Ectopic high endothelial venules in pancreatic ductal adenocarcinoma: A unique site for targeted delivery

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

doi:10.1016/j.ebiom.2018.11.030

Ectopic high endothelial venules in pancreatic ductal adenocarcinoma: A unique site for targeted delivery

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

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	79-88
Number of pages	10
Journal	EBioMedicine
Volume	38
DOIs	https://doi.org/10.1016/j.ebiom.2018.11.030
Publication status	Published - Dec-2018
Externally published	Yes

Keywords

Animals
Antineoplastic Agents/chemistry
Biomarkers
Carcinoma, Pancreatic Ductal/drug therapy
Cell Line
Disease Models, Animal
Endothelium, Lymphatic/drug effects
Female
Humans
Immunohistochemistry
Lymph Nodes/pathology
Male
Mice
Molecular Targeted Therapy
Nanoparticles/chemistry
Neovascularization, Pathologic/drug therapy
Paclitaxel/administration & dosage
Pancreatic Neoplasms/drug therapy
Theranostic Nanomedicine
Xenograft Model Antitumor Assays

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10.1016/j.ebiom.2018.11.030Licence: CC BY-NC-ND

Ectopic high endothelial venules in pancreatic ductal adenocarcinomaFinal publisher's version, 3.63 MBLicence: CC BY-NC-ND

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Bahmani, B., Uehara, M., Ordikhani, F., Li, X., Jiang, L., Banouni, N., Ichimura, T., Kasinath, V., Eskandari, S. K., Annabi, N., Bromberg, J. S., Shultz, L. D., Greiner, D. L., & Abdi, R. (2018). Ectopic high endothelial venules in pancreatic ductal adenocarcinoma: A unique site for targeted delivery. EBioMedicine, 38, 79-88. https://doi.org/10.1016/j.ebiom.2018.11.030

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title = "Ectopic high endothelial venules in pancreatic ductal adenocarcinoma: A unique site for targeted delivery",

abstract = "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.",

keywords = "Animals, Antineoplastic Agents/chemistry, Biomarkers, Carcinoma, Pancreatic Ductal/drug therapy, Cell Line, Disease Models, Animal, Endothelium, Lymphatic/drug effects, Female, Humans, Immunohistochemistry, Lymph Nodes/pathology, Male, Mice, Molecular Targeted Therapy, Nanoparticles/chemistry, Neovascularization, Pathologic/drug therapy, Paclitaxel/administration & dosage, Pancreatic Neoplasms/drug therapy, Theranostic Nanomedicine, Xenograft Model Antitumor Assays",

author = "Baharak Bahmani and Mayuko Uehara and Farideh Ordikhani and Xiaofei Li and Liwei Jiang and Naima Banouni and Takaharu Ichimura and Vivek Kasinath and Eskandari, {Siawosh K} and Nasim Annabi and Bromberg, {Jonathan S} and Shultz, {Leonard D} and Greiner, {Dale L} and Reza Abdi",

year = "2018",

month = dec,

doi = "10.1016/j.ebiom.2018.11.030",

language = "English",

volume = "38",

pages = "79--88",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "ELSEVIER SCIENCE BV",

}

TY - JOUR

T1 - Ectopic high endothelial venules in pancreatic ductal adenocarcinoma

T2 - A unique site for targeted delivery

AU - Bahmani, Baharak

AU - Uehara, Mayuko

AU - Ordikhani, Farideh

AU - Li, Xiaofei

AU - Jiang, Liwei

AU - Banouni, Naima

AU - Ichimura, Takaharu

AU - Kasinath, Vivek

AU - Eskandari, Siawosh K

AU - Annabi, Nasim

AU - Bromberg, Jonathan S

AU - Shultz, Leonard D

AU - Greiner, Dale L

AU - Abdi, Reza

PY - 2018/12

Y1 - 2018/12

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents/chemistry

KW - Biomarkers

KW - Carcinoma, Pancreatic Ductal/drug therapy

KW - Cell Line

KW - Disease Models, Animal

KW - Endothelium, Lymphatic/drug effects

KW - Female

KW - Humans

KW - Immunohistochemistry

KW - Lymph Nodes/pathology

KW - Male

KW - Mice

KW - Molecular Targeted Therapy

KW - Nanoparticles/chemistry

KW - Neovascularization, Pathologic/drug therapy

KW - Paclitaxel/administration & dosage

KW - Pancreatic Neoplasms/drug therapy

KW - Theranostic Nanomedicine

KW - Xenograft Model Antitumor Assays

U2 - 10.1016/j.ebiom.2018.11.030

DO - 10.1016/j.ebiom.2018.11.030

M3 - Article

C2 - 30497977

SN - 2352-3964

VL - 38

SP - 79

EP - 88

JO - EBioMedicine

JF - EBioMedicine

ER -

Ectopic high endothelial venules in pancreatic ductal adenocarcinoma: A unique site for targeted delivery

Abstract

Keywords

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