Graphene Fluorescent Nanoparticles Efficiently Targeting Cancer-Associated Fibroblasts and Pancreatic Cancer Cells

Abstract

Background: Pancreatic cancer is a highly aggressive, rapidly progressing fatal digestive tract tumor. Cancer-associated fibroblasts form a barrier to the penetration of drugs or therapeutic immune cells. Therefore, the inhibition of tumors by modulating CAFs or overcoming their barrier effect is a new tool for tumor therapy. This study aimed to reveal the efficiency of graphene fluorescent nanoparticles targeting cancer-associated fibroblasts and tumor cells and demonstrate the application prospects of nanomedicine. Methods: We observed the co-localization effect of synthetic GFNPs on tumor cells and Cancer-associated fibroblasts in primary and metastatic pancreatic cancer, and synthesized a new nano-drug based on GFNPs and gemcitabine. In vivo imaging system and confocal laser scanning microscope were used for observing the location of GFNPs in tissues. Immunofluorescence staining and Halo analysis are used to observe and count the co-location of GFNPs in the tumor microenvironment. Results: GFNPs is not only abundantly deposited nearby tumor vessels but also penetrate tumor tissues to reach those regions far away from tumor vessels. Tagging data are as follows, GFNPs can label up to 30% of tumor cells or cancer-associated fibroblast cells inside human pancreatic cancer tissue and mouse tumor metastasis tissue. Over 60% of cancer-associated fibroblast cells in orthotopic pancreatic tumor tissues were marked by GFNPs. GFNPs localize in the nuclei of both αSMA-CAFs and adjacent tumor cells, then the fluorescence signal intensity was proportional to the tumor development cycle. The differences in the co-localization of GFNPs with the nuclei of positive Ki67-expressing tumor cells in primary and metastatic pancreatic cancer were investigated in-depth, fully illustrating that the spatial location of GFNPs in the TME is closely related to the degree of tumor differentiation and progression, guiding the diagnosis of clinical tumors. Based on the dual targeting characteristics of GFNPs targeting CAFs and tumor cells, we combined GFNPs with gemcitabine to form a new nano-drug with an effective reduction of tumor volume and fewer side effects. Conclusion: This study will provide useful insights into a dual-targeting strategy utilized in the field of pancreatic cancer therapy by targeting both CAFs and pancreatic cancer cells simultaneously.