Optical imaging of tumor microenvironment

Abstract

Tumor microenvironment plays important roles in tumor development and metastasis. Features of the tumor microenvironment that are significantly different from normal tissues include acidity, hypoxia, overexpressed proteases and so on. Therefore, these features can serve as not only biomarkers for tumor diagnosis but also theraputic targets for tumor treatment. Imaging modalities such as optical, positron emission tomography (PET) and magnetic resonance imaging (MRI) have been intensively applied to investigate tumor microenvironment. Various imaging probes targeting pH, hypoxia and proteases in tumor microenvironment were thus well developed. In this review, we will focus on recent examples on fluorescent probes for optical imaging of tumor microenvironment. Construction of these fluorescent probes were based on characteristic feature of pH, hypoxia and proteases in tumor microenvironment. Strategies for development of these fluorescent probes and applications of these probes in optical imaging of tumor cells or tissues will be discussed in this review paper.

Keywords: Optical imaging; hypoxia; pH; protease; tumor microenvironment.

Figure 1

A. Mechanism for activation of pH sensitive Cy dyes. B. Structure of cRGD linked pH activatable Cy dye and its application in optical imaging of orthotopic 4T1/luc tumor, arrows indicated the tumor region. Adapted from reference [15].

Figure 2

A. Design of pH-activatable micellar nanoprobes. B. Different amine groups linked to the micelle backbone to make the nanoprobes activatable at different pH upon protonation of the amine group. C. Fluorescent images of cells treated of pH-activatable nanoprobe with (top panel) or without (bottom panel) the inhibition of lysosomal acidification. Nanoprobe activation was indicated by the red fluorescence signals. Adapted from reference [30].

Figure 3

A. Structure of the dual-labeled carbon nanodot as ratiometric pH nanoprobe. B. Fluorescent images of HeLa cells at pH 6.0, 6.5, 6.8, 7.2, 7.5 and 8.0, respectively. Adapted from reference [32].

Figure 4

A. Chemical structure of ratiometric probe C343-Pro4-BTP. B. Luminescent images of HeLa cells incubated under aerobic and hypoxic conditions. Adapted from reference [39].

Figure 5

A. Chemical structure of 2-nitroimidazoles modified NIR dye Cye. B. In vivo optical imaging of subcutaneous tumors. Adapted from reference [44].

Figure 6

A. Chemical structure of activity-based fluorescent probe LP-1. B. In vivo optical imaging of active legumain using LP-1. Adapted from reference [61].

Figure 7

A. Chemical structure of ANP_FAP. B. In vivo imaging of FAPα in C6 and U87MG tumor-bearing mice. Adapted from reference [69].