Peptide-based delivery to bone ☆ Kazuhiro Aoki a, ⁎, Neil Alles a , Niroshani Soysa a, b, 1 , Keiichi Ohya a a Dept. of Hard Tissue Engineering (Pharmacology), Graduate School, Tokyo Medical & Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan b Division of Pharmacology, Faculty of Dental Sciences, University of Peradeniya, Peradeniya, Sri Lanka abstract article info Article history: Received 17 November 2011 Accepted 29 May 2012 Available online 16 June 2012 Keywords: RANKL (receptor activator of NF-κB ligand) Antagonist Bone resorption inhibitory peptide Bone formation stimulatory peptide Cholesterol-bearing pullulan (CHP) nanogel BMP Collagen Thrombin Bone-targeting peptide Half-life Stability Peptides are attractive as novel therapeutic reagents, since they are flexible in adopting and mimicking the local structural features of proteins. Versatile capabilities to perform organic synthetic manipulations are an- other unique feature of peptides compared to protein-based medicines, such as antibodies. On the other hand, a disadvantage of using a peptide for a therapeutic purpose is its low stability and/or high level of aggregation. During the past two decades, numerous peptides were developed for the treatment of bone dis- eases, and some peptides have already been used for local applications to repair bone defects in the clinic. However, very few peptides have the ability to form bone themselves. We herein summarize the effects of the therapeutic peptides on bone loss and/or local bone defects, including the results from basic studies. We also herein describe some possible methods for overcoming the obstacles associated with using thera- peutic peptide candidates. © 2012 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221 2. The development of therapeutic peptides for bone resorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221 2.1. The WP9QY (W9) peptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1222 2.1.1. The mechanism by which the W9-peptide inhibits bone resorption . . . . . . . . . . . . . . . . . . . . . . . . . . . 1222 2.1.2. The effect of the W9-peptide on in vitro and in vivo bone resorption models . . . . . . . . . . . . . . . . . . . . . . . 1222 2.1.3. W9-peptide effects on inflammatory bone resorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1222 2.2. Osteoprotegerin-like peptide (OP3–4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1222 2.3. A RANKL inhibitor peptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1223 3. Development of therapeutic peptides for local application to bone defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1223 3.1. The B2A peptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1223 3.2. P-4 and P-24 peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1224 3.3. Other BMP-related peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1224 3.4. P-15 peptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1224 3.4.1. In vitro studies of P-15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225 3.4.2. In vivo studies of P-15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225 3.4.3. Clinical studies of P-15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225 3.5. The TP508 peptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226 3.5.1. In vitro studies for TP508 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226 3.5.2. In vivo studies of TP508 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226 Advanced Drug Delivery Reviews 64 (2012) 1220–1238 ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "Targeted delivery of therapeutics to bone and connective tissues". ⁎ Corresponding author at: Dept. of Hard Tissue Engineering (Pharmacology), Graduate School, Tokyo Medical & Dental Univ., 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan. Tel.: +81 3 5803 5461; fax: +81 3 5803 0190. E-mail addresses: kazu.hpha@tmd.ac.jp (K. Aoki), cnr-hpha@tmd.ac.jp (N. Alles), nir-hpha@tmd.ac.jp (N. Soysa), kohya.hpha@tmd.ac.jp (K. Ohya). 1 Tel.: +94 81 2389 7470; fax: +94 81 2388 948. 0169-409X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2012.05.017 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr