Albumin-conjugated flumethasone for targeting and normalization of pancreatic stellate cells

Abstract

The tumor microenvironment (TME) plays a critical role in the poor clinical outlook for pancreatic ductal adenocarcinoma (PDAC). Activated pancreatic stellate cells (PSC) drive the complex interactions within the TME, resulting in a microenvironment that is resistant to chemotherapy and tolerant to the immune system, thereby promoting tumor growth. Effective deactivation of PSC is vital in treating pancreatic cancer. However, previous studies have only focused on limited changes in PSC phenotype without comprehensively analysing their overall function. Our transcriptome analysis identified agents capable of modulating multiple biological functions of PSC, including fibrosis, extracellular matrix generation, and the secretion of cytokines and immune factors. Through this comprehensive assessment, we discovered that flumethasone (Flu) effectively deactivates PSC. This glucocorticoid analogue remodels the tumor microenvironment by regulating the secretomes of PSC and their interaction with tumor cells. Additionally, our research revealed that activated PSC exhibited heightened albumin endocytosis. As a result, we propose that albumin conjugation could serve as an effective targeted drug delivery approach for PSC. Our findings also demonstrate that albumin-conjugated Flu maintained reprogramming capabilities in stromal cells, and enhanced the efficacy of chemotherapy in orthotopic mouse models of PDAC and Kras^G12D/+; LSL-Trp53^R172H/+; Pdx-1-Cre (KPC) pancreatic tumor allograft mouse model. Our investigation into the mechanism of PSC deactivation by flumethasone has revealed its potential for clinical cancer treatment through its effects on the tumor microenvironment. Furthermore, the conjugation of flumethasone to albumin enhances its safety and targeted delivery, offering a promising approach for PSC-targeted drug application in pancreatic cancer treatment.