Bone-targeted polymer therapeutics for non-union fracture healing

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Of the more than 15 million Americans suffer from fractures each year, 5% result in nonunions. Standard nonunion management is revision surgery: debridement, followed by autograft, and/or additional fixation. However, revision surgery carries risks inherent to any surgery and fails in up to 60% of cases due to underlying comorbidities. Therefore, novel therapeutics for treating nonunions are critical and should obviate surgery through noninvasive delivery or increase revision surgery success. Mesenchymal stem cell (MSC) deficiencies underpin poor healing. Despite the promise of several drug candidates for augmenting MSC function for nonunion healing, side effects due to poor fracture biodistribution have hampered development. Thus, a critical technological gap exists in delivery of potent, regenerative drugs to fracture sites while limiting biodistribution to off-target tissues to improve safety and clinical translatability. To address these hurdles, we have developed a fracture-targeted nanoparticle (NP)-based delivery system for the GSK-3β inhibitor AR28 to upregulate the regenerative Wnt/β-catenin pathway. Targeting is achieved by incorporation of a peptide that binds specifically to tartrate resistant acid phosphatase (TRAP5b), a matrix-bound protein deposited by osteoclasts throughout healing and at nonunions. TRAP5b-binding peptide (TBP) targeted NP exhibit preferential accumulation at conventional femur fractures. Fracture localized activation of β-catenin is greatly increased compared with untreated, free drug, untargeted NP, and scrambled peptide NP controls. Expedited callus formation was observed in fractures treated with TBP-NPAR28 versus controls with more rapid ossification of cartilage callus. Finally, the maximum torque to failure of treated fractures was ~3-4-fold greater than controls 4 weeks after treatments. While promising to expedite healing in conventional fractures that will regenerate without intervention, the efficacy of this technology must be tested in more clinically rigorous and relevant preclinical models. We hypothesize that TBP-NPAR28 will enable drug delivery to fracture nonunions in aged and adult mice. With a long-term goal of treating fracture nonunions using this approach, we propose the following aims: Aim 1: Assess the therapeutic effect of a TBP-NPAR28 for the prevention of nonunion in adult and aged murine models. Aim 2: Assess the therapeutic effect of TBP-NPAR28 in fully established nonunions in adult and aged mice. Successful completion of these Aims will significantly advance our ability to target drugs to prevent or enable healing of adult and aged nonunion fractures.