Biomarkers and Molecular Probes for Cell Death Imaging and Targeted Therapeutics

Abstract

Cell death is a critically important biological process. Disruption of homeostasis, either by excessive or deficient cell death, is a hallmark of many pathological conditions. Recent research advances have greatly increased our molecular understanding of cell death and its role in a range of diseases and therapeutic treatments. Central to these ongoing research and clinical efforts is the need for imaging technologies that can locate and identify cell death in a wide array of in vitro and in vivo biomedical samples with varied spatiotemporal requirements. This review article summarizes community efforts over the past five years to identify useful biomarkers for dead and dying cells, and to develop molecular probes that target these biomarkers for optical, radionuclear, or magnetic resonance imaging. Apoptosis biomarkers are classified as either intracellular (caspase enzymes, mitochondrial membrane potential, cytosolic proteins) or extracellular (plasma membrane phospholipids, membrane potential, surface exposed histones). Necrosis, autophagy, and senescence biomarkers are described, as well as unexplored cell death biomarkers. The article discusses possible chemotherapeutic and theranostic strategies, and concludes with a summary of current challenges and expected eventual rewards of clinical cell death imaging.

Reporter nanoparticle that monitors its anticancer efficacy in real time

“…As shown in Fig. 2B, caspase-3 induced the highest activation rate and preferential cleavage over caspase-7, whereas caspase-6 and caspase-9 exhibited very low activation rates, consistent with the earlier observations (44). Similar results were obtained in the case of the 5-FAM-QSY-7-based FRET pair-conjugated reporter element when incubated with caspase-3 enzyme, supporting the applicability of the reporter element platform for a series of FRET pairs with a broad emission range from green to NIR (Fig.…”

“…Caspases are typically classified as initiators (caspase-8 and caspase-10 belonging to the extrinsic pathway and caspase-9 belonging to the intrinsic pathway) and effectors (caspase-3, caspase-6, and caspase-7), with the initiators converging into the effectors for an apoptotic outcome (43). Typically, the effectors have been shown to recognize the DEVD motif (44). To test the selectivity of different caspases for the reporter element, we incubated the reporter element with recombinant caspase-3, caspase-6, caspase-7, and caspase-9 and measured the NIR fluorescence intensity at different time points.…”

Molecular Imaging of Death Receptor 5 Occupancy and Saturation Kinetics In Vivo by Humanized Monoclonal Antibody CS-1008

“…Third, the data presented here show DR5 occupancy and therapeutic response to CS-1008 in COLO 205 and WiDr tumor models; however, in cells with similar or higher DR5 expression levels, but with slower induction of the apoptotic pathway, receptor turnover, receptor internalization, and antibody pharmacokinetics might play a much larger role. Although the results here have shown proof-of-principle that 111 In-CHX-A 00 -DTPA-CS-1008 can aid in patient selection and estimate optimal therapeutic dosing, further studies are warranted comparing resistant versus sensitive tumor models, and exploring the role of apoptosis pathway induction on effectiveness of treatment (24). Such studies are currently being performed by our laboratory.…”

Imaging Cell Death

“…The physiology and pathways of cell death have been studied extensively (1). Apoptosis plays an important role in cell growth and differentiation, organismal development, and tissue homeostasis, particularly in the immune system.…”