Development of triple-functionalized calcium phosphate nanoparticles as an advanced drug delivery system for bone tissue repair

Taichi Tenkumo; Benedikt Kruse; Kathrin Kostka; Viktoriya Sokolova; Toru Ogawa; Nobuhiro Yoda; Oleg Prymak; Osamu Suzuki; Keiichi Sasaki; Matthias Epple

doi:10.1016/j.reth.2023.11.010

Development of triple-functionalized calcium phosphate nanoparticles as an advanced drug delivery system for bone tissue repair

Regen Ther. 2023 Nov 28:25:49-60. doi: 10.1016/j.reth.2023.11.010. eCollection 2024 Mar.

Authors

Affiliations

¹ Division of Advanced Prosthetic Dentistry, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
² Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CENIDE), University of Duisburg-Essen, Universitaetsstr. 5-7, D-45117 Essen, Germany.
³ Division of Craniofacial Function Engineering, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.

Abstract

Introduction: During tissue repair or regeneration, several bioactive molecules are released and interact with each other and act as complex additives or inhibitors for tissue reconstruction. In this study, the bone-healing effects of the combination treatment with tumor necrosis factor-α (TNF-α) inhibition, vascular endothelial growth factor A (VEGF-A) and bone morphogenetic protein-7 (BMP-7) release by gene silencing, and gene transfection with calcium phosphate nanoparticles (CaP) in the rat femoral head was histologically, morphologically, and biochemically evaluated.

Methods: A triple-functionalized paste of CaP carrying plasmid DNA encoding for BMP-7 and for VEGF), and siRNA against TNF-α was developed and denoted as CaP3mix. To compare the effects of 3mixCaP, CaP with plasmid DNA encoding BMP-7, VEGF, or siRNA encoding TNF-α was prepared and denoted as CaP/PEI/pBMP-7/SiO₂, CaP/PEI/pVEGF/SiO₂, or CaP/PEI/siRNA-TNF-α/SiO₂, respectively. The bone healing in bone defects in the rat femoral head was investigated after 10 and 21 days of implantation.

Results: The levels of bone formation-related markers OCN, Runx2, and SP7 increased at the protein and gene levels in 3mixCaP after 10 days, and 3mixCaP significantly accelerated bone healing compared with the other treatments after 21 days of implantation.

Conclusion: The triple-functionalized CaP paste loading plasmid DNA encoding BMP-7 and VEGF and siRNA encoding TNF-α is a promising bioactive material for bone tissue repair.

Keywords: BMP-7; Bone regeneration; Gene silencing; Gene transfection; TNF-α; VEGF-A.