Dynamic dual-tracer MRI-guided fluorescence tomography to quantify receptor density in vivo

Abstract

The up-regulation of cell surface receptors has become a central focus in personalized cancer treatment; however, because of the complex nature of contrast agent pharmacokinetics in tumor tissue, methods to quantify receptor binding in vivo remain elusive. Here, we present a dual-tracer optical technique for noninvasive estimation of specific receptor binding in cancer. A multispectral MRI-coupled fluorescence molecular tomography system was used to image the uptake kinetics of two fluorescent tracers injected simultaneously, one tracer targeted to the receptor of interest and the other tracer a nontargeted reference. These dynamic tracer data were then fit to a dual-tracer compartmental model to estimate the density of receptors available for binding in the tissue. Applying this approach to mice with deep-seated gliomas that overexpress the EGF receptor produced an estimate of available receptor density of 2.3 ± 0.5 nM (n = 5), consistent with values estimated in comparative invasive imaging and ex vivo studies.

Tomography of epidermal growth factor receptor binding to fluorescent Affibodyin vivostudied with magnetic resonance guided fluorescence recovery in varying orthotopic glioma sizes

“…This tumor line was chosen because it is known to overexpress EGFR, enabling specific targeting using an engineered peptide with high affinity for EGFR, the anti-EGFR targeted Affibody (Affibody, Sweden). 3,[13][14][15] Transfection of the cell line with GFP allows the GFP signal to be measured ex vivo and provides definitive tumor localization. 16 The growth of the tumors was monitored using gadoliniumenhanced T1-weighted magnetic resonance imaging (MRI), which was also the method used to gather anatomical prior information for fluorescence tomography.…”

“…The mice to be imaged were injected via tail vein with 0.1 nmol of each tracer and imaged continuously over the course of ∼1 h, after which time each animal was sacrificed and then imaged ex vivo. The fluorescence tomography system used for imaging has been previously described, 3,13 so only the salient details that differ from previous work will be discussed here. For IRDye800, the excitation was performed with a 690-nm diode laser providing 0.8 mW output at the tissue surface, and the necessary filtering on the emission side was accomplished using 720-nm low pass (LP) filters located inside a custom entrance optic for each of the eight spectrometers used for detection.…”

“…Recently, a novel dual-tracer technique was introduced to overcome the problem of nonspecific uptake in molecular imaging and, thus, enable quantitative estimation of receptor concentration in vivo. [1][2][3] In this approach, two tracers are imaged simultaneously, one targeted to the receptor of interest and the other a nontargeted reference tracer. Comparing the uptake of these dyes enables recovery of binding potential, BP, a quantitative parameter proportional to the concentration of receptors available for binding.…”

“…While the first orthotopic study to report on this technique reported dual-tracer tomography imaging, 3 it did not examine the effect of tumor size on recovery of BP. As tumors grow, the feeding vessels and neovasculature growth and leakage are extremely heterogeneous, and it is conceivable that within the regions of tumors the ability to quantify BP will be compromised by this.…”

Self-prior strategy for organ reconstruction in fluorescence molecular tomography

“…From the methodological aspect, more reliable algorithms will be developed for accurate and stable self-prior information extraction. For biomedical applications, the proposed strategy can be combined with DFMT and multispectral FMT [5,23,24] to achieve dynamic and real-time metabolic imaging of organs in vivo. In the present study, only liver has been selected as the objective organ to be reconstructed, which has limited utility in terms of biological applications.…”