Yhee, Ji Young Yoon, Hong Yeol Kim, Hyunjoon Jeon, Sangmin Hergert, Polla Im, Jintaek Panyam, Jayanth Kim, Kwangmeyung Nho, Richard Seonghun 2024-01-20T01:01:20Z 2024-01-20T01:01:20Z 2021-09-05 2017-08 1176-9114 https://pubs.kist.re.kr/handle/201004/122453 Recent progress in nanomedicine has shown a strong possibility of targeted therapy for obstinate chronic lung diseases including idiopathic pulmonary fibrosis (IPF). IPF is a fatal lung disease characterized by persistent fibrotic fibroblasts in response to type I collagen-rich extracellular matrix. As a pathological microenvironment is important in understanding the biological behavior of nanoparticles, in vitro cellular uptake of glycol chitosan nanoparticles (CNPs) in human lung fibroblasts was comparatively studied in the presence or absence of type I collagen matrix. Primary human lung fibroblasts from non-IPF and IPF patients (n=6/group) showed significantly increased cellular uptake of CNPs (> 33.6-78.1 times) when they were cultured on collagen matrix. To elucidate the underlying mechanism of enhanced cellular delivery of CNPs in lung fibroblasts on collagen, cells were pretreated with chlorpromazine, genistein, and amiloride to inhibit clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis, respectively. Amiloride pretreatment remarkably reduced the cellular uptake of CNPs, suggesting that lung fibroblasts mainly utilize the macropinocytosis-dependent mechanism when interacted with collagen. In addition, the internalization of CNPs was predominantly suppressed by a phosphoinositide 3-kinase (PI3K) inhibitor in IPF fibroblasts, indicating that enhanced PI3K activity associated with late-stage macropinocytosis can be particularly important for the enhanced cellular delivery of CNPs in IPF fibroblasts. Our study strongly supports the concept that a pathological microenvironment which surrounds lung fibroblasts has a significant impact on the intracellular delivery of nanoparticles. Based on the property of enhanced intracellular delivery of CNPs when fibroblasts are made to interact with a collagen-rich matrix, we suggest that CNPs may have great potential as a drug-carrier system for targeting fibrotic lung fibroblasts. English DOVE MEDICAL PRESS LTD IDIOPATHIC PULMONARY-FIBROSIS SELF-ASSEMBLED NANOPARTICLES TARGETED DELIVERY CELLULAR UPTAKE PATHWAYS DRUG MACROPINOCYTOSIS MODEL ACID The effects of collagen-rich extracellular matrix on the intracellular delivery of glycol chitosan nanoparticles in human lung fibroblasts Article 10.2147/IJN.S138129 1 INTERNATIONAL JOURNAL OF NANOMEDICINE, v.12, pp.6089 - 6105 INTERNATIONAL JOURNAL OF NANOMEDICINE 12 6089 6105 scie scopus 000408054000002 2-s2.0-85028321135 Nanoscience & Nanotechnology Pharmacology & Pharmacy Science & Technology - Other Topics Pharmacology & Pharmacy Article IDIOPATHIC PULMONARY-FIBROSIS SELF-ASSEMBLED NANOPARTICLES TARGETED DELIVERY CELLULAR UPTAKE PATHWAYS DRUG MACROPINOCYTOSIS MODEL ACID cellular uptake glycol chitosan nanoparticles idiopathic pulmonary fibrosis macropinocytosis type I collagen matrix