Molecular imaging of cell death in vivo by a novel small molecule probe

Aloya, Revital; Shirvan, Anat; Grimberg, Hagit; Reshef, Ayelet; Levin, Galit; Kidron, Dvora; Cohen, Avi; Ziv, Ilan

doi:10.1007/s10495-006-0282-7

Cited by 100 publications

(81 citation statements)

References 28 publications

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“…Conceptually, low-molecular-weight probes can be advantageous over large proteins such as Annexin-V (MW=37 000 Da) in the aspects of radio-labeling, biodistribution and immunogenicity. Based on these considerations, we have developed and previously reported DDC [9][10][11] and NST-732 [12], which are members of the ApoSense family of recently developed small-molecule apoptosis probes. However, DDC or NST-732 do not comprise a Gla structural motif, which, as revealed in the present study, is unique in being the smallest structural motif for detection of apoptosis known to date.…”

Section: Discussionmentioning

confidence: 99%

“…Based on this hypothesis and on our previous experience in developing fluorescent small-molecule apoptosis probes of the ApoSense family, such as didansyl-Lcystine (DDC) [9,10,11] and NST-732 [12], we now present ML-10 (2-(5-fluoro-pentyl)-2-methyl-malonic acid), as a rationally designed molecule, with an amphipathic compact structure (MW=206 Da). We also describe the performance of this novel Gla-derived probe as a detector of apoptosis, and its mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

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From the Gla domain to a novel small-molecule detector of apoptosis

Cohen¹,

Shirvan²,

Levin³

et al. 2009

Cell Res

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Apoptosis plays a pivotal role in the etiology or pathogenesis of numerous medical disorders, and thus, targeting of apoptotic cells may substantially advance patient care. In our quest for novel low-molecular-weight probes for apoptosis, we focused on the uncommon amino acid γ-carboxyglutamic acid (Gla), which plays a vital role in the binding of clotting factors to negatively charged phospholipid surfaces. Based on the alkyl-malonic acid motif of Gla, we have developed and now present ML-10 (2-(5-fluoro-pentyl)-2-methyl-malonic acid, MW=206 Da), the prototypical member of a novel family of small-molecule detectors of apoptosis. ML-10 was found to perform selective uptake and accumulation in apoptotic cells, while being excluded from either viable or necrotic cells. ML-10 uptake correlates with the apoptotic hallmarks of caspase activation, Annexin-V binding and disruption of mitochondrial membrane potential. The malonate moiety was found to be crucial for ML-10 function in apoptosis detection. ML-10 responds to a unique complex of features of the cell in early apoptosis, comprising irreversible loss of membrane potential, permanent acidification of cell membrane and cytoplasm, and preservation of membrane integrity. ML-10 is therefore the most compact apoptosis probe known to date. Due to its fluorine atom, ML-10 is amenable to radiolabeling with the 18 F isotope, towards its potential future use for clinical positron emission tomography imaging of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

From the Gla domain to a novel small-molecule detector of apoptosis

Cohen¹,

Shirvan²,

Levin³

et al. 2009

Cell Res

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“…Additional prospects for future clinical applications as well as experimental studies on the mechanisms causing and controlling intestinal GVHD arise from the potential of applying novel tracers designed for imaging of more specific targets such as cellular subpopulations, inflammatory mediators, or signaling molecules. [52][53][54] BLOOD, 1 MARCH 2008 ⅐ VOLUME 111, NUMBER 5 For personal use only. on May 10, 2018. by guest www.bloodjournal.org From…”

Section: Discussionmentioning

confidence: 99%

Clinical molecular imaging in intestinal graft-versus-host disease: mapping of disease activity, prediction, and monitoring of treatment efficiency by positron emission tomography

Stelljes

Hermann

Albring

et al. 2008

Blood

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Gastrointestinal graft-versus-host disease (GVHD) is a common and potentially life-threatening complication after allogeneic hematopoietic stem-cell transplantation (HSCT). Noninvasive tests for assessment of GVHD activity are desirable but lacking. In the present study, we were able to visualize intestinal GVHDassociated inflammation in an allogeneic murine transplantation model by 18 IntroductionImproving results of allogeneic hematopoietic stem-cell transplantation (HSCT) have led to growing acceptance of this treatment as a potentially curative therapy for various malignant and nonmalignant diseases. [1][2][3][4][5][6][7] While the donor graft is enriched for hematopoietic progenitor and stem cells, it also contains T lymphocytes, which assist hematopoietic engraftment, restore T cell-dependent immunity, and are crucial to immunologic tumor control, usually referred to as graft-versus-tumor effect. 3,8 Besides these beneficial attributes, donor T cells are also responsible for graft-versus-host disease (GVHD), a leading cause of morbidity and lethality in patients who have undergone HSCT. 9,10 Depending on the source of the hematopoietic stem cell graft, the conditioning regimen, and the immunosuppressive treatment, the frequencies of acute GVHD vary from 20% to 50% in patients with an HLA-identical sibling donor, 11-13 and may reach 60% to 80% in patients with an HLAcompatible unrelated donor. 14 One remarkable feature of GVHD is its predilection for certain organ systems. Among them in descending frequency are the epithelial surfaces of the skin and mucous membranes, the crypts of the gastrointestinal tract, and the biliary ducts of the liver. About 80% of patients with acute GVHD have skin involvement, and more than 50% have gastrointestinal GVHD. 9,15 Intestinal GVHD is a progressive process that can affect all sections of the alimentary tract, albeit the terminal ileum and the colon are predominant sites. Symptoms are nonspecific and may include anorexia, nausea, vomiting, watery diarrhea, intestinal bleeding, abdominal pain, and ileus 16 that may also develop secondary to numerous other causes, such as infections, conditioning, and drug toxicity. [17][18][19][20] Although clinical investigation, laboratory tests, and histology usually lead to an early diagnosis of skin or liver GVHD, gastrointestinal GVHD is less readily diagnosed. 21 This is of particular concern, as GVHD remains one of the most detrimental complications after allogeneic transplantation, and the presence of gut involvement has been related to increased lethality and poor response to treatment. [22][23][24] Therefore, early recognition of intestinal GVHD is important, as prompt therapeutic intervention may prevent progression to higher-grade disease and improve outcome. [24][25][26][27][28][29] The current reference standard for diagnosis and staging of intestinal GVHD combines assessment of clinical symptoms with histologic analyses of mucosal biopsy specimens obtained by endoscopy of the upper and lower intestinal tract. 9 This appr...

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“…After systemic administration, these compounds can detect apoptotic cells from the early stages of the death process, cross the intact plasma membrane, and accumulate in the cytoplasm (7)(8)(9). The performance of the fluorescent analogous compounds didansyl-L-cystine (DDC) and NST-732 in the detection of cell death after systemic administration in vivo was previously reported in various animal models (7)(8)(9) including, among others, monitoring of the tumor response to treatment, acute renal failure, and acute cerebral ischemia. In all of these models, the accumulation of the compounds in apoptotic cells in vivo was well correlated with the in vitro standard assessment of the death process.…”

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confidence: 99%