CC Chemokine Receptor 2-Targeting Copper Nanoparticles for Positron Emission Tomography-Guided Delivery of Gemcitabine for Pancreatic Ductal Adenocarcinoma.
Xiaohui ZhangLisa DeteringDeborah SultanHannah LuehmannLin LiGyu Seong HeoXiuli ZhangLanlan LouPatrick M GriersonSuellen GrecoMarianna RuzinovaRichard LaforestFarrokh DehdashtiKian-Huat LimYongjian LiuPublished in: ACS nano (2021)
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.
Keyphrases
- positron emission tomography
- computed tomography
- mouse model
- cancer therapy
- dendritic cells
- induced apoptosis
- early stage
- high resolution
- locally advanced
- regulatory t cells
- aqueous solution
- pet ct
- cell cycle arrest
- pet imaging
- metal organic framework
- bone marrow
- drug delivery
- oxidative stress
- endoplasmic reticulum stress
- iron oxide
- loop mediated isothermal amplification
- acute myeloid leukemia
- rectal cancer
- liver fibrosis
- immune response
- neoadjuvant chemotherapy
- label free
- photodynamic therapy
- oxide nanoparticles
- lymph node
- mass spectrometry
- adverse drug
- case report
- heat shock
- fluorescence imaging
- quantum dots
- sensitive detection
- wound healing