Plectin-1 targeted AAV vector for the molecular imaging of pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is highly malignant disease that is the 4th leading cause of cancer-related death in the US. Gene therapy using AAV vectors to selectively deliver genes to PDAC cells is an attractive treatment option for pancreatic cancer. However, most AAV serotypes display...
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doaj-bc580d6f5e0549c082577fe778c9bea02020-11-24T23:05:17ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2013-04-01310.3389/fonc.2013.0008441020Plectin-1 targeted AAV vector for the molecular imaging of pancreatic cancerPrasad R. Konkalmatt0Defeng eDeng1Stephanie eThomas2Michael T. Wu3Craig D. Logsdon4Brent A. French5Kimberly A Kelly6University of VirginiaUniversity of Texas M. D. Anderson Cancer CenterUniversity of VirginiaUniversity of VirginiaUniversity of Texas M. D. Anderson Cancer CenterUniversity of VirginiaUniversity of VirginiaPancreatic ductal adenocarcinoma (PDAC) is highly malignant disease that is the 4th leading cause of cancer-related death in the US. Gene therapy using AAV vectors to selectively deliver genes to PDAC cells is an attractive treatment option for pancreatic cancer. However, most AAV serotypes display a broad spectrum of tissue tropism and none of the existing serotypes specifically target PDAC cells. This study tests the hypothesis that AAV2 can be genetically re-engineered to specifically target PDAC cells by modifying the capsid surface to display a peptide that has previously been shown to bind plectin-1. Towards this end, a Plectin-1 Targeting Peptide (PTP) was inserted into the loop IV region of the AAV2 capsid, and the resulting capsid (AAV-PTP) was used in a series of in vitro and in vivo experiments. In vitro, AAV-PTP was found to target all five human PDAC cell lines tested (PANC-1, MIA PaCa-2, HPAC, MPanc-96 and BxPC-3) preferentially over two non-neoplastic human pancreatic cell lines (HPDE and hPSC). In vivo, mice bearing subcutaneous tumor xenografts were generated using the PANC-1 cell line. Once tumors reached a size of ~1-2 mm in diameter, the mice were injected intravenously with luciferase reporter vectors packaged in the either AAV-PTP or wild type AAV2 capsids. Luciferase expression was then monitored by bioluminescence imaging on days 3, 7 and 14 after vector injection. The results indicate that the AAV-PTP capsid displays a 37-fold preference for PANC-1 tumor xenographs over liver and other tissues; whereas the wild type AAV2 capsid displays a complementary preference for liver over tumors and other tissues. Together, these results establish proof-of-principle for the ability of PTP-modified AAV capsids to selectively target gene delivery to PDAC cells in vivo, which opens promising new avenues for the early detection, diagnosis and treatment of pancreatic cancer.http://journal.frontiersin.org/Journal/10.3389/fonc.2013.00084/fullGene TherapyPancreatic Canceraavphage displaytargeted gene deliverycapsid modification |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Prasad R. Konkalmatt Defeng eDeng Stephanie eThomas Michael T. Wu Craig D. Logsdon Brent A. French Kimberly A Kelly |
spellingShingle |
Prasad R. Konkalmatt Defeng eDeng Stephanie eThomas Michael T. Wu Craig D. Logsdon Brent A. French Kimberly A Kelly Plectin-1 targeted AAV vector for the molecular imaging of pancreatic cancer Frontiers in Oncology Gene Therapy Pancreatic Cancer aav phage display targeted gene delivery capsid modification |
author_facet |
Prasad R. Konkalmatt Defeng eDeng Stephanie eThomas Michael T. Wu Craig D. Logsdon Brent A. French Kimberly A Kelly |
author_sort |
Prasad R. Konkalmatt |
title |
Plectin-1 targeted AAV vector for the molecular imaging of pancreatic cancer |
title_short |
Plectin-1 targeted AAV vector for the molecular imaging of pancreatic cancer |
title_full |
Plectin-1 targeted AAV vector for the molecular imaging of pancreatic cancer |
title_fullStr |
Plectin-1 targeted AAV vector for the molecular imaging of pancreatic cancer |
title_full_unstemmed |
Plectin-1 targeted AAV vector for the molecular imaging of pancreatic cancer |
title_sort |
plectin-1 targeted aav vector for the molecular imaging of pancreatic cancer |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2013-04-01 |
description |
Pancreatic ductal adenocarcinoma (PDAC) is highly malignant disease that is the 4th leading cause of cancer-related death in the US. Gene therapy using AAV vectors to selectively deliver genes to PDAC cells is an attractive treatment option for pancreatic cancer. However, most AAV serotypes display a broad spectrum of tissue tropism and none of the existing serotypes specifically target PDAC cells. This study tests the hypothesis that AAV2 can be genetically re-engineered to specifically target PDAC cells by modifying the capsid surface to display a peptide that has previously been shown to bind plectin-1. Towards this end, a Plectin-1 Targeting Peptide (PTP) was inserted into the loop IV region of the AAV2 capsid, and the resulting capsid (AAV-PTP) was used in a series of in vitro and in vivo experiments. In vitro, AAV-PTP was found to target all five human PDAC cell lines tested (PANC-1, MIA PaCa-2, HPAC, MPanc-96 and BxPC-3) preferentially over two non-neoplastic human pancreatic cell lines (HPDE and hPSC). In vivo, mice bearing subcutaneous tumor xenografts were generated using the PANC-1 cell line. Once tumors reached a size of ~1-2 mm in diameter, the mice were injected intravenously with luciferase reporter vectors packaged in the either AAV-PTP or wild type AAV2 capsids. Luciferase expression was then monitored by bioluminescence imaging on days 3, 7 and 14 after vector injection. The results indicate that the AAV-PTP capsid displays a 37-fold preference for PANC-1 tumor xenographs over liver and other tissues; whereas the wild type AAV2 capsid displays a complementary preference for liver over tumors and other tissues. Together, these results establish proof-of-principle for the ability of PTP-modified AAV capsids to selectively target gene delivery to PDAC cells in vivo, which opens promising new avenues for the early detection, diagnosis and treatment of pancreatic cancer. |
topic |
Gene Therapy Pancreatic Cancer aav phage display targeted gene delivery capsid modification |
url |
http://journal.frontiersin.org/Journal/10.3389/fonc.2013.00084/full |
work_keys_str_mv |
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