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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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Related in: MedlinePlus

SapC-DOPS inhibits glioblastoma growth in vivoNude mice (6 per group) were implanted with subcutaneous U87-MG xenografts and tumor size quantified by caliper measurement during systemic treatment with saline (Control) or SapC-DOPS.
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Figure 4: SapC-DOPS inhibits glioblastoma growth in vivoNude mice (6 per group) were implanted with subcutaneous U87-MG xenografts and tumor size quantified by caliper measurement during systemic treatment with saline (Control) or SapC-DOPS.

Mentions: In a previous report we showed the ability of SapC-DOPS to significantly prolong the survival of mice harboring orthotopic U87ΔEGFR-Luc GBM tumors that expressed the EGFRvIII mutation [11]. Here we sought to determine whether SapC-DOPS would also be effective against GBM tumors expressing the wild-type EGFR. To this end, nude mice were implanted subcutaneously with U87-MG cells, and when tumors reached ~100 mm3 mice were injected with a saline solution (control) or with SapC-DOPS (4 mg SapC/kg) daily for 7 days and every 2 days thereafter for 10 days. SapC-DOPS administration inhibited tumor growth by 56% (Fig. 4, n = 6, P < 0.05)


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)

SapC-DOPS inhibits glioblastoma growth in vivoNude mice (6 per group) were implanted with subcutaneous U87-MG xenografts and tumor size quantified by caliper measurement during systemic treatment with saline (Control) or SapC-DOPS.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: SapC-DOPS inhibits glioblastoma growth in vivoNude mice (6 per group) were implanted with subcutaneous U87-MG xenografts and tumor size quantified by caliper measurement during systemic treatment with saline (Control) or SapC-DOPS.
Mentions: In a previous report we showed the ability of SapC-DOPS to significantly prolong the survival of mice harboring orthotopic U87ΔEGFR-Luc GBM tumors that expressed the EGFRvIII mutation [11]. Here we sought to determine whether SapC-DOPS would also be effective against GBM tumors expressing the wild-type EGFR. To this end, nude mice were implanted subcutaneously with U87-MG cells, and when tumors reached ~100 mm3 mice were injected with a saline solution (control) or with SapC-DOPS (4 mg SapC/kg) daily for 7 days and every 2 days thereafter for 10 days. SapC-DOPS administration inhibited tumor growth by 56% (Fig. 4, n = 6, P < 0.05)

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