Ectopic high endothelial venules in pancreatic ductal adenocarcinoma: A unique site for targeted deliveryResearch in context
Baharak Bahmani,
Mayuko Uehara,
Farideh Ordikhani,
Xiaofei Li,
Liwei Jiang,
Naima Banouni,
Takaharu Ichimura,
Vivek Kasinath,
Siawosh K. Eskandari,
Nasim Annabi,
Jonathan S. Bromberg,
Leonard D. Shultz,
Dale L. Greiner,
Reza Abdi
Affiliations
Baharak Bahmani
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Mayuko Uehara
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Farideh Ordikhani
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Xiaofei Li
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Liwei Jiang
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Naima Banouni
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Takaharu Ichimura
Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Vivek Kasinath
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Siawosh K. Eskandari
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Nasim Annabi
Department of Chemical and Biomolecular Engineering, University of California Los Angeles, CA 90095, USA
Jonathan S. Bromberg
Department of Surgery and Microbiology and Immunobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Leonard D. Shultz
Department of Immunology, The Jackson Laboratory, Bar Harbor, ME 04609, USA
Dale L. Greiner
Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
Reza Abdi
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Corresponding author at: Transplant Research Center, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115, USA.
Background: Nanomedicine offers an excellent opportunity to tackle treatment-refractory malignancies by enhancing the delivery of therapeutics to the tumor site. High endothelial venules (HEVs) are found primarily in lymph nodes or formed de novo in peripheral tissues during inflammatory responses. They express peripheral node addressin (PNAd), which is recognized by the monoclonal antibody MECA79. Methods: Here, we demonstrated that HEVs form de novo in human pancreatic ductal adenocarcinoma (PDAC). We engineered MECA79 coated nanoparticles (MECA79-NPs) that recognize these ectopic HEVs in PDAC. Findings: The trafficking of MECA79-NPs following intravenous delivery to human PDAC implanted in a humanized mouse model was more robust than non-conjugated NPs. Treatment with MECA79-Taxol-NPs augmented the delivery of Paclitaxel (Taxol) to the tumor site and significantly reduced the tumor size. This effect was associated with a higher apoptosis rate of PDAC cells and reduced vascularization within the tumor. Interpretation: Targeting the HEVs of PDAC using MECA79-NPs could lay the ground for the localized delivery of a wide variety of drugs including chemotherapeutic agents. Fund: National Institutes of Health (NIH) grants: T32-EB016652 (B·B.), NIH Cancer Core Grant CA034196 (L.D.S.), National Institute of Allergy and Infectious Diseases grants R01-AI126596 and R01-HL141815 (R.A.). Keywords: Pancreatic ductal adenocarcinoma, High endothelial venules, Peripheral node addressin, MECA79 coated nanoparticles, Taxol
