Apoptosis Imaging: Beyond Annexin V

Abstract

Induction of apoptosis is the primary mechanism through which most chemotherapies cause tumor cell death. Early assessment of tumor response is required to manage patients in terms of quality of life versus intensive chemotherapy. Although imaging with radiolabeled annexin V has been intensively investigated, it is still not sufficiently mature for clinical application. This article will summarize various alternative imaging techniques for visualization of phosphatidylserine externalization, activity of caspases, and mitochondrial membrane potential. Such imaging studies will promote the identification of novel molecular targets and the development of highly specific apoptosis-detecting imaging probes with potential clinical applications. It is highly possible that quantitative imaging of apoptosis will greatly improve clinical decision making in apoptosis-related diseases.

Annexin V Incorporated into Influenza Virus Particles Inhibits Gamma Interferon Signaling and Promotes Viral Replication

“…Cellular programmed cell death is activated by IAV and, during such event, phosphatidylserine becomes exposed to the cell surface (32). A5 has a strong affinity for phosphatidylser- ine (33), making it a useful probe for the detection of apoptotic cells (34). Thus, most likely, cellular A5 is translocated from the cytoplasm to the cell surface through phosphatidylserine binding and flip-flop transmembrane translocation of lipids (35).…”

Imaging Cell Death

“…However, despite the early promise of 99m Tc-AnxV probes for detecting apoptosis in cardiovascular disorders (6) and for monitoring treatment response in head and neck cancer (1), AnxV has shown suboptimal biodistribution profiles, characterized by slow clearance and nonspecific binding to abdominal tissues (7). A second generation of site-specific mutants of AnxV has been proposed (8), yet the same problems persist, namely suboptimal pharmacokinetics and low specificity (9). These AnxV probes generated high background signal in the liver, kidneys, and gut, limiting the application of these probes for abdominal imaging and potentially contributing to organ and whole-body radiation exposure when radionuclide imaging is used (9).…”

“…A second generation of site-specific mutants of AnxV has been proposed (8), yet the same problems persist, namely suboptimal pharmacokinetics and low specificity (9). These AnxV probes generated high background signal in the liver, kidneys, and gut, limiting the application of these probes for abdominal imaging and potentially contributing to organ and whole-body radiation exposure when radionuclide imaging is used (9).…”

“…Various small-molecule and peptide-based probes have been proposed for phosphatidylserine imaging (9). These smaller probes have the potential advantages of favorable biodistribution and pharmacokinetics, leading to faster blood clearance, efficient phosphatidylserine targeting of remote tumor regions, and high tumor-to-background contrast.…”

“…However, 18 F-fluorobenzyl triphenylphosphonium, and other probes that target loss of mitochondrial membrane potential, generate negative contrast because they are released from cells on mitochondrial membrane depolarization. Moreover, cellular efflux mechanisms, mediated by multidrug resistance transporters, can lead to reduced cellular uptake through rapid probe efflux (9).…”