Fracture-Targeted Delivery of β-Catenin Agonists via Peptide-Functionalized Nanoparticles Augments Fracture Healing
| Autor: | Tzong-Jen Sheu, Marian A. Ackun-Farmmer, Yuchen Wang, Maureen R. Newman, J. Edward Puzas, Michael P. Baranello, Danielle S. W. Benoit |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Agonist Materials science medicine.drug_class General Physics and Astronomy Peptide 02 engineering and technology Bone healing Bone and Bones 03 medical and health sciences Mice Drug Delivery Systems medicine Animals General Materials Science GSK3B Protein Kinase Inhibitors Cells Cultured beta Catenin chemistry.chemical_classification Sulfonyl Fracture Healing Drug Carriers Glycogen Synthase Kinase 3 beta biology General Engineering Acid phosphatase 021001 nanoscience & nanotechnology Mice Inbred C57BL 030104 developmental biology Biochemistry chemistry Drug delivery Systemic administration biology.protein Biophysics Nanoparticles 0210 nano-technology Peptides |
| Zdroj: | ACS nano. 11(9) |
| ISSN: | 1936-086X |
| Popis: | Despite several decades of progress, bone-specific drug delivery is still a major challenge. Current bone-acting drugs require high-dose systemic administration which decreases therapeutic efficacy and increases off-target tissue effects. Here, a bone-targeted nanoparticle (NP) delivery system for a β-catenin agonist, 3-amino-6-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-N-(pyridin-3-yl)pyrazine-2-carboxamide, a glycogen synthase kinase 3 beta (GSK-3β) inhibitor, was developed to enhance fracture healing. The GSK-3β inhibitor loading capacity was found to be 15 wt % within highly stable poly(styrene-alt-maleic anhydride)-b-poly(styrene) NPs, resulting in ∼50 nm particles with ∼ -30 mV surface charge. A peptide with high affinity for tartrate-resistant acid phosphatase (TRAP), a protein deposited by osteoclasts on bone resorptive surfaces, was introduced to the NP corona to achieve preferential delivery to fractured bone. Targeted NPs showed improved pharmacokinetic profiles with greater accumulation at fractured bone, accompanied by significant uptake in regenerative cell types (mesenchymal stem cells (MSCs) and osteoblasts). MSCs treated with drug-loaded NPs in vitro exhibited 2-fold greater β-catenin signaling than free drug that was sustained for 5 days. To verify similar activity in vivo, TOPGAL reporter mice bearing fractures were treated with targeted GSK-3β inhibitor-loaded NPs. Robust β-galactosidase activity was observed in fracture callus and periosteum treated with targeted carriers versus controls, indicating potent β-catenin activation during the healing process. Enhanced bone formation and microarchitecture were observed in mice treated with GSK-3β inhibitor delivered via TRAP-binding peptide-targeted NPs. Specifically, increased bone bridging, ∼4-fold greater torsional rigidity, and greater volumes of newly deposited bone were observed 28 days after treatment, indicating expedited fracture healing. |
| Databáze: | OpenAIRE |
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