Phosphatidylserine-selective targeting and anticancer effects of SapC-DOPS nanovesicles on brain tumors
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Víctor M. Blanco1, Zhengtao Chu1,2, Subrahmanya D. Vallabhapurapu1, Mahaboob K. Sulaiman1, Ady Kendler3, Olivier Rixe4, Ronald E. Warnick5, Robert S. Franco1 and Xiaoyang Qi1,2
1 Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
2 Division of Human Genetics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
3 Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
4 Division of Hematology/Oncology, Georgia Regents University, GRU Cancer Center, Augusta, Georgia
5 Department of Neurosurgery, University of Cincinnati Brain Tumor Center, and Mayfield Clinic, Cincinnati, Ohio
Xiaoyang Qi, email:
Keywords: Glioblastoma; brain metastasis; SapC-DOPS; imaging; cancer therapy
Received: June 2, 2014 Accepted: July 13, 2014 Published: July 14, 2014
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 nanovesicles 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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