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The effects of collagen-rich extracellular matrix on the intracellular delivery of glycol chitosan nanoparticles in human lung fibroblasts.
- Source :
-
International journal of nanomedicine [Int J Nanomedicine] 2017 Aug 21; Vol. 12, pp. 6089-6105. Date of Electronic Publication: 2017 Aug 21 (Print Publication: 2017). - Publication Year :
- 2017
-
Abstract
- 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.<br />Competing Interests: Disclosure The authors report no conflicts of interest in this work.
- Subjects :
- Amiloride pharmacology
Cells, Cultured
Chitosan chemistry
Chitosan pharmacokinetics
Chlorpromazine pharmacology
Collagen Type I metabolism
Drug Carriers administration & dosage
Drug Carriers chemistry
Drug Delivery Systems methods
Endocytosis drug effects
Extracellular Matrix metabolism
Fibroblasts metabolism
Genistein pharmacology
Humans
Lung metabolism
Nanoparticles chemistry
Phosphatidylinositol 3-Kinases metabolism
Chitosan administration & dosage
Fibroblasts drug effects
Idiopathic Pulmonary Fibrosis pathology
Lung cytology
Nanoparticles administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1178-2013
- Volume :
- 12
- Database :
- MEDLINE
- Journal :
- International journal of nanomedicine
- Publication Type :
- Academic Journal
- Accession number :
- 28860768
- Full Text :
- https://doi.org/10.2147/IJN.S138129