Multimodal Imaging of Pancreatic Ductal Adenocarcinoma Using Multifunctional Nanoparticles as Contrast Agents.

Ying Zhao,Fei Ye,Sandra Oerther,Wolfgang J Parak,Moustapha Hassan,Joydeep Dutta,Mamoun Muhammed,Rainer Heuchel,Xuan Li,Torkel B Brismar,Ramy El-Sayed,Neus Feliu,Wenyi Zheng,Rui He

doi:10.1021/acsami.0c15430

Abstract

Late diagnosis and refractory behavior toward current treatment protocols make pancreatic ductal adenocarcinoma (PDAC) one of the most difficult cancer forms to treat. The imaging-based approach plays an important role to identify potentially curable PDAC patients in high-risk groups at the early stage. In the present study, we developed a core–shell structured gold nanorod (AuNR) as a contrast agent for multimodal imaging and investigated its application for PDAC diagnosis. The composite nanoparticles composed of a AuNR core inside a layer of mesoporous silica that was then coated with a gadolinium oxide carbonate shell (AuNR–SiO2–Gd) are designed to be used in magnetic resonance imaging (MRI), X-ray computed tomography (CT), and photoacoustic imaging (PAI). A phantom study with the AuNR–SiO2–Gd NPs demonstrated higher MRI contrast compared to Gadovist and higher X-ray attenuation than Visipaque. A strong, stable, and broad wavelength range signal with a peak at 800 nm was observed in PAI. The AuNR–SiO2–Gd NPs showed significant contrast enhancement under PAI/MRI/CT in both the liver and spleen of control mice after intravenous administration. The utility in PDAC was studied in a genetically engineered mouse model carrying Kras and p53 mutations, which develops spontaneous tumors and keeps the desmoplasia and hypovascularity feature of PDAC in patients. The AuNR–SiO2–Gd NPs were highly accumulated in the surrounding soft tissues but were sparsely distributed throughout the tumor due to dense stroma infiltration and poor tumor vascularization. Hence, a negative contrast within the tumor area in CT/PAI and a positive contrast in MRI were observed. In conclusion, AuNR–SiO2–Gd NPs have good potential to be developed as a multimodal contrast agent for PDAC, which might improve early diagnosis and benefit the clinical outcome for PDAC patients.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in Europe, and it is one of the most difficult cancers to treat
The large-area transmission electron microscopy (TEM) image in Figure S1 demonstrates that the morphology of a core−shell structured gold nanorod (AuNR)@mSiO2@Gd2O(CO3)[2] is fairly homogeneous and of ellipsoidal shape with an average aspect ratio of ca. 1.3
Unlike a previous report in which uniform mSiO2 layers were coated on cetyltrimethylammonium bromide (CTAB)-capped gold NRs at room temperature,[18] we found that low-temperature reactions (25 °C and 45 °C) led to interconnected core−shell particles and extra mSiO2 structures (Figure S2a,b)

Summary

■ INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in Europe, and it is one of the most difficult cancers to treat. Significantly higher ratios (fold) of Au and Gd concentration were found in the spleen, liver, and kidneys, which is consistent with the results obtained from MRI, PAI, and CT imaging To our knowledge, this is the first time a triple modality imaging contrast agent was developed and evaluated in the. Schematic Illustration of the Procedure for the Synthesis of AuNR@mSiO2@ Gd2O(CO3)[2] Composite NPs as the Contrast Agent for Multimodal Imaging (RDWc), were not affected by systemic administration of AuNR−SiO2−Gd NPs. There was a slight but not significant increase in the ALT value on day 1, and the enzyme value was within the normal range. The AST level was not affected by AuNR−SiO2−Gd NPs, indicating that the accumulation of NPs in the liver does not cause an elevation in liver enzymes

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES