title: A platform technique for growth factor delivery with novel mode of action.
abstract: Though growth factors allow tissue regeneration, the trade-off between their effectiveness and adverse effects limits clinical application. The key issues in current growth factor therapy largely derive from initial burst pharmacokinetics, rapid clearance, and proteolytic cleavage resulting in clinical ineffectiveness and diverse complications. While a number of studies have focused on the development of carriers, issues arising from soluble growth factor remain. In this study, we report a prodrug of growth factors constituting a novel mode of action (MoA). To mimic endogenous protein processing in cells, we developed a recombinant BMP-2 polypeptide based on a protein transduction domain (PTD) to transduce the protein into cells followed by furin-mediated protein cleavage and secretion of active growth factor. As proof of concept, a few micrograms scale of PTD-BMP-2 polypeptide sufficed to induce bone regeneration in vivo. As a simple platform, our technique can easily be extended to delivery of BMP-7 and DKK-1 as therapeutics for TGF-β and canonical Wnt signaling, respectively, to suppress the epithelial-mesenchymal transition (EMT), which constitutes a fundamental biological mechanism of many diseases. This technique largely overcomes the limitations of current soluble growth factors and opens the door to next generation growth factor therapeutics.
authors.affiliation: Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 120-752, South Korea.
authors.forename: Nam Hee
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 120-752, South Korea.
authors.forename: Yong Hoon
authors.initials: YH
authors.lastname: Cha
authors.affiliation: Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 120-752, South Korea.
authors.forename: Hyun Sil
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Soo Eon
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Oral and Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul 120-752, South Korea.
authors.forename: Jong-Ki
authors.initials: JK
authors.lastname: Huh
authors.affiliation: Ortholution, 104 Suntechcity, 513-15, Sangdaewon-dong, Joongwon-gu, Seongnam-si, Kyunggi-do 462-725, South Korea.
authors.forename: Jung Kook
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Ortholution, 104 Suntechcity, 513-15, Sangdaewon-dong, Joongwon-gu, Seongnam-si, Kyunggi-do 462-725, South Korea.
authors.forename: Jeong Moon
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 120-752, South Korea.
authors.forename: Joo Kyung
authors.initials: JK
authors.lastname: Ryu
authors.affiliation: Department of Anatomy, Yonsei University College of Dentistry, Seoul 120-752, South Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 120-752, South Korea.
authors.forename: Yoonmi
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Chemical Engineering, Seoul National Universtiy of Science and Technology, Seoul 139-743, South Korea; Convergence Institute of Biomedical Engineering and Biomaterials, Seoul National University of Science and Technology, Seoul 139-743, South Korea.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Chemical Engineering, Seoul National Universtiy of Science and Technology, Seoul 139-743, South Korea; Convergence Institute of Biomedical Engineering and Biomaterials, Seoul National University of Science and Technology, Seoul 139-743, South Korea.
authors.forename: Insup
authors.initials: I
authors.lastname: Noh
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine and the Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Li
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine and the Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
authors.affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-799, South Korea. Electronic address: taj@snu.ac.kr.
authors.forename: Tae-Ahn
authors.initials: TA
authors.lastname: Jahng
authors.affiliation: Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 120-752, South Korea. Electronic address: jiyook@yuhs.ac.
authors.forename: Jong In
authors.initials: JI
authors.lastname: Yook
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D001861:Bone Regeneration / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D005260:Female; D045683:Furin / Q000378:metabolism; D006801:Humans; D051379:Mice; D010455:Peptides / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D044968:Regenerative Medicine; D014161:Transduction, Genetic / Q000379:methods*; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D055396:Bone Morphogenetic Protein 2; D010455:Peptides; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D045683:Furin
keywords: Growth factors; Mode of action (MoA); Protein transduction domain (PTD); Regenerative medicine