Therapeutic Strategies to Overcome Fibrotic Barriers to Nanomedicine in the Pancreatic Tumor Microenvironment

Pancreatic cancer is notorious for its dismal prognosis. The enhanced permeability and retention (EPR) effect theory posits that nanomedicines (therapeutics in the size range of approximately 10–200 nm) selectively accumulate in tumors. Nanomedicine has thus been suggested to be the “magic bullet”—both effective and safe—to treat pancreatic cancer. However, the densely fibrotic tumor microenvironment of pancreatic cancer impedes nanomedicine delivery. The EPR effect is thus insufficient to achieve a significant therapeutic effect. Intratumoral fibrosis is chiefly driven by aberrantly activated fibroblasts and the extracellular matrix (ECM) components secreted. Fibroblast and ECM abnormalities offer various potential targets for therapeutic intervention. In this review, we detail the diverse strategies being tested to overcome the fibrotic barriers to nanomedicine in pancreatic cancer. Strategies that target the fibrotic tissue/process are discussed first, which are followed by strategies to optimize nanomedicine design. We provide an overview of how a deeper understanding, increasingly at single-cell resolution, of fibroblast biology is revealing the complex role of the fibrotic stroma in pancreatic cancer pathogenesis and consider the therapeutic implications. Finally, we discuss critical gaps in our understanding and how we might better formulate strategies to successfully overcome the fibrotic barriers in pancreatic cancer

Therapeutic Strategies to Overcome Fibrotic Barriers to Nanomedicine in the Pancreatic Tumor Microenvironment

Simple Summary Pancreatic cancer is difficult to treat. Novel treatment strategies are urgently needed to improve the survival rate, which is approximately 10% five years after diagnosis. The use of nanomedicines, which are formulated within a characteristic size range that favors its specific delivery to the diseased tissue, is being actively explored in cancer treatment. However, fibrosis (the abnormal accumulation of a cell type called fibroblasts and the fibrous protein network that they create) is characteristically seen in pancreatic cancer and hinders the delivery of nanomedicines into cancerous tissue. The decreased efficiency of delivery limits the therapeutic effects of nanomedicine in pancreatic cancer. We call this the "fibrotic barrier" to nanomedicine. To overcome the fibrotic barrier, we could target the fibrotic process and/or optimize the nanomedicine design. In this review, we give a detailed overview of strategies to overcome the fibrotic barriers in pancreatic cancer and highlight key gaps in our understanding. Pancreatic cancer is notorious for its dismal prognosis. The enhanced permeability and retention (EPR) effect theory posits that nanomedicines (therapeutics in the size range of approximately 10-200 nm) selectively accumulate in tumors. Nanomedicine has thus been suggested to be the "magic bullet"-both effective and safe-to treat pancreatic cancer. However, the densely fibrotic tumor microenvironment of pancreatic cancer impedes nanomedicine delivery. The EPR effect is thus insufficient to achieve a significant therapeutic effect. Intratumoral fibrosis is chiefly driven by aberrantly activated fibroblasts and the extracellular matrix (ECM) components secreted. Fibroblast and ECM abnormalities offer various potential targets for therapeutic intervention. In this review, we detail the diverse strategies being tested to overcome the fibrotic barriers to nanomedicine in pancreatic cancer. Strategies that target the fibrotic tissue/process are discussed first, which are followed by strategies to optimize nanomedicine design. We provide an overview of how a deeper understanding, increasingly at single-cell resolution, of fibroblast biology is revealing the complex role of the fibrotic stroma in pancreatic cancer pathogenesis and consider the therapeutic implications. Finally, we discuss critical gaps in our understanding and how we might better formulate strategies to successfully overcome the fibrotic barriers in pancreatic cancer

Long-term Prognosis for Non-ischemic Heart Disease Patients with Premature Ventricular Contraction and Non-sustained Ventricular Tachycardia

There are few long-term reports of patients with frequent PVCs in the absence of ischemic heart disease. In 86 patients without ischemic heart disease, who had 1000 or more PVCs in 24-hour Holter ECG, the number of PVCs during 24-hours Holter ECG and echocardiographic parameters were followed at least 1 year (66.5 ± 39.7 months). PVC was significantly reduced in the patients with or without underlying diseases (UD). The reduction rate in the number of PVCs was prominent in patients with UD. PVC was significantly reduced in patients under medication, but not in patients without medication. In the comparison between the initial and follow up observation using Wilcoxon's rank test, the number of PVC was significantly reduced (P < 0.05), and EF was also improved (P < 0.05) in angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) group, and in β-blocker group. In Ca-antagonist group and antiarrhythmic drug group, the number of PVCs was also significantly reduced (P < 0.05). Multivariate analysis revealed significantly higher incidence (60% or more with PVC reduction) in ACEI/ARB group. These results suggest that the administration of ACEI/ARB may contribute to the reduction of PVC in non-ischemic heart disease cases with multiple PVC