期刊
ACS NANO
卷 11, 期 9, 页码 9445-9458出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.7b05103
关键词
nanoparticles; fracture healing; peptide; drug delivery; small molecule drug
类别
资金
- National Science Foundation (NSF) [DMR1206219, CBET1450987]
- National Institutes of Health (NIH) [R01 AR064200, R01 AR056696, UL1 TR002001]
- New York State Stem Cell Science (NYSTEM) funding [N11G-035]
- NIH funds [S10-RR026542, P30-AR069655, S10-RR027340]
- Directorate For Engineering [1450987] Funding Source: National Science Foundation
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR002001] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR027340, S10RR026542] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [P30AR069655, R01AR064200, R01AR056696] Funding Source: NIH RePORTER
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 beta-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-3 beta) inhibitor, was developed to enhance fracture healing. The GSK-3 beta inhibitor loading capacity was found to be 15 wt % within highly stable poly(styrene-alt-maleic anhydride)-b-poly(styrene) NPs, resulting in similar to 50 nm particles with similar to-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 beta-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-3 beta inhibitor-loaded NPs. Robust beta-galactosidase activity was observed in fracture callus and periosteum treated with targeted carriers versus controls, indicating potent beta-catenin activation during the healing process. Enhanced bone formation and microarchitecture were observed in mice treated with GSK-3 beta inhibitor delivered via TRAP-binding peptide-targeted NPs. Specifically, increased bone bridging, similar to 4-fold greater torsional rigidity, and greater volumes of newly deposited bone were observed 28 days after treatment, indicating expedited fracture healing.
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