Abstract. Molecular imaging allows the non-invasive assessment of membrane transporter expression and function in living subjects. Such technologies have the potential to become diagnostic and prognostic tools, allowing detection, localization, and prediction of response of tumors and their metastases to therapy. Beyond tumors, imaging can also help understand the role of transporters in adverse drug effects and drug clearance. Here, we review molecular imaging technologies that monitor transporter-mediated processes. We emphasize emerging probe substrates and potential clinical applications of imaging the function of membrane transporters in cancer.
CD55 (decay-accelerating factor, DAF) is overexpressed in several types of cancer, including colorectal cancer. Because of its inhibitory effect on the complement system, it has been suggested as a possible target for cancer immunotherapy. However, CD55 is also expressed in normal tissues, body fluids and stroma, limiting the use of anti-CD55 therapeutic antibodies. Two novel CD55 splice variants or isoforms have recently been identified. These have been shown to contain part or all of intron 7 (CD55(int7+)), in contrast to the previously identified splice variants (CD55(wt)), which do not contain intron 7. Our aim was to determine the pattern of expression of the CD55(int7+) isoforms in normal and cancer tissues and to compare it to CD55(wt). We found that while CD55's isoforms levels vary directly, CD55(wt) is much more abundant (on average 48 times more) than CD55(int7+). Moreover, colon cancers that express high CD55(wt) mRNA levels tend to upregulate CD55(int7+) to a further extent. Finally, we compared the protein levels of CD55(int7+) to CD55(wt) by immunohistochemistry in various colorectal pathological conditions including neoplasia, and found that the levels of both isoforms were elevated in all types of colonic pathology. These results show that the levels of CD55(int7+) in normal tissue are much lower than CD55(wt), while in tumors it is restricted to the epithelial structures unlike CD55(wt). Thus, CD55(int7+) may be a more suitable target for cancer immunotherapy.
Aim: The multidrug resistance protein 1 (MDR1; P-glycoprotein) has been associated with efflux of chemotherapeutic agents from tumor cells and with poor patient prognosis. This study evaluated the feasibility of non-invasive, non-radioactive near infrared (NIR) imaging methodology for detection of MDR1 functional activity in tumors.Methods: Initial accumulation assays were conducted in MDR1-overexpressing MDCK cells (MDCK-MDR1) and control MDCK cells (MDCK-CT) using the NIR dyes indocyanine green (ICG), IR-783, IR-775, rhodamine 800, XenoLight DiR, and Genhance 750, at 0.4 μM–100 μM. ICG and IR-783 were also evaluated in HT-29 cells in which MDR1 overexpression was induced by colchicine (HT-29-MDR1) and their controls (HT-29-CT). In vivo optical imaging studies were conducted using immunodeficient mice bearing HT-29-CT and HT-29-MDR1 xenografts.Results: ICG’s emission intensity was 2.0- and 2.2-fold higher in control versus MDR1-overexpressing cells, in MDCK and HT-29 cell lines, respectively. The respective IR-783 control:MDR1 ratio was 1.4 in both MDCK and HT-29 cells. Optical imaging of mice bearing HT-29-CT and HT-29-MDR1 xenografts revealed a statistically non-significant, 1.7-fold difference (p > 0.05) in ICG emission intensity between control and MDR1 tumors. No such differences were observed with IR-783.Conclusion: ICG and IR-783 appear to be weak MDR1 substrates. In vivo, low sensitivity and high between-subject variability impair the ability to use the currently studied probes as markers of tumor MDR1 activity. The results suggest that, for future use of this technology, additional NIR probes should be screened as MDR1 substrates.
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