
CC Chemokine Receptor 2-Targeting Copper Nanoparticles for Positron Emission Tomography-Guided Delivery of Gemcitabine for Pancreatic Ductal Adenocarcinoma
Author(s) -
Xiaohui Zhang,
Lisa Detering,
Deborah Sultan,
Hannah Luehmann,
Lin Li,
Gyu Seong Heo,
Xiuli Zhang,
LanLan Lou,
Patrick Grierson,
Suellen Greco,
Marianna B. Ruzinova,
Richard Laforest,
Farrokh Dehdashti,
Kian Huat Lim,
Yongjian Liu
Publication year - 2021
Publication title -
acs nano
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.554
H-Index - 382
eISSN - 1936-086X
pISSN - 1936-0851
DOI - 10.1021/acsnano.0c08185
Subject(s) - gemcitabine , cancer research , stromal cell , tumor microenvironment , positron emission tomography , chemokine receptor , malignancy , chemokine , pancreatic cancer , medicine , ccr2 , pathology , chemotherapy , receptor , cancer , nuclear medicine , tumor cells
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@CuO x ) as nanovehicles not only for targeted positron emission tomography imaging by intrinsic radiolabeling with 64 Cu but also for loading and delivery of the chemotherapy drug gemcitabine to PDAC. This 64 Cu-radiolabeled nanovehicle allowed sensitive and accurate detection of PDAC malignancy in autochthonous genetically engineered mouse models. The ultrasmall Cu@CuO x showed efficient renal clearance, favorable pharmacokinetics, and minimal in vivo toxicity. Systemic administration of gemcitabine-loaded Cu@CuO x 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.