&gt;10 million Americans suffer fractures annually, of which ～20% have impaired fracture healing resulting from dysfunctional mesenchymal stem cell (MSC) function. The Wnt/β-catenin pathway is a promising target to augment MSC function during healing. However, systemic delivery of β-catenin agonists at doses necessary to affect bone results in myriad off-target effects. Therefore, fracture-targeted nanoparticles (NPs) were designed to provide greater s selectivity of β-catenin agonist, AR28. Specifically, diblock copolymers of poly(styrene-alt-maleic anhydride)-b-poly(styrene) were synthesized, self-assembled into NPs, and functionalized with a peptide with high affinity toward tartrate resistant acid phosphatase 5b (TRAP5b), a protein deposited by osteoclasts during bone remodeling. AR28-loaded NP, TBP-NP, and scrambled control peptide (SCP)-NP exhibited sizes of ~50 nm and surface charge of ~-26 mV with 14 wt% AR28. NP, SCP-NP, and TBP-NP showed minimal biodistribution to liver and TBP-NP showed ~5- and 2-fold higher accumulation at fractured femur compared with SCP-NP and untargeted NPs, respectively. Fracture localized β-catenin activation was also observed, with TBP-NP-AR28 resulting in robust β-galactosidase staining in TOPGAL reporter mice and x-ray showing enhanced callus formation with more rapid ossification of cartilage callus versus controls. Finally, torsional biomechanics of healing fractures were significantly greater (~2.5-4-fold) than controls 3 weeks after treatments altogether highlighting that TBP-NP provide robust targeting for small molecule bone regenerative drugs with reduced off-target side effects, which is not currently possible via systemic delivery.

Fracture healing is expedited via preferential upregulation of Wnt/β-catenin using targeted nanoparticle GSK3β inhibitor delivery

256th National Meeting (2018)

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