Updated developments on molecular imaging and therapeutic strategies directed against necrosis

Abstract

Cell death plays important roles in living organisms and is a hallmark of numerous disorders such as cardiovascular diseases, sepsis and acute pancreatitis. Moreover, cell death also plays a pivotal role in the treatment of certain diseases, for example, cancer. Noninvasive visualization of cell death contributes to gained insight into diseases, development of individualized treatment plans, evaluation of treatment responses, and prediction of patient prognosis. On the other hand, cell death can also be targeted for the treatment of diseases. Although there are many ways for a cell to die, only apoptosis and necrosis have been extensively studied in terms of cell death related theranostics. This review mainly focuses on molecular imaging and therapeutic strategies directed against necrosis. Necrosis shares common morphological characteristics including the rupture of cell membrane integrity and release of cellular contents, which provide potential biomarkers for visualization of necrosis and necrosis targeted therapy. In the present review, we summarize the updated joint efforts to develop molecular imaging probes and therapeutic strategies targeting the biomarkers exposed by necrotic cells. Moreover, we also discuss the challenges in developing necrosis imaging probes and propose several biomarkers of necrosis that deserve to be explored in future imaging and therapy research.

Keywords: Exposed DNA; Molecular imaging; Myocardial infarction; Necrosis avid agents; Solid tumor; Targeted therapy.

Graphical abstract

Figure 1

Chemical structures of some representative small molecule probes targeting necrosis.

Figure 2

(A) Coronal and transversal SPECT/CT images obtained at 4 h post injection of ¹³¹I-Shyp or ¹³¹I-Hyp in rats with reperfused myocardium infarction (MI) or sham operation. (B) TTC staining images (upper panels) and corresponding autoradiographs (under panels) of myocardial sections from rats with MI. Necrotic myocardial areas showed pale, while viable myocardial areas were stained brick red. N, necrotic area; V, viable area (Adapted from Ref. with permission. Copyright © 2017 Elsevier).

Figure 3

(A) Representative coronal SPECT/CT images of rats with reperfused myocardium infarction or sham operation obtained at 6 h post injection of ¹³¹I-rhein or ¹³¹I-Hyp. Red arrows indicate the heart. (B) Postmortem verification in model rats after SPECT/CT imaging. (a) Biodistribution of ¹³¹I-rhein and ¹³¹I-Hyp at 6 h post injection (n=5 for each tracer). %ID/g represents the percentage of injected dose per gram of tissue. Data are mean±standard deviation. Viable. m, viable myocardium; Necrotic. M, necrotic myocardium. (b)–(e) Postmortem analysis of myocardial slices from model rats receiving ¹³¹I-rhein: (b) TTC staining image of 2 mm thick slice; (c) autoradiograph of 50 μm frozen section; (d) H&E staining image of 10 μm frozen section; (e) H&E staining microphotograph, proving the presence of necrosis. N, necrotic area, V, viable area (Adapted with permission from Ref. . https://creativecommons.org/licenses/by/4.0/).

Figure 4

(A) Representative coronal PET/CT images of control rats and model rats with reperfused myocardium infarction (MI) at 1 h after administration of [¹⁸F]FDG (A1, A3) and [¹⁸F]FA3OP (A2, A4). White arrows indicate the location of necrotic myocardium. (B) Representative coronal (B1, B2) and transversal (B3, B4) SPECT/CT images of rats with reperfused MI or sham operation at 1 h after injection of ^99mTc(EDDA)-HYNIC-2C-rhein. White arrows indicate the heart. (Adapted with permission from Refs. and . Copyright © 2017 American Chemical Society).

Figure 5

(A) Representative coronal SPECT/CT images of W256 tumor-bearing rats obtained at 4 h post injection of ¹³¹I-vitexin. W256 tumor-bearing rats were pretreated with 20 mg/kg combretastatin A-4 disodium phosphate (CA4P) or were left untreated (Control) for 24 h. White arrows indicate significantly different uptakes of the tracer in the tumors of model and control rats. (B) Autoradiographs, corresponding H&E staining images and micrographs of 10 μm tumor slices from model and control rats administered with ¹³¹I-vitexin. (Adapted with permission from Ref. . Copyright © 2018 American Chemical Society).

Figure 6

Representative enhanced CT and corresponding SPECT/CT images of rats with liver necrosis (large arrow) and muscle necrosis (small arrow) at 72 h after administration of 3.7 MBq of ¹³¹I-skyrin or ¹³¹I-Hyp. (A) Coronal images of model rats. (B) Transversal images of rat liver. (C) Transversal images of rat hind limb. Red arrows indicate the necrotic region of liver/muscle. N, necrotic area. (Reprinted with permission from Ref. . Copyright © 2016 American Chemical Society).