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Phosphatidylserine-selective targeting and anticancer effects of SapC-DOPS nanovesicles on brain tumors.

Blanco VM, Chu Z, Vallabhapurapu SD, Sulaiman MK, Kendler A, Rixe O, Warnick RE, Franco RS, Qi X - Oncotarget (2014)

Bottom Line: These actions are a consequence of the affinity of SapC-DOPS for phosphatidylserine, an acidic phospholipid abundantly present in the outer membrane of a variety of tumor cells and tumor-associated vasculature.In this study, we first characterize SapC-DOPS bioavailability and antitumor effects on human glioblastoma xenografts, and confirm SapC-DOPS specificity towards phosphatidylserine by showing that glioblastoma targeting is abrogated after in vivo exposure to lactadherin, which binds phosphatidylserine with high affinity.Taken together, these results support the potential of SapC-DOPS for the diagnosis and therapy of primary and metastatic brain tumors.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.

ABSTRACT
Brain tumors, either primary (e.g., glioblastoma multiforme) or secondary (metastatic), remain among the most intractable and fatal of all cancers. We have shown that nanovesicles consisting of Saposin C (SapC) and dioleylphosphatidylserine (DOPS) are able to effectively target and kill cancer cells both in vitro and in vivo. These actions are a consequence of the affinity of SapC-DOPS for phosphatidylserine, an acidic phospholipid abundantly present in the outer membrane of a variety of tumor cells and tumor-associated vasculature. In this study, we first characterize SapC-DOPS bioavailability and antitumor effects on human glioblastoma xenografts, and confirm SapC-DOPS specificity towards phosphatidylserine by showing that glioblastoma targeting is abrogated after in vivo exposure to lactadherin, which binds phosphatidylserine with high affinity. Second, we demonstrate that SapC-DOPS selectively targets brain metastases-forming cancer cells both in vitro, in co-cultures with human astrocytes, and in vivo, in mouse models of brain metastases derived from human breast or lung cancer cells. Third, we demonstrate that SapC-DOPS have cytotoxic activity against metastatic breast cancer cells in vitro, and prolong the survival of mice harboring brain metastases. Taken together, these results support the potential of SapC-DOPS for the diagnosis and therapy of primary and metastatic brain tumors.

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Glioblastoma vascularization and permeabilityMouse brain section imaged with confocal microscopy showing a U87ΔEGFR-Luc tumor and adjacent normal brain parenchyma. Vascular structures (lectin-FITC), vascular permeability (dextran-TRITC) and intra-tumor SapC-DOPS-CVM accumulation were simultaneously assessed. Lectin-FITC, Dextran-TRITC and SapC-DOPS-CVM were injected i.v. 2 min, 30 min and 48 hs before sacrifice, respectively. Scale bar = 100 μm.
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Figure 2: Glioblastoma vascularization and permeabilityMouse brain section imaged with confocal microscopy showing a U87ΔEGFR-Luc tumor and adjacent normal brain parenchyma. Vascular structures (lectin-FITC), vascular permeability (dextran-TRITC) and intra-tumor SapC-DOPS-CVM accumulation were simultaneously assessed. Lectin-FITC, Dextran-TRITC and SapC-DOPS-CVM were injected i.v. 2 min, 30 min and 48 hs before sacrifice, respectively. Scale bar = 100 μm.

Mentions: Aberrant angiogenesis and enhanced vascular permeability characterize many solid tumors in the brain as well as in peripheral organs, and may contribute to the tumor-selective targeting capacity of SapC-DOPS in our GBM model. We used fluorescently labeled lectin, dextran and SapC-DOPS to simultaneously assess vascular structure, vascular permeability and SapC-DOPS uptake in orthotopic U87ΔEGFR-Luc GBM in mice. As shown in Fig. 2, in vivo lectin-FITC staining revealed an enlarged, irregular tumor vasculature, while extravasation of dextran-TRITC (70 kDa) evidenced its marked permeability. By 48 hs after intravenous injection, SapC-DOPS-CVM extensively and specifically accumulated within the tumor. Incomplete colocalization of SapC-DOPS-CVM and lectin-FITC indicated that SapC-DOPS accumulated in the extravascular tumor space, thus confirming that SapC-DOPS nanovesicles are able to cross the blood-brain-tumor-barrier, but not the intact brain endothelium.


Phosphatidylserine-selective targeting and anticancer effects of SapC-DOPS nanovesicles on brain tumors.

Blanco VM, Chu Z, Vallabhapurapu SD, Sulaiman MK, Kendler A, Rixe O, Warnick RE, Franco RS, Qi X - Oncotarget (2014)

Glioblastoma vascularization and permeabilityMouse brain section imaged with confocal microscopy showing a U87ΔEGFR-Luc tumor and adjacent normal brain parenchyma. Vascular structures (lectin-FITC), vascular permeability (dextran-TRITC) and intra-tumor SapC-DOPS-CVM accumulation were simultaneously assessed. Lectin-FITC, Dextran-TRITC and SapC-DOPS-CVM were injected i.v. 2 min, 30 min and 48 hs before sacrifice, respectively. Scale bar = 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196187&req=5

Figure 2: Glioblastoma vascularization and permeabilityMouse brain section imaged with confocal microscopy showing a U87ΔEGFR-Luc tumor and adjacent normal brain parenchyma. Vascular structures (lectin-FITC), vascular permeability (dextran-TRITC) and intra-tumor SapC-DOPS-CVM accumulation were simultaneously assessed. Lectin-FITC, Dextran-TRITC and SapC-DOPS-CVM were injected i.v. 2 min, 30 min and 48 hs before sacrifice, respectively. Scale bar = 100 μm.
Mentions: Aberrant angiogenesis and enhanced vascular permeability characterize many solid tumors in the brain as well as in peripheral organs, and may contribute to the tumor-selective targeting capacity of SapC-DOPS in our GBM model. We used fluorescently labeled lectin, dextran and SapC-DOPS to simultaneously assess vascular structure, vascular permeability and SapC-DOPS uptake in orthotopic U87ΔEGFR-Luc GBM in mice. As shown in Fig. 2, in vivo lectin-FITC staining revealed an enlarged, irregular tumor vasculature, while extravasation of dextran-TRITC (70 kDa) evidenced its marked permeability. By 48 hs after intravenous injection, SapC-DOPS-CVM extensively and specifically accumulated within the tumor. Incomplete colocalization of SapC-DOPS-CVM and lectin-FITC indicated that SapC-DOPS accumulated in the extravascular tumor space, thus confirming that SapC-DOPS nanovesicles are able to cross the blood-brain-tumor-barrier, but not the intact brain endothelium.

Bottom Line: These actions are a consequence of the affinity of SapC-DOPS for phosphatidylserine, an acidic phospholipid abundantly present in the outer membrane of a variety of tumor cells and tumor-associated vasculature.In this study, we first characterize SapC-DOPS bioavailability and antitumor effects on human glioblastoma xenografts, and confirm SapC-DOPS specificity towards phosphatidylserine by showing that glioblastoma targeting is abrogated after in vivo exposure to lactadherin, which binds phosphatidylserine with high affinity.Taken together, these results support the potential of SapC-DOPS for the diagnosis and therapy of primary and metastatic brain tumors.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.

ABSTRACT
Brain tumors, either primary (e.g., glioblastoma multiforme) or secondary (metastatic), remain among the most intractable and fatal of all cancers. We have shown that nanovesicles consisting of Saposin C (SapC) and dioleylphosphatidylserine (DOPS) are able to effectively target and kill cancer cells both in vitro and in vivo. These actions are a consequence of the affinity of SapC-DOPS for phosphatidylserine, an acidic phospholipid abundantly present in the outer membrane of a variety of tumor cells and tumor-associated vasculature. In this study, we first characterize SapC-DOPS bioavailability and antitumor effects on human glioblastoma xenografts, and confirm SapC-DOPS specificity towards phosphatidylserine by showing that glioblastoma targeting is abrogated after in vivo exposure to lactadherin, which binds phosphatidylserine with high affinity. Second, we demonstrate that SapC-DOPS selectively targets brain metastases-forming cancer cells both in vitro, in co-cultures with human astrocytes, and in vivo, in mouse models of brain metastases derived from human breast or lung cancer cells. Third, we demonstrate that SapC-DOPS have cytotoxic activity against metastatic breast cancer cells in vitro, and prolong the survival of mice harboring brain metastases. Taken together, these results support the potential of SapC-DOPS for the diagnosis and therapy of primary and metastatic brain tumors.

Show MeSH
Related in: MedlinePlus