Metformin-Induced Stromal Depletion to Enhance the Penetration of Gemcitabine-Loaded Magnetic Nanoparticles for Pancreatic Cancer Targeted Therapy

Abstract

Pancreatic ductal adenocarcinoma, as one of the most aggressive cancers, is characterized by rich desmoplastic stroma that forms a physical barrier for anticancer drugs. To address this issue, we herein report a two-step sequential delivery strategy for targeted therapy of pancreatic cancer with gemcitabine (GEM). In this sequential strategy, metformin (MET) was first administrated to disrupt the dense stroma, based on the fact that MET downregulated the expression of fibrogenic cytokine TGF-β to suppress the activity of pancreatic stellate cells (PSCs), through the 5′-adenosine monophosphate-activated protein kinase pathway of PANC-1 pancreatic cancer cells. In consequence, the PSC-mediated desmoplastic reactions generating αsmooth muscle actin and collagen were inhibited, which promoted the delivery of GEM and pH (low) insertion peptide (pHLIP) comodified magnetic nanoparticles (denoted as GEM-MNP-pHLIP). In addition, pHLIP largely increased the binding affinity of the nanodrug to PANC-1 cells. The targeted delivery and effective accumulation of MET/GEM-MNP-pHLIP in vivo were confirmed by magnetic resonance imaging enhanced by the underlying magnetic nanoparticles. The tumor growth inhibition of the sequential MET and GEM-MNP-pHLIP treatment were investigated on both subcutaneous and orthotopic tumor mice models. A remarkably improved therapeutic efficacy, for example, up to 91.2% growth inhibition ratio over 30 d of treatment, well-exemplified the novel cascade treatment for pancreatic cancer and the innovative use of MET.

Adipose‐derived mesenchymal stem cells differentiate into pancreatic cancer‐associated fibroblasts in vitro

“…Recent studies have suggested that CAFs were derived from MSCs, which may be either populated in the pancreas or recruited by neoplastic cells [7,30]. Whereas pancreatic stellate cells from mice or from human patients were used in previous studies [31,32], they were unstable and quite variable, as their characteristics were not accurately assessed. We focused on AD-MSCs as the source of CAFs because they are available, easy to handle, and are multipotent, allowing their differentiation into CAFs [33,34].…”

The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives

“…Duan et al indicated that metformin suppressed paracrine-mediated activation of PSCs in the coculture setting of PCCs–PSCs ( 200 ). Han et al revealed that metformin inhibited the PSC-mediated desmoplastic reactions, thus reducing tumor size and improving the perfusion of GEM-loaded magnetic nanoparticles in a murine orthotopic PDAC model ( 157 ). More recently, metformin was shown to suppress angiogenesis and increase GEM chemosensitivity via deactivating PSCs in KPC mice ( 201 ).…”

Recent Progress of Nanocarrier-Based Therapy for Solid Malignancies

“…Findings suggested that targeted delivery and effective accumulation of the nanomedicine both in vitro and in vivo. Furthermore, the configuration change of pHLIP is controlled by the acidic environment of the tumor, which is beneficial to deliver GEM into the tumor sites [ 127 ].…”