Targeting Activated Hepatic Stellate Cells Using Collagen-Binding Chitosan Nanoparticles for siRNA Delivery to Fibrotic Livers.
Menna AzzamSara El SafySarah A AbdelgelilRalf WeiskirchenAnastasia AsimakopoulouFederica de LorenziTwan LammersSamar MansourSalma TammamPublished in: Pharmaceutics (2020)
Activated hepatic stellate cells (aHSCs) are the main orchestrators of the fibrotic cascade in inflamed livers, with transforming growth factor-beta (TGF-β) being the most potent pro-fibrotic cytokine. Hence, aHSCs serve as interesting therapeutic targets. However, drug delivery to aHSCs is hindered by excessive collagen deposition in the extracellular matrix (ECM) and capillarization of liver sinusoids. Chitosan-nanoparticles (CS-NPs) show intrinsic affinity for collagen, holding potential for drug delivery to fibrotic livers. Here, we employed CS-NPs for anti-TGF-β siRNA delivery, promoting delivery into aHSCs via modification with platelet-derived growth factor receptor-beta binding peptides. In-vitro experiments using aHSCs demonstrated the association of unmodified CS-NPs to the collagen-rich ECM, with reduced intracellular accumulation. Peptide-modified CS-NPs showed a higher propensity to localize intracellularly; however, this was only the case upon ECM-collagen reduction via collagenase treatment. Peptide-modified CS-NPs were more potent than unmodified CS-NPs in reducing TGF-β expression, implying that while collagen binding promotes liver accumulation, it hinders cell-specific siRNA delivery. In-vivo, CS-NPs successfully accumulated in fibrotic livers via collagen binding. Similar to in-vitro findings, when mice were pretreated with collagenase-loaded CS-NPs, the accumulation of peptide-modified NPs increased. Our findings demonstrate the usefulness of NPs modification with targeting ligands and collagenase treatment for aHSCs targeting and highlight the importance of chitosan-collagen binding in drug delivery to fibrotic diseases.
Keyphrases
- drug delivery
- cancer therapy
- wound healing
- transforming growth factor
- extracellular matrix
- oxide nanoparticles
- systemic sclerosis
- tissue engineering
- idiopathic pulmonary fibrosis
- growth factor
- epithelial mesenchymal transition
- induced apoptosis
- binding protein
- drug release
- cell cycle arrest
- dna binding
- hyaluronic acid
- single cell
- body mass index
- anti inflammatory
- metabolic syndrome
- endoplasmic reticulum stress
- oxidative stress
- adipose tissue
- cell death
- combination therapy
- weight gain
- transcription factor
- physical activity