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 invivo. 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.
|Number of pages||9|
|Publication status||Published - 2014 Dec 1|
Bibliographical noteFunding Information:
We thank E. Tunkle for preparation of the manuscript and professor S. G. Ahn at Chosun University for helpful discussion of PTD technique. This work was supported by grants from the Ortholution and from the National Research Foundation of Korea ( NRF-2012M3A9B2052523 , NRF-2013R1A1A1011652 , NRF-2014R1A2A1A05004670 ) and from the Seoul R&BD Program ( PA110028) .
All Science Journal Classification (ASJC) codes
- Ceramics and Composites
- Mechanics of Materials