TY - JOUR
T1 - Nanoencapsulation of Gla-Rich Protein (GRP) as a Novel Approach to Target Inflammation
AU - Viegas, Carla S B
AU - Araújo, Nuna
AU - Carreira, Joana
AU - Pontes, Jorge F
AU - Macedo, Anjos L
AU - Vinhas, Maurícia
AU - Moreira, Ana S
AU - Faria, Tiago Q
AU - Grenha, Ana
AU - de Matos, António A
AU - Schurgers, Leon
AU - Vermeer, Cees
AU - Simes, Dina C
N1 - Funding Information:
Funding: This research was funded by Portuguese National Funds from FCT—Foundation for Science and Technology, through the transitional provision DL57/2016/CP1361/CT0006, projects EXPL/BTM-TEC/0990/2021, UIDB/04326/2020, UIDP/04326/2020 and LA/P/0101/2020; through UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences— UCIBIO, LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB, and by AAC nº 41/ALG/2020—Project nº 072583—NUTRISAFE. Nuna Araújo is the recipient of the Portuguese Science and Technology Foundation (FCT) fellowship SFRH/BD/111824/2015. Jorge F. Pontes is the recipient of the Portuguese Science and Technology Foundation (FCT) fellowship PD/BD/137064/2018.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/5
Y1 - 2022/5
N2 - Chronic inflammation is a major driver of chronic inflammatory diseases (CIDs), with a tremendous impact worldwide. Besides its function as a pathological calcification inhibitor, vitamin K-dependent protein Gla-rich protein (GRP) was shown to act as an anti-inflammatory agent independently of its gamma-carboxylation status. Although GRP's therapeutic potential has been highlighted, its low solubility at physiological pH still constitutes a major challenge for its biomedical application. In this work, we produced fluorescein-labeled chitosan-tripolyphosphate nanoparticles containing non-carboxylated GRP (ucGRP) (FCNG) via ionotropic gelation, increasing its bioavailability, stability, and anti-inflammatory potential. The results indicate the nanosized nature of FCNG with PDI and a zeta potential suitable for biomedical applications. FCNG's anti-inflammatory activity was studied in macrophage-differentiated THP1 cells, and in primary vascular smooth muscle cells and chondrocytes, inflamed with LPS, TNFα and IL-1β, respectively. In all these in vitro human cell systems, FCNG treatments resulted in increased intra and extracellular GRP levels, and decreased pro-inflammatory responses of target cells, by decreasing pro-inflammatory cytokines and inflammation mediators. These results suggest the retained anti-inflammatory bioactivity of ucGRP in FCNG, strengthening the potential use of ucGRP as an anti-inflammatory agent with a wide spectrum of application, and opening up perspectives for its therapeutic application in CIDs.
AB - Chronic inflammation is a major driver of chronic inflammatory diseases (CIDs), with a tremendous impact worldwide. Besides its function as a pathological calcification inhibitor, vitamin K-dependent protein Gla-rich protein (GRP) was shown to act as an anti-inflammatory agent independently of its gamma-carboxylation status. Although GRP's therapeutic potential has been highlighted, its low solubility at physiological pH still constitutes a major challenge for its biomedical application. In this work, we produced fluorescein-labeled chitosan-tripolyphosphate nanoparticles containing non-carboxylated GRP (ucGRP) (FCNG) via ionotropic gelation, increasing its bioavailability, stability, and anti-inflammatory potential. The results indicate the nanosized nature of FCNG with PDI and a zeta potential suitable for biomedical applications. FCNG's anti-inflammatory activity was studied in macrophage-differentiated THP1 cells, and in primary vascular smooth muscle cells and chondrocytes, inflamed with LPS, TNFα and IL-1β, respectively. In all these in vitro human cell systems, FCNG treatments resulted in increased intra and extracellular GRP levels, and decreased pro-inflammatory responses of target cells, by decreasing pro-inflammatory cytokines and inflammation mediators. These results suggest the retained anti-inflammatory bioactivity of ucGRP in FCNG, strengthening the potential use of ucGRP as an anti-inflammatory agent with a wide spectrum of application, and opening up perspectives for its therapeutic application in CIDs.
KW - Calcinosis/pathology
KW - Chondrocytes/metabolism
KW - Humans
KW - Inflammation/drug therapy
KW - Vitamin K/metabolism
KW - CALCIPROTEIN PARTICLES
KW - UPPER ZONE
KW - VASCULAR CALCIFICATION
KW - vitamin K-dependent protein (VKDP)
KW - CHITOSAN NANOPARTICLES
KW - CARTILAGE
KW - DELIVERY
KW - nanoparticles
KW - MATRIX-ASSOCIATED PROTEIN
KW - inflammation
KW - chronic inflammatory diseases (CIDs)
KW - SMOOTH-MUSCLE-CELLS
KW - GROWTH-PLATE
KW - TNF-ALPHA
KW - Gla-rich protein (GRP)
U2 - 10.3390/ijms23094813
DO - 10.3390/ijms23094813
M3 - Article
C2 - 35563203
SN - 1661-6596
VL - 23
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 9
M1 - 4813
ER -