Targeting and cytotoxicity of SapC-DOPS nanovesicles in pancreatic cancer.
Only a small number of promising drugs target pancreatic cancer, which is the fourth leading cause of cancer deaths with a 5-year survival of less than 5%. Our goal is to develop a new biotherapeutic agent in which a lysosomal protein (saposin C, SapC) and a phospholipid (dioleoylphosphatidylserine,...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3790873?pdf=render |
| _version_ | 1811205989973622784 |
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| author | Zhengtao Chu Shadi Abu-Baker Mary B Palascak Syed A Ahmad Robert S Franco Xiaoyang Qi |
| author_facet | Zhengtao Chu Shadi Abu-Baker Mary B Palascak Syed A Ahmad Robert S Franco Xiaoyang Qi |
| author_sort | Zhengtao Chu |
| collection | DOAJ |
| description | Only a small number of promising drugs target pancreatic cancer, which is the fourth leading cause of cancer deaths with a 5-year survival of less than 5%. Our goal is to develop a new biotherapeutic agent in which a lysosomal protein (saposin C, SapC) and a phospholipid (dioleoylphosphatidylserine, DOPS) are assembled into nanovesicles (SapC-DOPS) for treating pancreatic cancer. A distinguishing feature of SapC-DOPS nanovesicles is their high affinity for phosphatidylserine (PS) rich microdomains, which are abnormally exposed on the membrane surface of human pancreatic tumor cells. To evaluate the role of external cell PS, in vitro assays were used to correlate PS exposure and the cytotoxic effect of SapC-DOPS in human tumor and nontumorigenic pancreatic cells. Next, pancreatic tumor xenografts (orthotopic and subcutaneous models) were used for tumor targeting and therapeutic efficacy studies with systemic SapC-DOPS treatment. We observed that the nanovesicles selectively killed human pancreatic cancer cells in vitro by inducing apoptotic death, whereas untransformed cells remained unaffected. This in vitro cytotoxic effect correlated to the surface exposure level of PS on the tumor cells. Using xenografts, animals treated with SapC-DOPS showed clear survival benefits and their tumors shrank or disappeared. Furthermore, using a double-tracking method in live mice, we showed that the nanovesicles were specifically targeted to orthotopically-implanted, bioluminescent pancreatic tumors. These data suggest that the acidic phospholipid PS is a biomarker for pancreatic cancer that can be effectively targeted for therapy utilizing cancer-selective SapC-DOPS nanovesicles. This study provides convincing evidence in support of developing a new therapeutic approach to pancreatic cancer. |
| first_indexed | 2024-04-12T03:40:39Z |
| format | Article |
| id | doaj.art-23295dfceb754c17866ca45f5d541eba |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T03:40:39Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-23295dfceb754c17866ca45f5d541eba2022-12-22T03:49:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01810e7550710.1371/journal.pone.0075507Targeting and cytotoxicity of SapC-DOPS nanovesicles in pancreatic cancer.Zhengtao ChuShadi Abu-BakerMary B PalascakSyed A AhmadRobert S FrancoXiaoyang QiOnly a small number of promising drugs target pancreatic cancer, which is the fourth leading cause of cancer deaths with a 5-year survival of less than 5%. Our goal is to develop a new biotherapeutic agent in which a lysosomal protein (saposin C, SapC) and a phospholipid (dioleoylphosphatidylserine, DOPS) are assembled into nanovesicles (SapC-DOPS) for treating pancreatic cancer. A distinguishing feature of SapC-DOPS nanovesicles is their high affinity for phosphatidylserine (PS) rich microdomains, which are abnormally exposed on the membrane surface of human pancreatic tumor cells. To evaluate the role of external cell PS, in vitro assays were used to correlate PS exposure and the cytotoxic effect of SapC-DOPS in human tumor and nontumorigenic pancreatic cells. Next, pancreatic tumor xenografts (orthotopic and subcutaneous models) were used for tumor targeting and therapeutic efficacy studies with systemic SapC-DOPS treatment. We observed that the nanovesicles selectively killed human pancreatic cancer cells in vitro by inducing apoptotic death, whereas untransformed cells remained unaffected. This in vitro cytotoxic effect correlated to the surface exposure level of PS on the tumor cells. Using xenografts, animals treated with SapC-DOPS showed clear survival benefits and their tumors shrank or disappeared. Furthermore, using a double-tracking method in live mice, we showed that the nanovesicles were specifically targeted to orthotopically-implanted, bioluminescent pancreatic tumors. These data suggest that the acidic phospholipid PS is a biomarker for pancreatic cancer that can be effectively targeted for therapy utilizing cancer-selective SapC-DOPS nanovesicles. This study provides convincing evidence in support of developing a new therapeutic approach to pancreatic cancer.http://europepmc.org/articles/PMC3790873?pdf=render |
| spellingShingle | Zhengtao Chu Shadi Abu-Baker Mary B Palascak Syed A Ahmad Robert S Franco Xiaoyang Qi Targeting and cytotoxicity of SapC-DOPS nanovesicles in pancreatic cancer. PLoS ONE |
| title | Targeting and cytotoxicity of SapC-DOPS nanovesicles in pancreatic cancer. |
| title_full | Targeting and cytotoxicity of SapC-DOPS nanovesicles in pancreatic cancer. |
| title_fullStr | Targeting and cytotoxicity of SapC-DOPS nanovesicles in pancreatic cancer. |
| title_full_unstemmed | Targeting and cytotoxicity of SapC-DOPS nanovesicles in pancreatic cancer. |
| title_short | Targeting and cytotoxicity of SapC-DOPS nanovesicles in pancreatic cancer. |
| title_sort | targeting and cytotoxicity of sapc dops nanovesicles in pancreatic cancer |
| url | http://europepmc.org/articles/PMC3790873?pdf=render |
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