its limited signal detection sensitivity. We postulate that it will be challenging to improve the imaging properties of targeted SPIOs further. Therefore, molecular MRI by targeted SPIOs is currently not suitable for clinical tumor imaging using routinely applicable sequences and field strength.

0 0
 · 
0 Bookmarks
 · 
92 Views
  • [show abstract] [hide abstract]
    ABSTRACT: Introduction: Although cancer treatment has evolved substantially in the past decades, cancer-related mortality rates are still increasing. Therapies targeting tumor angiogenesis, crucial for the growth of solid tumors, mainly target vascular endothelial growth factor (VEGF) and have been clinically applied during the last decade. However, these therapies have not met high expectations, which were based on therapeutic efficacy in animal models. This can partly be explained by the upregulation of alternative angiogenic pathways. Therefore, additional therapies targeting other pro-angiogenic pathways are needed. Areas covered: The transforming growth factor (TGF)-β signaling pathway plays an important role in (tumor) angiogenesis. Therefore, components of this pathway are interesting candidates for anti-angiogenic therapy. Endoglin, a co-receptor for various TGF-β family members, is specifically overexpressed in tumor vessels and endoglin expression is associated with metastasis and patient survival. Therefore, endoglin might be a good candidate for anti-angiogenic therapy. In this review, we discuss the potential of using endoglin to target the tumor vasculature for imaging and therapeutic purposes. Expert opinion: Considering the promising results from various in vitro studies, in vivo animal models and the first clinical trial targeting endoglin, we are convinced that endoglin is a valuable tool for the diagnosis, visualization and ultimately treatment of solid cancers.
    Expert opinion on therapeutic targets 01/2013; · 3.72 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Although a considerable amount is known about molecular dysregulations in later stages of tumor progression, much less is known about the regulated processes supporting initial tumor growth. Insight into such processes can provide a fuller understanding of carcinogenesis, with implications for cancer treatment and risk assessment. Work from our laboratory suggests that organized substructure emerges during tumor formation. The goal here was to examine the feasibility of using state-of-the-art differential phase contrast X-ray imaging to investigate density differentials that evolve during early tumor development. To this end the beamline for TOmographic Microscopy and Coherent rAdiology experimenTs (TOMCAT) at the Swiss Light Source was used to examine the time-dependent assembly of substructure in developing tumors. Differential phase contrast (DPC) imaging based on grating interferometry as implemented with TOMCAT, offers sensitivity to density differentials within soft tissues and a unique combination of high resolution coupled with a large field of view that permits the accommodation of larger tissue sizes (1 cm in diameter), difficult with other imaging modalities.
    Radiation Research 10/2013; · 2.70 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The sentinel lymph node (SLN) concept has become standard of care for patients with breast cancer and melanoma, yet its clinical application to other cancer types has been somewhat limited. This is mainly due to the reduced accuracy of conventional SLN mapping techniques (using blue dye and/or radiocolloids as lymphatic tracers) in cancer types where lymphatic drainage is more complex, and SLNs are within close proximity to other nodes or the tumour site. In recent years, many novel techniques for SLN mapping have been developed including fluorescence, x-ray, and magnetic resonant detection. Whilst each technique has its own advantages/disadvantages, the role of targeted contrast agents (for enhanced retention in the SLN, or for immunostaging) is increasing, and may represent the new standard for mapping the SLN in many solid organ tumours. This review article discusses current limitations of conventional techniques, limiting factors of nanoparticulate based contrast agents, and efforts to circumvent these limitations with modern tracer architecture.
    Biotechnology advances 11/2013; · 8.25 Impact Factor

Full-text

View
51 Downloads
Available from
Nov 29, 2012