title: Systemic delivery of SapC-DOPS has antiangiogenic and antitumor effects against glioblastoma.
abstract: Saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles are a nanotherapeutic which effectively target and destroy cancer cells. Here, we explore the systemic use of SapC-DOPS in several models of brain cancer, including glioblastoma multiforme (GBM), and the molecular mechanism behind its tumor-selective targeting specificity. Using two validated spontaneous brain tumor models, we demonstrate the ability of SapC-DOPS to selectively and effectively cross the blood-brain tumor barrier (BBTB) to target brain tumors in vivo and reveal the targeting to be contingent on the exposure of the anionic phospholipid phosphatidylserine (PtdSer). Increased cell surface expression of PtdSer levels was found to correlate with SapC-DOPS-induced killing efficacy, and tumor targeting in vivo was inhibited by blocking PtdSer exposed on cells. Apart from cancer cell killing, SapC-DOPS also exerted a strong antiangiogenic activity in vitro and in vivo. Interestingly, unlike traditional chemotherapy, hypoxic cells were sensitized to SapC-DOPS-mediated killing. This study emphasizes the importance of PtdSer exposure for SapC-DOPS targeting and supports the further development of SapC-DOPS as a novel antitumor and antiangiogenic agent for brain tumors.
authors.affiliation: Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wojton
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Chu
authors.forename: Haritha
authors.initials: H
authors.lastname: Mathsyaraja
authors.forename: Walter H
authors.initials: WH
authors.lastname: Meisen
authors.forename: Nicholas
authors.initials: N
authors.lastname: Denton
authors.forename: Chang-Hyuk
authors.initials: CH
authors.lastname: Kwon
authors.forename: Lionel Ml
authors.initials: LM
authors.lastname: Chow
authors.forename: Mary
authors.initials: M
authors.lastname: Palascak
authors.forename: Robert
authors.initials: R
authors.lastname: Franco
authors.forename: Tristan
authors.initials: T
authors.lastname: Bourdeau
authors.forename: Sherry
authors.initials: S
authors.lastname: Thornton
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Qi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010718:Phosphatidylserines / Q000737:chemistry*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D049231:Saposins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010718:Phosphatidylserines; D011994:Recombinant Proteins; D049231:Saposins; C042511:1,2-dioleoylphosphatidylserine