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Bone-Targeting Systems to Systemically Deliver Therapeutics to Bone Fractures for Accelerated Healing

  • Therapeutics and Medical Management (S Jan De Beur and B Clarke, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Compared with the current standard of implanting bone anabolics for fracture repair, bone fracture-targeted anabolics would be more effective, less invasive, and less toxic and would allow for control over what phase of fracture healing is being affected. We therefore sought to identify the optimal bone-targeting molecule to allow for systemic administration of therapeutics to bone fractures.

Recent Findings

We found that many bone-targeting molecules exist, but most have been developed for the treatment of bone cancers, osteomyelitis, or osteoporosis. There are a few examples of bone-targeting ligands that have been developed for bone fractures that are selective for the bone fracture over the body and skeleton.

Summary

Acidic oligopeptides have the ideal half-life, toxicity profile, and selectivity for a bone fracture-targeting ligand and are the most developed and promising of these bone fracture-targeting ligands. However, many other promising ligands have been developed that could be used for bone fractures.

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Abbreviations

6BIO:

6-Bromoindirubin-3′-oxime

EP1:

Prostaglandin E2 receptor 1

HA:

Hydroxyapatite

BMP:

Bone morphogenetic proteins

MSC:

Mesenchymal stem cells

LIPUS:

Low-intensity pulsed ultrasound

BRONJ:

Osteonecrosis of the jaw

FFPS:

Farnesyl pyrophosphate

TRAP:

Tartrate-resistant acid phosphate

ELVIS:

Extravasation through Leaky Vasculature and Inflammatory cell-mediated Sequestration

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. The Bone and Joint Initative. The burden of musculoskeletal diseases in the United States. 4th; 2019.

  2. Nyman JS. Effect of diabetes on the fracture resistance of bone. Clin Rev Bone Miner Metab. 2013;11(1):38–48.

    CAS  Google Scholar 

  3. Nyman JS, Even JL, Jo CH, Herbert EG, Murry MR, Cockrell GE, et al. Increasing duration of type 1 diabetes perturbs the strength-structure relationship and increases brittleness of bone. Bone. 2011;48(4):733–40.

    PubMed  Google Scholar 

  4. Nyman JS, Kalaitzoglou E, Clay Bunn R, Uppuganti S, Thrailkill KM, Fowlkes JL. Preserving and restoring bone with continuous insulin infusion therapy in a mouse model of type 1 diabetes. Bone Rep. 2017;7:1–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Henderson S, Ibe I, Cahill S, Chung YH, Lee FY. Bone quality and fracture-healing in type-1 and type-2 diabetes mellitus. J Bone Jt Surg Am Vol. 2019;101(15):1399–410.

    Google Scholar 

  6. Schnell S, Friedman SM, Mendelson DA, Bingham KW, Kates SL. The 1-year mortality of patients treated in a hip fracture program for elders. Geriatr Orthop Surg Rehabil. 2010;1(1):6–14.

    PubMed  PubMed Central  Google Scholar 

  7. Carpintero P, Caeiro JR, Carpintero R, Morales A, Silva S, Mesa M, et al. Complications of hip fractures : a review. World J Orthop. 2014;5(4):402–11.

    PubMed  PubMed Central  Google Scholar 

  8. Einhorn TA, Gerstenfeld L. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2015;11(1):45–54.

    PubMed  Google Scholar 

  9. White AP, Vaccaro AR, Hall JA, Whang PG, Friel BC, McKee MD. Clinical applications of BMP-7/OP-1 in fractures, nonunions and spinal fusion. Int Orthop. 2007;31(6):735–41.

    PubMed  PubMed Central  Google Scholar 

  10. Ebara S, Nakayama K. Mechanism for the action of bone morphogenetic proteins and regulation of their activity. Spine (Phila Pa 1976). 2002;27(16 SUPPL):10–5.

    Google Scholar 

  11. Bergeron E, Leblanc E, Drevelle O, Giguère R, Beauvais S, Grenier G, et al. The evaluation of ectopic bone formation induced by delivery systems for bone morphogenetic protein-9 or its derived peptide. Tissue Eng A. 2012;18(3–4):342–52.

    CAS  Google Scholar 

  12. Haas AV, LeBoff MS. Osteoanabolic agents for osteoporosis. J Endocr Soc. 2018;2(8):922–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kyllönen L, D’Este M, Alini M, Eglin D. Local drug delivery for enhancing fracture healing in osteoporotic bone. Acta Biomater. 2015;11:412–34.

    PubMed  Google Scholar 

  14. Wang Y, Malcolm DW, Benoit DSW. Controlled and sustained delivery of siRNA/NPs from hydrogels expedites bone fracture healing. Biomaterials. 2017;139:127–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Bhongade ML, Tiwari IR. A comparative evaluation of the effectiveness of an anorganic bone matrix/cell binding peptide with an open flap debridement in human infrabony defects: a clinical and radiographic study. J Contemp Dent Pract. 2007;8(6):25–34.

    PubMed  Google Scholar 

  16. Shih YRV, Hwang Y, Phadke A, Kang H, Hwang NS, Caro EJ, et al. Calcium phosphate-bearing matrices induce osteogenic differentiation of stem cells through adenosine signaling. Proc Natl Acad Sci U S A. 2014;111:990–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Beaupre LA, Jones CA, Saunders LD, Johnston DWC, Frcs C, Buckingham J, et al. Best practices for elderly hip fracture patients a systematic overview of the evidence. J Gen Intern Med [Internet]. 2005;20(C):1019–25 Available from: http://www.labolsa.com/finanzas/precio+del+aluminio+por+kilo+en+colombia.

    Google Scholar 

  18. McClung MR. Romosozumab for the treatment of osteoporosis. Osteoporos Sarcopenia [internet]. 2018;4(1):11–5. https://doi.org/10.1016/j.afos.2018.03.002.

    Article  Google Scholar 

  19. Johansson T. PTH 1-34 ( teriparatide ) may not improve healing in proximal humerus fractures. Acta Orthop. 2016;87(1):79–82.

    PubMed  Google Scholar 

  20. Bhandari M, Jin L, See K, Burge R, Mbchb NG, Witvrouw R, et al. Does teriparatide improve femoral neck fracture healing : results from a randomized placebo-controlled trial. Clin Orthop Relat Res. 2016;474(5):1234–44.

    PubMed  PubMed Central  Google Scholar 

  21. Prospective HA, Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, et al. Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures*. JBMR. 2010;25(2):404–14.

    Google Scholar 

  22. Aspenberg P, Johansson T. Teriparatide improves early callus formation in distal radial fractures: analysis of a subgroup of patients within a randomized trial. Acta Orthop ISSN. 2010;81(2):234–6.

    Google Scholar 

  23. James AW, LaChaud G, Shen J, Asatrian G, Nguyen V, Zhang X, et al. A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng B Rev. 2016;22(4):284–97.

    CAS  Google Scholar 

  24. Shea JE, Miller SC. Skeletal function and structure: implications for tissue-targeted therapeutics. Adv Drug Deliv Rev. 2005;57(7):945–57.

    CAS  PubMed  Google Scholar 

  25. Roussignol X, Currey C, Duparc F, Dujardin F. Indications and results for the Exogen™ ultrasound system in the management of non-union: a 59-case pilot study. Orthop Traumatol Surg Res [Internet]. 2012;98(2):206–13. https://doi.org/10.1016/j.otsr.2011.10.011.

    Article  CAS  Google Scholar 

  26. Rotman SG, Grijpma DW, Richards RG, Moriarty TF, Eglin D, Guillaume O. Drug delivery systems functionalized with bone mineral seeking agents for bone targeted therapeutics [Internet]. J Control Release. Elsevier. 2018;269:88–99. https://doi.org/10.1016/j.jconrel.2017.11.009.

    Article  CAS  PubMed  Google Scholar 

  27. Zinnen SP, Karpeisky A, Von Hoff DD, Plekhova L, Alexandrov A. First-in-human phase I study of MBC-11, a novel bone-targeted cytarabine-etidronate conjugate in patients with cancer-induced bone disease. Oncologist. 2019;24(3):303–e102.

    CAS  PubMed  Google Scholar 

  28. Wang H, Xiao L, Tao J, Srinivasan V, Boyce BF, Ebetino FH, et al. Synthesis of a bone-targeted bortezomib with in vivo anti-myeloma effects in mice. Pharmaceutics. 2018;10(3):1–13.

    Google Scholar 

  29. Cole LE, Vargo-Gogola T, Roeder RK. Targeted delivery to bone and mineral deposits using bisphosphonate ligands. Adv Drug Deliv Rev. 2016;99:12–27.

    CAS  PubMed  Google Scholar 

  30. Bergmann R, Meckel M, Kubíček V, Pietzsch J, Steinbach J, Hermann P, et al. 177Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment. EJNMMI Res. 2016;6(1):1–12.

    CAS  Google Scholar 

  31. Ogawa K, Kawashima H, Shiba K, Washiyama K, Yoshimoto M, Kiyono Y, et al. Development of [90Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases. Nucl Med Biol [Internet]. 2009;36(2):129–35. https://doi.org/10.1016/j.nucmedbio.2008.11.007.

    Article  CAS  Google Scholar 

  32. Miller K, Erez R, Segal E, Shabat D, Satchi-Fainaro R. Targeting bone metastases with a bispecific anticancer and antiangiogenic polymer-alendronate-taxane conjugate. Angew Chem Int Ed. 2009;48(16):2949–54.

    CAS  Google Scholar 

  33. Wang G, Mostafa NZ, Incani V, Kucharski C, Uludaĝ H. Bisphosphonate-decorated lipid nanoparticles designed as drug carriers for bone diseases. J Biomed Mater Res A. 2012;100 A(3):684–93.

    Google Scholar 

  34. Chaudhari KR, Kumar A, Khandelwal VKM, Mishra AK, Monkkonen J, Murthy RSR. Targeting efficiency and biodistribution of zoledronate conjugated docetaxel loaded pegylated pbca nanoparticles for bone metastasis. Adv Funct Mater. 2012;22(19):4101–14.

    CAS  Google Scholar 

  35. Miller K, Clementi C, Polyak D, Eldar-Boock A, Benayoun L, Barshack I, et al. Poly(ethylene glycol)-paclitaxel-alendronate self-assembled micelles for the targeted treatment of breast cancer bone metastases. Biomaterials [Internet]. 2013;34(15):3795–806. https://doi.org/10.1016/j.biomaterials.2013.01.052.

    Article  CAS  Google Scholar 

  36. Yu L, Cai L, Hu H, Zhang Y. Experiments and synthesis of bone-targeting epirubicin with the water-soluble macromolecular drug delivery systems of oxidized-dextran. J Drug Target. 2014;22(4):343–51.

    CAS  PubMed  Google Scholar 

  37. Tanaka KSE, Dietrich E, Ciblat S, Métayer C, Arhin FF, Sarmiento I, et al. Synthesis and in vitro evaluation of bisphosphonated glycopeptide prodrugs for the treatment of osteomyelitis. Bioorganic Med Chem Lett. 2010;20(4):1355–9.

    CAS  Google Scholar 

  38. Houghton TJ, Tanaka KSE, Kang T, Dietrich E, Lafontaine Y, Delorme D, et al. Linking bisphosphonates to the free amino groups in fluoroquinolones: preparation of osteotropic prodrugs for the prevention of osteomyelitis. J Med Chem. 2008;51(21):6955–69.

    CAS  PubMed  Google Scholar 

  39. Sedghizadeh PP, Sun S, Junka AF, Richard E, Sadrerafi K, Mahabady S, et al. Design, synthesis, and antimicrobial evaluation of a novel bone-targeting bisphosphonate-ciprofloxacin conjugate for the treatment of osteomyelitis biofilms. J Med Chem. 2017;60:2326–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu XM, Wiswall AT, Rutledge JE, Akhter MP, Cullen DM, Reinhardt RA, et al. Osteotropic β-cyclodextrin for local bone regeneration. Biomaterials. 2008;29(11):1686–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Arns S, Gibe R, Moreau A, Monzur Morshed M, Young RN. Design and synthesis of novel bone-targeting dual-action pro-drugs for the treatment and reversal of osteoporosis. Bioorganic Med Chem. 2012;20(6):2131–40.

    CAS  Google Scholar 

  42. Chen G, Arns S, Young RN. Determination of the rat in vivo pharmacokinetic profile of a bone-targeting dual-action pro-drug for treatment of osteoporosis. Bioconjug Chem. 2015;26(6):1095–103.

    CAS  PubMed  Google Scholar 

  43. Gil L, Han Y, Opas EE, Rodan GA, Ruel R, Seedor JG, et al. Prostaglandin E2-bisphosphonate conjugates: potential agents for treatment of osteoporosis. Bioorg Med Chem. 1999;7(5):901–19.

    CAS  PubMed  Google Scholar 

  44. Liu CC, Hu S, Chen G, Georgiou J, Arns S, Kumar NS, et al. Novel EP4 receptor agonist-bisphosphonate conjugate drug (C1) promotes bone formation and improves vertebral mechanical properties in the ovariectomized rat model of postmenopausal bone loss. J Bone Miner Res. 2015;30(4):670–80.

    CAS  PubMed  Google Scholar 

  45. Morioka M, Kamizono A, Takikawa H, Mori A, Ueno H, Kadowaki S-i, et al. Design, synthesis, and biological evaluation of novel estradiol-bisphosphonate conjugates as bone-specific estrogens. Bioorg Med Chem. 2010;18:1143–8.

    CAS  PubMed  Google Scholar 

  46. Yewle JN, Puleo DA, Bachas LG. Bifunctional bisphosphonates for delivering PTH (1-34) to bone mineral with enhanced bioactivity. Biomaterials [Internet]. 2013;34(12):3141–9. https://doi.org/10.1016/j.biomaterials.2013.01.059.

    Article  CAS  Google Scholar 

  47. Yang Y, Aghazadeh-Habashi A, Panahifar A, Wu Y, Bhandari KH, Doschak MR. Bone-targeting parathyroid hormone conjugates outperform unmodified PTH in the anabolic treatment of osteoporosis in rats. Drug Deliv Transl Res. 2017;7(4):482–96.

    CAS  PubMed  Google Scholar 

  48. Chen F, Liu XM, Rice KC, Li X, Yu F, Reinhardt RA, et al. Tooth-binding micelles for dental caries prevention. Antimicrob Agents Chemother. 2009;53(11):4898–902.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Killeen AC, Rakes PA, Schmid MJ, Zhang Y, Narayana N, Marx DB, et al. Impact of local and systemic alendronate on simvastatin-induced new bone around periodontal defects. J Periodontol. 2012;83(12):1463–71.

    CAS  PubMed  Google Scholar 

  50. Yao W, Lane NE. Targeted delivery of mesenchymal stem cells to the bone. Bone [Internet]. 2015;70:62–5. https://doi.org/10.1016/j.bone.2014.07.026.

    Article  CAS  Google Scholar 

  51. Katsumi H, Sano JI, Nishikawa M, Hanzawa K, Sakane T, Yamamoto A. Molecular design of bisphosphonate-modified proteins for efficient bone targeting in vivo. PLoS One. 2015;10(8):1–15.

    Google Scholar 

  52. Cole LE, Vargo-gogola T, Roeder RK. Targeted delivery to bone and mineral deposits using bisphosphonate ligands [Internet]. Adv Drug Del Rev. Elsevier B.V. 2016;99:12–27. https://doi.org/10.1016/j.addr.2015.10.005.

    Article  CAS  Google Scholar 

  53. Brown JP, Morin S, Leslie MW, Papaioannou A, Cheung AM, Davison KS, et al. Bisphosphonates for treatment of osteoporosis: expected benefits, potential harms, and drug holidays. Can Fam Physician. 2014;60(4):324–33.

    PubMed  PubMed Central  Google Scholar 

  54. Rotman SG, Grijpma DW, Richards RG, Moriarty TF, Eglin D, Guillaume O. Drug delivery systems functionalized with bone mineral seeking agents for bone targeted therapeutics. J Control Release. 2018;269(November 2017):88–99.

    CAS  PubMed  Google Scholar 

  55. Low SA, Kopeček J. Targeting polymer therapeutics to bone. Adv Drug Deliv Rev [Internet]. 2012;64(12):1189–204.

    CAS  Google Scholar 

  56. Newman MR, Benoit DSW. Local and targeted drug delivery for bone regeneration. Curr Opin Biotechnol. 2016;40:125–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Stapleton M, Sawamoto K, Alm CJ, Mackenzie WG, Mason RW, Orii T, et al. Development of bone targeting drugs. Int J Mol Sci. 2017;18(1345):1–15.

    Google Scholar 

  58. Farrell KB, Karpeisky A, Thamm DH, Zinnen S. Bisphosphonate conjugation for bone specific drug targeting. Bone Rep [internet]. 2018;9(June):47–60. https://doi.org/10.1016/j.bonr.2018.06.007.

    Article  Google Scholar 

  59. Young RN, Grynpas MD. Targeting therapeutics to bone by conjugation with bisphosphonates. Curr Opin Pharmacol [internet]. 2018;40:87–94. https://doi.org/10.1016/j.coph.2018.03.010.

    Article  CAS  Google Scholar 

  60. Cutbirth ST. A restorative challenge: tetracycline-stained teeth. Denistry Today. 2015;(July):3–6.

  61. Chai G, Hu F. Tetracycline-grafted PLGA nanoparticles as bone-targeting drug delivery system. Int J Nanomedicine. 2015;10:5671–85.

    PubMed  PubMed Central  Google Scholar 

  62. Neale JR, Richter NB, Merten KE, Taylor KG, Singh S, Waite LC, et al. Bioorganic & Medicinal Chemistry Letters Bone selective effect of an estradiol conjugate with a novel tetracycline-derived bone-targeting agent. Bioorg Med Chem Lett [Internet]. 2009;19(3):680–3. https://doi.org/10.1016/j.bmcl.2008.12.051.

    Article  CAS  Google Scholar 

  63. Low SA, Galliford CV, Yang J, Low PS, City SL, Chemistry P, et al. Biodistribution of fracture-targeted GSK3β inhibitor-loaded micelles for improved fracture healing. Biomacromolecules. 2015;16:3145–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Low SA, Galliford CV, Jones-Hall YL, Roy J, Yang J, Low PS, et al. Healing efficacy of fracture-targeted GSK3β inhibitor-loaded micelles for improved fracture repair. Nanomedicine [internet]. 2017;12(3):185–93.

    CAS  Google Scholar 

  65. Wang M, Park S, Nam Y, Nielsen J, Low SA, Srinivasarao M, et al. Bone-fracture-targeted dasatinib-oligoaspartic acid conjugate potently accelerates fracture repair [Internet]. Bioconjugate Chem. 2018;29:3800–9.

    CAS  Google Scholar 

  66. Nakato T, Yoshitake M, Matsubara K, Tomida M, Kakuchi T. Relationships between structure and properties of poly(aspartic acid)s. Macromolecules. 1998;31:2107–13.

    CAS  Google Scholar 

  67. Ishizaki J, Waki Y, Takahashi-Nishioka T, Yokogawa K, Miyamoto KI. Selective drug delivery to bone using acidic oligopeptides. J Bone Miner Metab. 2009;27:1–8.

    PubMed  Google Scholar 

  68. Sekido T, Sakura N, Higashi Y, Miya K, Nitta Y, Nomura M, et al. Novel drug delivery system to bone using acidic oligopeptide: pharmacokinetic characteristics and pharmacological potential. Vol. 9, Journal of Drug Targeting. 2001. 111–121 p.

  69. Ogawa K, Ishizaki A, Takai K, Kitamura Y, Makino A, Kozaka T, et al. Evaluation of Ga-DOTA-(D-Asp)n as bone imaging agents: D-aspartic acid peptides as carriers to bone. Sci Rep. 2017;7(1):1–11.

    Google Scholar 

  70. Yamashita S, Katsumi H, Hibino N, Isobe Y, Yagi Y, Tanaka Y, et al. Development of PEGylated aspartic acid-modified liposome as a bone-targeting carrier for the delivery of paclitaxel and treatment of bone metastasis [Internet]. Biomaterials. Elsevier Ltd. 2018;154:74–85. https://doi.org/10.1016/j.biomaterials.2017.10.053.

    Article  CAS  PubMed  Google Scholar 

  71. Wang Y, Newman MR, Ackun-farmmer M, Baranello MP, Sheu T, Puzas JE, et al. Fracture-targeted delivery of β-catenin agonists via peptide-functionalized nanoparticles augments fracture healing. ACS Nano. 2017;11(9):9445–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Liu Y, Jia Z, Akhter MP, Gao X, Wang X, Wang X, et al. Bone-targeting liposome formulation of Salvianic acid A accelerates the healing of delayed fracture Union in Mice. Nanomed Nanotechnol Biol Med. 2018;14(7):2271–82.

    CAS  Google Scholar 

  73. Yarbrough DK, Hagerman E, Eckert R, He J, Choi H, Cao N, et al. Specific binding and mineralization of calcified surfaces by small peptides. Calcif Tissue Int. 2010;86(1):58–66.

    CAS  PubMed  Google Scholar 

  74. Saidak Z, Le Henaff C, Azzi S, Marty C, Da Nascimento S, Sonnet P, et al. Wnt/beta-catenin signaling mediates osteoblast differentiation triggered by peptide-induced alpha 5 beta1 integrin priming in mesenchymal skeletal cells. J Biol Chem. 2015;290(11):6903–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Segvich SJ, Smith HC, Kohn DH. The adsorption of preferential binding peptides to apatite-based materials. Biomaterials [Internet]. 2009;30(7):1287–98. https://doi.org/10.1016/j.biomaterials.2008.11.008.

    Article  CAS  Google Scholar 

  76. Addison WN, Miller SJ, Ramaswamy J, Mansouri A, Kohn DH, McKee MD. Phosphorylation-dependent mineral-type specificity for apatite-binding peptide sequences. Biomaterials [Internet]. 2010;31(36):9422–30. https://doi.org/10.1016/j.biomaterials.2010.08.064.

    Article  CAS  Google Scholar 

  77. Dinjaski N, Plowright R, Zhou S, Belton DJ, Perry CC, Kaplan DL. Osteoinductive recombinant silk fusion proteins for bone regeneration. Acta Biomater. 2017;49:127–39.

    CAS  PubMed  Google Scholar 

  78. Ramaswamy J, Nam HK, Ramaraju H, Hatch NE, Kohn DH. Inhibition of osteoblast mineralization by phosphorylated phage-derived apatite-specific peptide. Biomaterials [Internet]. 2015;73:120–30. https://doi.org/10.1016/j.biomaterials.2015.09.021.

    Article  CAS  Google Scholar 

  79. Mao J, Shi X, Wu YB, Gong SQ. Identification of specific hydroxyapatite {001} binding heptapeptide by phage display and its nucleation effect. Materials. 2016;9:700. https://doi.org/10.3390/ma9080700.

  80. Sun Y, Ye X, Cai M, Liu X, Xiao J, Zhang C, et al. Osteoblast-targeting-peptide modified nanoparticle for siRNA/microRNA delivery. ACS Nano. 2016;10(6):5759–68.

    CAS  PubMed  Google Scholar 

  81. Liang C, Guo B, Wu H, Shao N, Li D, Liu J, et al. Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA interference-based bone anabolic strategy. Nat Med. 2015;21(3):288–94.

    PubMed  PubMed Central  Google Scholar 

  82. Miller SC, Pan H, Wang D, Bowman BM, Kopečková P, Kopeček J. Feasibility of using a bone-targeted, macromolecular delivery system coupled with prostaglandin E1 to promote bone formation in aged, estrogen-deficient rats. Pharm Res. 2008;25(12):2889–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Vincent K, Durrant MC. Journal of Molecular Graphics and Modelling A structural and functional model for human bone sialoprotein [Internet]. Vol. 39, Journal of Molecular Graphics and Modelling. Elsevier Inc.; 2013. 108–117 p. https://doi.org/10.1016/j.jmgm.2012.10.007

  84. Tavafoghi M, Cerruti M. The role of amino acids in hydroxyapatite mineralization. J R Soc Interface. 2016;13:20160462.https://doi.org/10.1098/rsif.2016.0462.

  85. Yamashita S, Katsumi H, Hibino N, Isobe Y, Yagi Y, Kusamori K, et al. Development of PEGylated carboxylic acid-modified polyamidoamine dendrimers as bone-targeting carriers for the treatment of bone diseases [Internet]. J Control Release. Elsevier. 2017;262:10–7. https://doi.org/10.1016/j.jconrel.2017.07.018.

    Article  CAS  PubMed  Google Scholar 

  86. Matsumoto M, Hosoda H, Kitajima Y, Morozumi N, Minamitake Y, Tanaka S, et al. Structure-activity relationship of ghrelin: pharmacological study of ghrelin peptides. Biochem Biophys Res Commun. 2001;287(1):142–6.

    CAS  PubMed  Google Scholar 

  87. Wang D, Sima M, Mosley RL, Davda JP, Tietze N, Miller SC, et al. Pharmacokinetic and biodistribution studies of a bone-targeting drug delivery system based on N-(2-hydroxypropyl)methacrylamide copolymers. Mol Pharm. 2006;3(6):717–25.

  88. Takahashi T, Yokogawa K, Sakura N, Nomura M, Kobayashi S, Miyamoto KI. Bone-targeting of quinolones conjugated with an acidic oligopeptide. Pharm Res. 2008;25(12):2881–8.

    CAS  PubMed  Google Scholar 

  89. Low SA, Yang J, Kopeček J. Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics. Bioconjug Chem. 2014;25(11):2012–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Yanagi M, Uehara T, Uchida Y, Kiyota S, Kinoshita M, Higaki Y, et al. Chemical design of 99mTc-labeled probes for targeting osteogenic bone region. Bioconjug Chem. 2013;24(7):1248–55.

    CAS  PubMed  Google Scholar 

  91. Wang Y, Yang J, Liu H, Wang X, Zhou Z, Huang Q, et al. Osteotropic peptide-mediated bone targeting for photothermal treatment of bone tumors [Internet]. Biomaterials. Elsevier Ltd. 2017;114:97–105. https://doi.org/10.1016/j.biomaterials.2016.11.010.

    Article  CAS  PubMed  Google Scholar 

  92. Wang Y, Newman MR, Benoit DSW. Development of controlled drug delivery systems for bone fracture-targeted therapeutic delivery: a review. Eur J Pharm Biopharm. 2018;127(February):223–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Jia Z, Zhang Y, Chen YH, Dusad A, Yuan H, Ren K, et al. Simvastatin prodrug micelles target fracture and improve healing. J Control Release [Internet]. 2015;200:23–34. https://doi.org/10.1016/j.jconrel.2014.12.028.

    Article  CAS  Google Scholar 

  94. Zhang Y, Jia Z, Yuan H, Dusad A, Ren K, Wei X, et al. The evaluation of therapeutic efficacy and safety profile of simvastatin prodrug micelles in a closed fracture mouse model. Pharm Res [Internet]. 2016;33(8):1959–71. https://doi.org/10.1007/s11095-016-1932-2.

    Article  CAS  Google Scholar 

  95. Dang L, Liu J, Li F, Wang L, Li D, Guo B, et al. Targeted delivery systems for molecular therapy in skeletal disorders. Int J Mol Sci. 2016;17(3):1–15.

    Google Scholar 

  96. Zhang G, Guo B, Wu H, Tang T, Zhang BT, Zheng L, et al. A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy. Nat Med. 2012;18(2):307–14.

    PubMed  Google Scholar 

  97. Huang Z-b, Shi X, Mao J, Gong SQ. Design of a hydroxyapatite-binding antimicrobial peptide with improved retention and antibacterial efficacy for oral pathogen control. Scie Rep. Nat Publ Group. 2016;6:1–11.

    Google Scholar 

  98. Wahyudi H, Reynolds AA, Li Y, Owen SC, Yu SM. Targeting collagen for diagnostic imaging and therapeutic delivery. J Control Release. 2016;240:323–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Ponnapakkam T, Katikaneni R, Sakon J, Stratford R, Gensure RC. Treating osteoporosis by targeting parathyroid hormone to bone. Drug Discovery Today. 2014;19:204–8.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN, 47907, USA

    Jeffery J. Nielsen

  2. Novosteo Inc., West Lafayette, IN, USA

    Stewart A. Low

  3. Department of Chemistry, Purdue University, West Lafayette, IN, USA

    Stewart A. Low

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  1. Jeffery J. Nielsen
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  2. Stewart A. Low
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Correspondence to Jeffery J. Nielsen.

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Jeffery Nielsen reports having patents pending.

Dr. Stewart Low reports that he is an employee of Novosteo, which works on targeting bone anabolics to fractures. This is primarily why he understands the field in such depth, qualifying him to discuss the topic.

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Nielsen, J.J., Low, S.A. Bone-Targeting Systems to Systemically Deliver Therapeutics to Bone Fractures for Accelerated Healing. Curr Osteoporos Rep 18, 449–459 (2020). https://doi.org/10.1007/s11914-020-00604-4

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