@article{28cc8829dd464810ab6fe16fee080e11,
title = "CC Chemokine Receptor 2-Targeting Copper Nanoparticles for Positron Emission Tomography-Guided Delivery of Gemcitabine for Pancreatic Ductal Adenocarcinoma",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with dire prognosis due to aggressive biology, lack of effective tools for diagnosis at an early stage, and limited treatment options. Detection of PDAC using conventional radiographic imaging is limited by the dense, hypovascular stromal component and relatively scarce neoplastic cells within the tumor microenvironment (TME). The CC motif chemokine 2 (CCL2) and its cognate receptor CCR2 (CCL2/CCR2) axis are critical in fostering and maintaining this kind of TME by recruiting immunosuppressive myeloid cells such as the tumor-associated macrophages, thereby presenting an opportunity to exploit this axis for both diagnostic and therapeutic purposes. We engineered CCR2-targeting ultrasmall copper nanoparticles (Cu@CuOx) as nanovehicles not only for targeted positron emission tomography imaging by intrinsic radiolabeling with 64Cu but also for loading and delivery of the chemotherapy drug gemcitabine to PDAC. This 64Cu-radiolabeled nanovehicle allowed sensitive and accurate detection of PDAC malignancy in autochthonous genetically engineered mouse models. The ultrasmall Cu@CuOx showed efficient renal clearance, favorable pharmacokinetics, and minimal in vivo toxicity. Systemic administration of gemcitabine-loaded Cu@CuOx effectively suppressed the progression of PDAC tumors in a syngeneic xenograft mouse model and prolonged survival. These CCR2-targeted ultrasmall nanoparticles offer a promising image-guided therapeutic agent and show great potential for translation.",
keywords = "CCR2, PET, cancer treatment, pancreatic ductal adenocarcinoma, ultrasmall copper nanoparticle",
author = "Xiaohui Zhang and Lisa Detering and Deborah Sultan and Hannah Luehmann and Lin Li and Heo, {Gyu Seong} and Xiuli Zhang and Lanlan Lou and Grierson, {Patrick M.} and Suellen Greco and Marianna Ruzinova and Richard Laforest and Farrokh Dehdashti and Lim, {Kian Huat} and Yongjian Liu",
note = "Funding Information: This research is supported by Grant No. P50CA196510 from the National Cancer Institute; Washington University in St. Louis School of Medicine, the Department of Surgery, and Siteman Cancer Center; University of Rochester, University of North Carolina at Chapel Hill (Lineberger Comprehensive Cancer Center), and Johns Hopkins Medicine (The Sidney Kimmel Comprehensive Cancer Center). This work was partially supported by the National Cancer Institute (R01CA235672). This work was partially performed at the Nano Research Facility (NRF), a member of the National Nanotechnology Infrastructure Network (NNIN), which is supported by the National Science Foundation under Grant No. ECS-0335765. Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. NRF is part of the School of Engineering and Applied Science at Washington University in St. Louis. This work was performed with the support from the Siteman Cancer Center Small Animal Imaging Core at Washington University in St. Louis. We appreciate the staff members from Washington University cyclotron facility for Cu production. Experiments were performed in part through the use of Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children{\textquoteright}s Discovery Institute of Washington University and St. Louis Children{\textquoteright}s Hospital (CDI-CORE-2015-505) and the National Institute for Neurological Disorders and Stroke (NS086741). The authors acknowledge financial support from Washington University in St. Louis and the Institute of Materials Science and Engineering for the use of instruments and staff assistance. 64 Funding Information: This research is supported by Grant No. P50CA196510 from the National Cancer Institute; Washington University in St. Louis School of Medicine, the Department of Surgery, and Siteman Cancer Center; University of Rochester, University of North Carolina at Chapel Hill (Lineberger Comprehensive Cancer Center), and Johns Hopkins Medicine (The Sidney Kimmel Comprehensive Cancer Center). This work was partially supported by the National Cancer Institute (R01CA235672). This work was partially performed at the Nano Research Facility (NRF), a member of the National Nanotechnology Infrastructure Network (NNIN), which is supported by the National Science Foundation under Grant No. ECS-0335765. Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. NRF is part of the School of Engineering and Applied Science at Washington University in St. Louis. This work was performed with the support from the Siteman Cancer Center Small Animal Imaging Core at Washington University in St. Louis. We appreciate the staff members from Washington University cyclotron facility for 64Cu production. Experiments were performed in part through the use of Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children's Discovery Institute of Washington University and St. Louis Children's Hospital (CDI-CORE-2015-505) and the National Institute for Neurological Disorders and Stroke (NS086741). The authors acknowledge financial support from Washington University in St. Louis and the Institute of Materials Science and Engineering for the use of instruments and staff assistance. Publisher Copyright: {\textcopyright} 2021 American Chemical Society. All rights reserved.",
year = "2021",
month = jan,
day = "26",
doi = "10.1021/acsnano.0c08185",
language = "English",
volume = "15",
pages = "1186--1198",
journal = "ACS nano",
issn = "1936-0851",
number = "1",
}