&lt;em&gt;In Vivo&lt;/em&gt; Optical Imaging of Brain Tumors and Arthritis Using Fluorescent SapC-DOPS Nanovesicles

Chu, Zhengtao; LaSance, Kathleen; Blanco, Víctor; Kwon, Chang‐Hyuk; Kaur, Balveen; Frederick, Malinda; Thornton, Sherry; Lemen, Lisa; Qi, Xiaoyang

doi:10.3791/51187

Cited by 13 publications

(13 citation statements)

References 13 publications

(11 reference statements)

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“…By targeting PS-rich domains on neoplastic cell membranes, SapC-DOPS has been shown to selectively initiate lipid-mediated pathways that lead to lysosomal destabilization and necrosis on glioblastoma cells [13–15] or to apoptosis, secondary to ceramide accumulation, as in neuroblastoma, pancreatic, skin and lung cancer cells [16–20]. The potential of SapC-DOPS for cancer imaging has been reported using optical and MRI techniques in several solid tumor models, including glioblastoma [21–23]. In this study, we describe the synthesis of monomolecular, phenol-substituted membrane intercalating lipophilic dyes, and a simple iodination procedure that allows the generation of dual (optical/nuclear) imaging probes (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Optical and nuclear imaging of glioblastoma with phosphatidylserine-targeted nanovesicles

et al. 2016

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Multimodal tumor imaging with targeted nanoparticles potentially offers both enhanced specificity and sensitivity, leading to more precise cancer diagnosis and monitoring. We describe the synthesis and characterization of phenol-substituted, lipophilic orange and far-red fluorescent dyes and a simple radioiodination procedure to generate a dual (optical and nuclear) imaging probe. MALDI-ToF analyses revealed high iodination efficiency of the lipophilic reporters, achieved by electrophilic aromatic substitution using the chloramide 1,3,4,6-tetrachloro-3α,6α-diphenyl glycoluril (Iodogen) as the oxidizing agent in an organic/aqueous co-solvent mixture. Upon conjugation of iodine-127 or iodine-124-labeled reporters to tumor-targeting SapC-DOPS nanovesicles, optical (fluorescent) and PET imaging was performed in mice bearing intracranial glioblastomas. In addition, tumor vs non-tumor (normal brain) uptake was compared using iodine-125. These data provide proof-of-principle for the potential value of SapC-DOPS for multimodal imaging of glioblastoma, the most aggressive primary brain tumor.

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Section: Introductionmentioning

confidence: 99%

Optical and nuclear imaging of glioblastoma with phosphatidylserine-targeted nanovesicles

et al. 2016

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“…In in vivo glioblastoma (GBM) tumors, SapC-DOPS showcased its ability to cross the blood-brain tumor barrier (BBTB) as well as target tumor cells, in vitro [7,10,16,[32][33][34]. Tumor targeting by SapC-DOPS in vivo was inhibited by blocking PS exposed on cells with lactadherin, a PS binding protein [10].…”

Section: Theraeutic Studies Of Sapc-dops In Cancer Cellsmentioning

confidence: 99%

“…The overexpression of PS on the surface of cancer cells has presented an opportunity for selective therapeutic targeting of cancer cells without effecting healthy cells with low surface PS [2,11]. PS can be used for identification and killing of cancer cells [2,7,[12][13][14][15][16][17]. Strategies for achieving this therapeutic effect have included the use of PStargeting antibodies that block PS-mediated immunosuppression by binding to PS on tumor cells and vasculature; annexins which inhibit tumor angiogenesis by binding to PS on tumor cells; and PS-targeting synthetic peptides which enhance membrane poration through binding to PS leading to increased cell death [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

SapC-DOPS – a Phosphatidylserine-targeted Nanovesicle for selective Cancer therapy

N’Guessan

Patel

2020

Cell Commun Signal

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Phosphatidylserine (PS) is normally located in the inner leaflet of the membrane bilayer of healthy cells, however it is expressed at high levels on the surface of cancer cells. This has allowed for the development of selective therapeutic agents against cancer cells (without affecting healthy cells). SapC-DOPS is a PS-targeting nanovesicle which effectively targets and kills several cancer types including pancreatic, lung, brain, and pediatric tumors. Our studies have demonstrated that SapC-DOPS selectively induces apoptotic cell death in malignant and metastatic cells, whereas untransformed cells remain unaffected due to low surface PS expression. Furthermore, SapC-DOPS can be used in combination with standard therapies such as irradiation and chemotherapeutic drugs to significantly enhance the antitumor efficacy of these treatments. While the PS-targeting nanovesicles are a promising selective therapeutic option for the treatment of cancers, more preclinical studies are needed to fully understand the mechanisms leading to non-apoptotic PS expression on the surface of viable cancer cells and to determine the effectiveness of SapC-DOPS in advanced metastatic disease. In addition, the completion of clinical studies will determine therapeutic effects and drug safety in patients. A phase I clinical trial using SapC-DOPS has been completed on patients with solid tumors and has demonstrated compelling patient outcomes with a strong safety profile. Results from this study are informing future studies with SapC-DOPS.

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“…In the past, several attempts have been made to formulate nanovesicles from components normally present in cells [ 4 ]. In this direction, SapC-DOPS, a nanovesicle made from saposin C and dioleylphosphatidylserine, is a unique protein-lipid complex that selectively targets and kills human cancer cells in vitro and in vivo [ 1 , 5 - 12 ] . Saposin C is an 80 kDa heat-stable, protease-resistant protein containing distinct functional domains; that functions as a co-activator of sphingolipid-degrading lysosomal hydrolases (sphingomyelinase and acid β-glucosidase) [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…This interaction occurs at low pH (pKa of 5.3) and is critical for SapC activation [ 13 , 14 ]. We have previously assembled SapC and DOPS into stable nanovesicles and its efficacy and safety profiles have been established in various forms of cancer [ 1 , 5 , 6 , 8 , 12 ]. SapC-DOPS is hypothesized to bind to exposed PS on the cancer cell surface and induce apoptosis by increasing intracellular ceramide level leading to subsequent caspase activation [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

SapC-DOPS nanovesicles induce Smac- and Bax-dependent apoptosis through mitochondrial activation in neuroblastomas

et al. 2015

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BackgroundHigh toxicity, morbidity and secondary malignancy render chemotherapy of neuroblastoma inefficient, prompting the search for novel compounds. Nanovesicles offer great promise in imaging and treatment of cancer. SapC-DOPS, a stable nanovesicle formed from the lysosomal protein saposin C and dioleoylphosphatidylserine possess strong affinity for abundantly exposed surface phosphatidylserine on cancer cells. Here, we show that SapC-DOPS effectively targets and suppresses neuroblastoma growth and elucidate the molecular mechanism of SapC-DOPS action in neuroblastoma in vitro.MethodsIn vivo targeting of neuroblastoma was assessed in xenograft mice injected intravenously with fluorescently-labeled SapC-DOPS. Xenografted tumors were also used to demonstrate its therapeutic efficacy. Apoptosis induction in vivo was evaluated in tumor sections using the TUNEL assay. The mechanisms underlying the induction of apoptosis by SapC-DOPS were addressed through measurements of cell viability, mitochondrial membrane potential (ΔΨM), flow cytometric DNA fragmentation assays and by immunoblot analysis of second mitochondria-derived activator of caspases (Smac), Bax, Cytochrome c (Cyto c) and Caspase-3 in the cytosol or in mitochondrial fractions of cultured neuroblastoma cells.ResultsSapC-DOPS showed specific targeting and prevented the growth of human neuroblastoma xenografts in mice. In neuroblastoma cells in vitro, apoptosis occurred via a series of steps that included: (1) loss of ΔΨM and increased mitochondrial superoxide formation; (2) cytosolic release of Smac, Cyto c, AIF; and (3) mitochondrial translocation and polymerization of Bax. ShRNA-mediated Smac knockdown and V5 peptide-mediated Bax inhibition decreased cytosolic Smac and Cyto c release along with caspase activation and abrogated apoptosis, indicating that Smac and Bax are critical mediators of SapC-DOPS action. Similarly, pretreatment with the mitochondria-stabilizing agent bongkrekic acid decreased apoptosis indicating that loss of ΔΨM is critical for SapC-DOPS activity. Apoptosis induction was not critically dependent on reactive oxygen species (ROS) production and Cyclophilin D, since pretreatment with N-acetyl cysteine and cyclosporine A, respectively, did not prevent Smac or Cyto c release.ConclusionsTaken together, our results indicate that SapC-DOPS acts through a mitochondria-mediated pathway accompanied by an early release of Smac and Bax. Specific tumor-targeting capacity and anticancer efficacy of SapC-DOPS supports its potential as a dual imaging and therapeutic agent in neuroblastoma therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0336-y) contains supplementary material, which is available to authorized users.

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<em>In Vivo</em> Optical Imaging of Brain Tumors and Arthritis Using Fluorescent SapC-DOPS Nanovesicles

Cited by 13 publications

References 13 publications

Optical and nuclear imaging of glioblastoma with phosphatidylserine-targeted nanovesicles

Optical and nuclear imaging of glioblastoma with phosphatidylserine-targeted nanovesicles

SapC-DOPS – a Phosphatidylserine-targeted Nanovesicle for selective Cancer therapy

SapC-DOPS nanovesicles induce Smac- and Bax-dependent apoptosis through mitochondrial activation in neuroblastomas

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