Noninvasive optical imaging of apoptosis by caspase-targeted activity-based probes

Edgington, Laura; Berger, Alicia B.; Blum, Galia; Albrow, Victoria E.; Paulick, Margot G.; Lineberry, Neil; Bogyo, Matthew

doi:10.1038/nm.1938

Cited by 263 publications

(275 citation statements)

References 30 publications

(39 reference statements)

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“…Peptide imaging agents can be used to visualize a range of targets, including integrins (20,57,294), matrix metalloproteinases (36,187), caspases (91,95), somatostatin receptors (82,136,331), neuropeptide Y receptor (253,485), and gastrin releasing peptide receptor (372,427,428). See TABLE 2 for some specific examples of peptide molecular imaging agents that can be used for optical, PET, and SPECT imaging.…”

Section: Peptidesmentioning

confidence: 99%

A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications

James

Gambhir

2012

Physiological Reviews

942

954

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Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.

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Section: Peptidesmentioning

confidence: 99%

A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications

James

Gambhir

2012

Physiological Reviews

942

954

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“…Intracellular caspase activation imaged by using molecular beacons comprised of dye-labeled caspase substrates (Edgington et al 2009;Lee et al 2008;Martinez et al 2010b;Riedl and Shi 2004) or the application of fluorescent caspase inhibitors ). 2.…”

Section: Introductionmentioning

confidence: 99%

Beyond annexin V: fluorescence response of cellular membranes to apoptosis

2012

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Dramatic changes in the structure of cell membranes on apoptosis allow easy, sensitive and non-destructive analysis of this process with the application of fluorescence methods. The strong plasma membrane asymmetry is present in living cells, and its loss on apoptosis is commonly detected with the probes interacting strongly and specifically with phosphatidylserine (PS). This phospholipid becomes exposed to the cell surface, and the application of annexin V labeled with fluorescent dye is presently the most popular tool for its detection. Several methods have been suggested recently that offer important advantages over annexin V assay with the ability to study apoptosis by spectroscopy of cell suspensions, flow cytometry and confocal or twophoton microscopy. The PS exposure marks the integrated changes in the outer leaflet of cell membrane that involve electrostatic potential and hydration, and the attempts are being made to provide direct probing of these changes. This review describes the basic mechanisms underlying the loss of membrane asymmetry during apoptosis and discusses, in comparison with the annexin V-binding assay, the novel fluorescence techniques of detecting apoptosis on cellular membrane level. In more detail we describe the detection method based on smart fluorescent dye F2N12S incorporated into outer leaflet of cell membrane and reporting on apoptotic cell transformation by easily detectable change of the spectral distribution of fluorescent emission. It can be adapted to any assay format.

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“…For example, annexin V-conjugated tracers have been used to detect the exposed phosphatidylserine on the outer leaflet of the cell membrane during apoptosis (62,63). Similarly, probes have been developed that can monitor caspase activity (35,(64)(65)(66). For example, a caspase-3-binding radiotracer, [ 18 F]ICMT-11, was recently used to study the induction of apoptosis by chemotherapeutic agents (67).…”

Section: Discussionmentioning

confidence: 99%

“…Both intrinsic and extrinsic apoptotic pathways converge into caspases, a family of cysteine proteases, which are known to cleave precise substrates (34). Indeed, the activation of caspases has been extensively used to monitor cell death (35)(36)(37). We rationalized that the pathophysiological caspase activation in a drug-responsive tumor following the release of the cytotoxic effector could be used to trigger the cleavage of a quenched dye in the design of the reporter nanoparticle.…”

Section: Design and Synthesis Of The Reporter And Effector Componentsmentioning

confidence: 99%

Reporter nanoparticle that monitors its anticancer efficacy in real time

Kulkarni

Rao

Natarajan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The ability to monitor the efficacy of an anticancer treatment in real time can have a critical effect on the outcome. Currently, clinical readouts of efficacy rely on indirect or anatomic measurements, which occur over prolonged time scales postchemotherapy or postimmunotherapy and may not be concordant with the actual effect. Here we describe the biology-inspired engineering of a simple 2-in-1 reporter nanoparticle that not only delivers a cytotoxic or an immunotherapy payload to the tumor but also reports back on the efficacy in real time. The reporter nanoparticles are engineered from a novel two-staged stimuli-responsive polymeric material with an optimal ratio of an enzyme-cleavable drug or immunotherapy (effector elements) and a drug function-activatable reporter element. The spatiotemporally constrained delivery of the effector and the reporter elements in a single nanoparticle produces maximum signal enhancement due to the availability of the reporter element in the same cell as the drug, thereby effectively capturing the temporal apoptosis process. Using chemotherapy-sensitive and chemotherapy-resistant tumors in vivo, we show that the reporter nanoparticles can provide a real-time noninvasive readout of tumor response to chemotherapy. The reporter nanoparticle can also monitor the efficacy of immune checkpoint inhibition in melanoma. The self-reporting capability, for the first time to our knowledge, captures an anticancer nanoparticle in action in vivo.T he failure of anticancer therapy is a major cause of mortality (1). Although the current dogma underlying resistance is based on the Darwinian selection of mutations acquired over time under chemotherapy pressure, emerging evidence indicates that anticancer drugs can be rendered ineffective early on by intrinsic or adaptive resistance as a function of tumor heterogeneity (2-4). For example, response rates to first-line chemotherapy treatments in metastatic breast cancer patients range from a dismal 30% to 70%, and patients with disease progression need to be switched to a different drug (5). Similarly, about 40-60% of patients with a wild-type KRAS do not respond to cetuximab (6). The ability to detect early whether a treatment is working or not and to switch, if necessary, to a regimen that is effective can have a significant effect on the outcome as well as quality of life (7,8).Currently, tumor response to therapy is determined using techniques for direct anatomical measurements, such as computed tomography (CT) and magnetic resonance imaging, or indirectly using positron emission tomography with 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG-PET) to quantify metabolic activity. However, these techniques lack the sensitivity or specificity to enable very early response assessment, and often, clinicopathological and metabolic readouts can be discordant (5, 9, 10). In the case of immunotherapy, for example, a productive immune response (T cell infiltration) and the unimpeded growth of the tumor will both be manifest as progression on the conventional ...

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Noninvasive optical imaging of apoptosis by caspase-targeted activity-based probes

Cited by 263 publications

References 30 publications

A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications

A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications

Beyond annexin V: fluorescence response of cellular membranes to apoptosis

Reporter nanoparticle that monitors its anticancer efficacy in real time

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