Harnessing Competing Endocytic Pathways for Overcoming the Tumor-Blood Barrier: Magnetic Resonance Imaging and Near-Infrared Imaging of Bifunctional Contrast Media

Migalovich, Helena Sheikhet; Kalchenko, Vyacheslav; Nevo, Nava; Meir, Gila; Kohen, Förtüne; Neeman, Michal

doi:10.1158/0008-5472.can-08-4967

Cited by 9 publications

(15 citation statements)

References 46 publications

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“…Suppression of caveola-mediated internalization by nystatin remarkably increases the uptake of such contrast media by tumor cells. 14 Recently, Ishida et al 15 reported that a copper chelator enhances the uptake and the therapeutic efficacy of cisplatin in cancerous tissues via attenuating the competing effect of copper on cisplatin uptake.…”

Section: Introductionmentioning

confidence: 99%

Cholesterol sequestration by nystatin enhances the uptake and activity of endostatin in endothelium via regulating distinct endocytic pathways

Chen

Wang

et al. 2011

Blood

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Specific internalization of endostatin into endothelial cells has been proved to be important for its biologic functions. However, the mechanism of endostatin internalization still remains elusive. In this study, we report for the first time that both caveolae/lipid rafts and clathrin-coated pits are involved in endostatin internalization. Inhibition of either the caveolae pathway or the clathrin pathway with the use of chemical inhibitors, small interfering RNAs, or dominant-negative mutants alters endostatin internalization in vitro.

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Section: Introductionmentioning

confidence: 99%

Cholesterol sequestration by nystatin enhances the uptake and activity of endostatin in endothelium via regulating distinct endocytic pathways

Chen

Wang

et al. 2011

Blood

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“…Further modification of the contrast media such as generation of bifunctional daidzein-BSA-GdDTPA, led to enhanced delivery and retention by the tumor cells, across the perivascular stroma myofibroblasts [19]. …”

Section: Imaging Interstitial Convection and Lymphatic Drainmentioning

confidence: 99%

“…In addition, albumin can be further modified so as to include fluorescent or NIR tags (Fig. 2a) or additional targeting moieties [16, 19] widening the possible in vitro and in vivo follow up methods.…”

Section: Introductionmentioning

confidence: 99%

Visualizing vascular permeability and lymphatic drainage using labeled serum albumin

2010

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During the early stages of angiogenesis, following stimulation of endothelial cells by vascular endothelial growth factor (VEGF), the vascular wall is breached, allowing high molecular weight proteins to leak from the vessels to the interstitial space. This hallmark of angiogenesis results in deposition of a provisional matrix, elevation of the interstitial pressure and induction of interstitial convection. Albumin, the major plasma protein appears to be an innocent bystander that is significantly affected by these changes, and thus can be used as a biomarker for vascular permeability associated with angiogenesis. Traditionally, albumin leak in superficial organs was followed by colorimetry or morphometry with the use of albumin binding vital dyes. Over the last years, the introduction of tagged-albumin that can be detected by various imaging methods, such as magnetic resonance imaging and positron emission tomography, opened new possibilities for quantitative three dimension dynamic analysis of permeability in any organ. Using these tools it is now possible to follow not only vascular permeability, but also interstitial convection and lymphatic drain. Active uptake of tagged albumin by caveolae-mediated endocytosis opens the possibility for using labeled albumin for vital staining of cells and cell tracking. This approach was used for monitoring recruitment of perivascular stroma fibroblasts associated with tumor angiogenesis.

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“…Our above mentioned studies with targeted alliinase conjugates suggested that a similar targeted strategy could be used against ovarian cancer cells which are known to express recognition sites for the isoflavone daidzein (Migalovich et al, 2009). The main goal of the present study was to develop a daidzein-alliinase conjugate and to assess its ability to target ovarian cancer cells and to effectively produce in vivo, cytotoxic allicin molecules in an animal model of ovarian cancer.…”

Section: Introductionmentioning

confidence: 96%

“…In addition, daidzein appears to act as a weak estrogen, it recognizes a putative plasma membrane estrogen receptor (Somjen et al, 2005), a membrane located ERβ-related protein (de Wilde et al, 2006) or a nuclear estrogen receptor of the β-type (Kuiper et al, 1998). In a previous study we have shown that conjugation of daidzein to bovine serum albumin labeled with the fluorescent probe CyTE-777, enabled the specific delivery of the probe to the ovarian cancer cells (Migalovich et al, 2009). Furthermore a chemical conjugate between daidzein and the anticancer drug daunomycin was shown to be more effective and less toxic at low concentrations, than daunomycin alone in killing the MLS human ovarian cancer cells (Somjen et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Conjugates of daidzein-alliinase as a targeted pro-drug enzyme system against ovarian carcinoma

Appel

Rabinkov

Neeman

et al. 2010

Journal of Drug Targeting

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Human ovarian cancer cells specifically bind the isoflavone daidzein. A chemical conjugate between daidzein and the garlic enzyme alliinase was prepared. The conjugate specifically bound to ovarian cancer cells and upon addition of the prodrug alliin, it effectively produced cytotoxic allicin molecules which killed the cancer cells. In vivo targeting and antitumor effect was confirmed by NIR and bioluminescence imaging using daidzein-alliinase-CyTE-777 conjugates and luciferase-expressing ovarian cancer cells. Co-localization of the fluorescent conjugate with bioluminescence was observed for intraperitoneal tumors while nonconjugated alliinase did not accumulate. Biodistribution studies with Europium-labeled conjugate revealed a five fold higher uptake in tumors as compared to other tissues. Treatment of tumor bearing mice with daidzein-alliinase and alliin effectively attenuated tumor progression during the first 12 days while a 5-fold increase in bioluminescence was detected in placebo-treated animals. Autopsy revealed only small individual foci of luminescence at the site of tumor cells inoculation. Histological examination of organs and tissues did not reveal any additional foci of carcinoma or signs of toxicity. These results suggest that the targeted alliinase conjugates in the presence of alliin, generated therapeutically effective levels of allicin which were capable of suppressing tumor progression of intraperitoneal ovarian cancer in an animal model.

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Harnessing Competing Endocytic Pathways for Overcoming the Tumor-Blood Barrier: Magnetic Resonance Imaging and Near-Infrared Imaging of Bifunctional Contrast Media

Abstract: Ovarian cancer is the most lethal gynecologic malignancy, often diagnosed at advanced stage leading to poor prognosis.

Cited by 9 publications

References 46 publications

Cholesterol sequestration by nystatin enhances the uptake and activity of endostatin in endothelium via regulating distinct endocytic pathways

Cholesterol sequestration by nystatin enhances the uptake and activity of endostatin in endothelium via regulating distinct endocytic pathways

Visualizing vascular permeability and lymphatic drainage using labeled serum albumin

Conjugates of daidzein-alliinase as a targeted pro-drug enzyme system against ovarian carcinoma

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