화학공학소재연구정보센터
홈 로그인 로그아웃 연락처 사이트맵
Journal of Industrial and Engineering Chemistry, Vol.78, 396-409, October, 2019
DOI10.1016/j.jiec.2019.05.030  Export Citation
PEGylated substance P augments therapeutic angiogenesis in diabetic critical limb ischemia
Hyun-Ji Park, Suna Kim1, Eun Je Jeon, In-Taek Song2, Haeshin Lee2, Youngsook Son1, Hyun Sook Hong3, †, and Seung-Woo Cho†
  • Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
  • 1Department of Genetic Engineering, College of Life Sciences and Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Republic of Korea
  • 2Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
  • 3College of Medicine/East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea
E-mail:,
Substance P (SP) is a therapeutic peptide that has been widely used to induce angiogenesis and tissue regeneration. However, its therapeutic efficacy is often limited due to rapid degradation in vivo and a short half-life (~1 min) after systemic administration. In the present study, we chemically modified SP with polyethylene glycol (PEG) to generate long-lasting formulations with increased stability and extended retention time in vivo and evaluated their ability to enhance therapeutic angiogenesis. Compared to the unmodified SP, PEGylated SP (PEG-SP) exhibited significantly increased half-life in vivo (~360-fold increase in normal mouse and~120-fold increase in diabetic mouse). Systemic injection of PEGSP led to a marked increase in therapeutic efficacy and angiogenesis in diabetic hindlimb ischemia, as evident from the remarkable improvement in salvage of ischemic limb and recovery of blood perfusion in diabetic mice with limb ischemia. These formulations increased endogenous stem cell mobilization to the injured site and modulated the immune system to increase microvessel formation and reduce systemic inflammation. Importantly, PEGylation efficiently reduced the injection doses of SP while still maintaining its therapeutic efficacy. To conclude, our study demonstrated that PEG-SP formulations exhibited an improved in vivo pharmacokinetic profile with enhanced efficacy and clinically acceptable treatment regimens, thus acting as a potent therapeutic for diabetic ischemia and inflammation.
Keywords:Substance P;PEGylation;Therapeutic angiogenesis;Diabetic limb ischemia
  1. Hong HS, Lee J, Lee E, Kwon YS, Lee E, Ahn W, Jiang MH, Kim JC, Son Y, Nat. Med., 15(4), 425 (2009)
  2. Park JH, Kim S, Hong HS, Son Y, Wound Repair Regen., 24(2), 337 (2016)
  3. Jiang MH, Lim JE, Chi GF, Ahn W, Zhang M, Chung E, Son Y, Neuroreport, 24(15), 846 (2013)
  4. Hong HS, Kim S, Nam S, Um J, Kim YH, Son Y, Wound Repair Regen., 23(2), 268 (2015)
  5. Kim SJ, Kim JE, Kim SH, Kim SJ, Jeon SJ, Kim SH, Jung Y, Biomaterials, 74, 119 (2016)
  6. Bot I, de Jager SC, Bot M, van Heiningen SH, de Groot P, Veldhuizen RW, van Berkel TJ, von der Thusen JH, Biessen EA, Circ Res, 106(1), 89 (2010)
  7. Andersson G, Backman LJ, Scott A, Lorentzon R, Forsgren S, Danielson P, Br J Sports Med, 45(13), 1017 (2011)
  8. La WG, Jin M, Park S, Yoon HH, Jeong GJ, Bhang SH, Park H, Char K, Kim BS, Int. J. Nanomed., 9, 107 (2014)
  9. Mashaghi A, Marmalidou A, Tehrani M, Grace PM, Pothoulakis C, Dana R, Cell. Mol. Life Sci., 73(22), 4249 (2016)
  10. Lim JE, Chung E, Son Y, Sci. Rep., 7(1), 9417 (2017)
  11. Skidgel RA, Engelbrecht S, Johnson AR, Erdos EG, Peptides, 5(4), 769 (1984)
  12. Bowden JJ, Garland AM, Baluk P, Lefevre P, Grady EF, Vigna SR, Bunnett NW, Mcdonald DM, Proc. Natl. Acad. Sci. U.S.A., 91(19), 8964 (1994)
  13. Park HJ, Kuai R, Jeon EJ, Seo Y, Jung Y, Moon JJ, Schwendeman A, Cho SW, Biomaterials, 161, 69 (2018)
  14. Wang Q, Muffley LA, Hall K, Chase M, Gibran NS, Shock, 32(5), 491 (2009)
  15. Levy HL, Sarkissian CN, Scriver CR, Mol. Genet. Metab., 124(4), 223 (2018)
  16. Furber KL, Van Agten M, Evans C, Haddadi A, Doucette JR, Nazarali AJ, Degener. Neurol. Neuromuscul. Dis., 7, 47 (2017)
  17. Konkle BA, Stasyshyn O, Chowdary P, Bevan DH, Mant T, Shima M, Engl W, Dyck-Jones J, Fuerlinger M, Patrone L, Ewenstein B, Abbuehl B, Blood, 126(9), 1078 (2015)
  18. Roberts MJ, Bentley MD, Harris JM, Adv. Drug Deliv. Rev., 54(4), 459 (2002)
  19. Fishburn CS, J. Pharm. Sci., 97(10), 4167 (2008)
  20. Valentin-Hansen L, Park M, Huber T, Grunbeck A, Naganathan S, Schwartz TW, Sakmar TP, J. Biol. Chem., 289(26), 18045 (2014)
  21. Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW, Physiol Rev, 94(1), 265 (2014)
  22. Ko IK, Ju YM, Chen T, Atala A, Yoo JJ, Lee SJ, Faseb J., 26(1), 158 (2012)
  23. Liu H, Kemeny DM, Heng BC, Ouyang HW, Melendez AJ, Cao T, J. Immunol., 176(5), 2865 (2006)
  24. Muangman P, Spenny ML, Tamura RN, Gibran NS, Shock, 19(6), 508 (2003)
  25. Lerman OZ, Galiano RD, Armour M, Levine JP, Gurtner GC, Am. J. Pathol., 162(1), 303 (2003)
  26. Eming SA, Martin P, Tomic-Canic M, Sci. Transl. Med., 6(265), 265sr6 (2014)
  27. Bassi EJ, Moraes-Vieira PM, Moreira-Sa CS, Almeida DC, Vieira LM, Cunha CS, Hiyane MI, Basso AS, Pacheco-Silva A, Camara NO, Diabetes, 61(10), 2534 (2012)
  28. Tolosano E, Fagoonee S, Hirsch E, Berger FG, Baumann H, Silengo L, Altruda F, Blood, 100(12), 4201 (2002)
  29. Kiang JG, Zhai M, Liao PJ, Bolduc DL, Elliott TB, Gorbunov NV, Oxid. Med. Cell. Longev. (2014), 481392 (2014).
  30. Sica A, Mantovani A, J. Clin. Investig., 122(3), 787 (2012)
  31. Kim S, Piao J, Hwang DY, Park JS, Son Y, Hong HS, Life Sci., 225, 98 (2019)
  32. Gibran NS, Jang YC, Isik FF, Greenhalgh DG, Muffley LA, Underwood RA, Usui ML, Larsen J, Smith DG, Bunnett N, Ansel JC, Olerud JE, J. Surg. Res., 108(1), 122 (2002)
  33. Antezana MA, Sullivan SR, Usui ML, Gibran NS, Spenny ML, Larsen JA, Ansel JC, Bunnett NW, Olerud JE, J. Invest. Dermatol., 119(6), 1400 (2002)
  34. Armstrong DG, Lavery LA, Harkless LB, Diabetes Care, 21(5), 855 (1998)
  35. Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC, Circulation, 106(22), 2781 (2002)
  36. Tamarat R, Silvestre JS, Le Ricousse-Roussanne S, Barateau V, Lecomte-Raclet L, Clergue M, Duriez M, Tobelem G, Levy BI, Am. J. Pathol., 164(2), 457 (2004)
  37. Ferraro F, Lymperi S, Mendez-Ferrer S, Saez B, Spencer JA, Yeap BY, et al., Sci. Transl. Med., 3(104), 104ra1 (2011)
  38. Rennert RC, Sorkin M, Januszyk M, Duscher D, Kosaraju R, Chung MT, et al., Stem. Cell. Res. Ther., 5(3), 79 (2014)
  39. Yoon D, Kim H, Lee E, Park MH, Chung S, Jeon H, Ahn CH, Lee K, Biomater. Res., 20(25) (2016)
  40. Schellenberger V, Wang CW, Geething NC, Spink BJ, Campbell A, To W, Scholle MD, Yin Y, Yao Y, Bogin O, Cleland JL, Silverman J, Stemmer WP, Nat. Biotechnol., 27(12), 1186 (2009)
  41. Nischan N, Chakrabarti A, Serwa RA, Bovee-Geurts PH, Brock R, Hackenberger CP, Angew. Chem.-Int. Edit., 52(45), 11920 (2013)
  42. Deepankumar K, Prabhu NS, Kim JH, Yun H, Biotechnol. Bioproc. E, 22(3), 248 (2017)
  43. Harris JM, Chess RB, Nat. Rev. Drug Discov., 2(3), 214 (2003)
  44. Visentin R, Pasut G, Veronese FM, Mazzi U, Bioconjugate Chem., 15(5), 1046 (2004)
  45. Harris JM, Martin NE, Modi M, Clin. Pharmacokinet., 40(7), 539 (2001)
  46. Savoca KV, Abuchowski A, van Es T, Davis FF, Palczuk NC, Biochim. Biophys. Acta, 578(1), 47 (1979)
  47. Hershfield MS, Chaffee S, Koro-Johnson L, Mary A, Smith AA, Short SA, Proc. Natl. Acad. Sci. U.S.A., 88(16), 7185 (1991)
  48. Zhang XW, Wang H, Ma ZG, Wu BJ, Expert Opin. Drug Metab., 10(12), 1691 (2014)
  49. Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW, Physiol. Rev., 94(1), 265 (2014)
  50. Valentin-Hansen L, Park M, Huber T, Grunbeck A, Naganathan S, Schwartz TW, Sakmar TP, J. Biol. Chem., 289(26), 18045 (2014)
  51. Mantyh PW, Allen CJ, Ghilardi JR, Rogers SD, Mantyh CR, Liu H, Basbaum AI, Vigna SR, Maggio JE, Proc. Natl. Acad. Sci. U.S.A., 92, 2622 (1995)
  52. Jensen DD, Lieu T, Halls ML, Veldhuis NA, Imlach WL, Mai QN, Poole DP, et al., Sci. Transl. Med, 9(392), eaal34 (2017)
  53. Liu Y, Li J, Shao K, Huang R, Ye L, Lou J, Jiang C, Biomaterials, 31(19), 5246 (2010)
  54. Li JR, Sculley J, Zhou HC, Chem. Rev., 112(2), 869 (2012)