Key parameters affecting the initial leaky effect of hemoglobin-loaded nanoparticles as blood substitutes

  • Xiaolan Zhang
  • Changsheng Liu
  • Yuan Yuan
  • Shiyu Zhang
  • Xiaoqian Shan
  • Yan Sheng
  • Feng Xu


In order to realize long-term carrying/delivering oxygen and minimize the adverse effects of free hemoglobin (Hb) in vivo, Hb is desired to be confined in Hb-loaded nanoparticles (HbP), a novel blood substitute with potential clinical applications, and thus functions as the native red blood cells (RBCs). However, the initial burst release of Hb (“leaky effect”) greatly underscores the significance of this work. The study described here wants to disclose the key preparative parameters, including polymer, excipients in the inner aqueous phase and solvent profile, affecting the Hb release behavior (the initial 24 h) from HbP fabricated by commonly used solvent diffusion/evaporation double emulsion technique. The results demonstrate that PEGlytated polymers, regardless of two- or tri-block copolymers show slower release compared with the corresponding non-PEGlytated ones. The higher polymer concentration yields lower initial release. PEG200, added as excipient facilitates Hb burst effect to about 38.4%, almost 17% increase compared to the control (∼21%), whereas, PVA and Poloxamer188, due to amphiphilic nature, can effectively attenuate this leakage to about 13.0 and 5.1%, respectively. The diffusion/extraction rate from oil phase and the subsequent evaporation rate from the aqueous continuous phase of solvents impose different influences on Hb release. To reduce the burst effect, the initial diffusion/extraction rate should be slow, whereas, the concomitant evaporation rate should be as fast as possible. The results obtained here will be guidance’s for the future tailored design of more desirable polymersome nanoparticle blood substitutes.


Drug Release Double Emulsion Blood Substitute Multiple Emulsion Aqueous Continuous Phase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors appreciate the financial support from the National High Technology Research and Development Program of China (863 Program) (No. 2004AA-302050) and from Shanghai Nanotechnology Special Foundation (No. 0452nm022).


  1. 1.
    R.M. Winslow, Adv. Drug. Deliv. Rev. 40, 131 (2000)CrossRefGoogle Scholar
  2. 2.
    C. Chauvierre, M.C. Marden, C. Vauthier, D. Labarre, P. Couvreur, L. Lecler, Biomaterials 25, 3081 (2004)CrossRefGoogle Scholar
  3. 3.
    S.L. Li, J. Nickels, A.F. Palmer, Biomaterials 26, 3759 (2005)CrossRefGoogle Scholar
  4. 4.
    V. Budhiraja, J.D. Hellums, Microvasc. Res. 64, 220 (2002)CrossRefGoogle Scholar
  5. 5.
    T.M.S. Chang, J. Intern. Med. 253, 527 (2003)CrossRefGoogle Scholar
  6. 6.
    F.T. Meng, G.H. Ma, Y.D. Liu, W. Qiu, Z.G. Su, Colloid Surf. B: Biointerf. 33, 177 (2004)CrossRefGoogle Scholar
  7. 7.
    J. Zhao, C.S. Liu, Y. Yuan, X.Y. Tao, X.Q. Shan, Y. Sheng, F. Wu, Biomaterials 28, 1414 (2007)CrossRefGoogle Scholar
  8. 8.
    A. Gabizon, D. Papahadjopoulos, Proc. Natl. Acad. Sci. 85, 6949 (1988)CrossRefGoogle Scholar
  9. 9.
    N. Iodoshima, C. Udagawa, T. Ando, H. Fukuyasu, H. Watanabe, S. Nakabayashi, Int. J. Pharm. 146, 81 (1997)CrossRefGoogle Scholar
  10. 10.
    C.D. Reiter, X.D. Wang, J.E. Tanus-Santos, N. Hogg, R.O. Cannon, A.N. Schechter, M.T. Gladwin, Nat. Med. 8, 1383 (2002)CrossRefGoogle Scholar
  11. 11.
    R. Lee, K. Neya, T.A. Svizzero, G.J. Vlahakes, J. Appl. Physiol. 79, 236 (1995)Google Scholar
  12. 12.
    J.S. Olson, E.W. Foley, C. Rogge, A.L. Tsai, M.P. Doyle, D.D. Lemon, Free Radic. Biol. Med. 36, 685 (2004)CrossRefGoogle Scholar
  13. 13.
    K. Sampei, J.A. Ulatowski, Y. Asano, H. Kwansa, E. Bucci, R.C. Koehler, Am. J. Physiol.: Heart Circ. Physiol. 289, H1191 (2005)CrossRefGoogle Scholar
  14. 14.
    F.D. Cui, K. Shi, L.Q. Zhang, A.J. Tao, Y. Kawashima, J. Control Release 114, 242 (2006)CrossRefGoogle Scholar
  15. 15.
    S. Ghosh, J. Chem. Res. 4, 241 (2004)CrossRefGoogle Scholar
  16. 16.
    V. Coccoli, A. Luciani, S. Orsi, V. Guarino, F. Causa, P.A. Netti, J. Mater. Sci.: Mater. Med. doi: 10.1007/S10856-007-3253-9
  17. 17.
    Y.Y. Yang, H.H. Chia, T.S. Chung, J. Control Release 69, 81 (2000)CrossRefGoogle Scholar
  18. 18.
    J. Wang, B.M. Wang, S.P. Schwendeman, Biomaterials 25, 1919 (2004)CrossRefGoogle Scholar
  19. 19.
    A.K. Bajpai, S. Bhanu, J. Mater. Sci.: Mater. Med. 18, 1613 (2007)CrossRefGoogle Scholar
  20. 20.
    W.G. Zijlstra, A. Buursma, Comp. Biochem. Physiol. 118b, 743 (1997)Google Scholar
  21. 21.
    Y. Zhang, R.X. Zhuo, Biomaterials 26, 6736 (2005)CrossRefGoogle Scholar
  22. 22.
    Z.P. Zhang, S.S. Feng, Biomaterials 27, 4025 (2006)CrossRefGoogle Scholar
  23. 23.
    Y.P. Li, Y.Y. Pei, Z.H. Zhou, X.Y. Zhang, Z.H. Gu , J. Ding, J.J. Zhou, X.J. Gao, J. Control Release 71, 287 (2001)CrossRefGoogle Scholar
  24. 24.
    D. Klose, F. Siepmann, K. Elkharraz, S. Krenzlin, J. Siepmann, Int. J. Pharm. 314, 198 (2006)CrossRefGoogle Scholar
  25. 25.
    P. Johansen, Y. Men, R. Audran, G. Corradin, H.P. Merkle, B. Gander, Pharm. Res. 15, 1103 (1998)CrossRefGoogle Scholar
  26. 26.
    Y.K. Katare, A.K. Pand, Eur. J. Pharm. Sci. 28, 179 (2006)CrossRefGoogle Scholar
  27. 27.
    K.M. Shakesheff, C. Evora, I. Soriano, R. Langer, J. Colloid Interf. Sci. 185, 538 (1997)CrossRefGoogle Scholar
  28. 28.
    C. Bouissou, J.J. Rouse, R. Price, C.F.V. Walle, Pharm. Res. 23, 1295 (2006)CrossRefGoogle Scholar
  29. 29.
    F. Boury, T. Ivanova, I. Panaiotov, J.E. Proust, A. Bois, J. Richou, J. Colloid Interf. Sci. 169, 380 (1995)CrossRefGoogle Scholar
  30. 30.
    L. Mu, S.S. Feng, J. Control Release 80, 129 (2002)CrossRefGoogle Scholar
  31. 31.
    M.D. Blanco, M.J. Alonso, Eur. J. Pharm. Biopharm. 43, 287 (1997)CrossRefGoogle Scholar
  32. 32.
    J.M. Péan, F. Boury, M.C. Venier-Julienne, P. Menei, J.E. Proust, J.P. Benoit, Pharm. Res. 16, 1294 (1999)CrossRefGoogle Scholar
  33. 33.
    T. Sato, M. Kanke, H.G. Schroeder, P.P. Deluca, Pharm. Res. 5, 21 (1988)CrossRefGoogle Scholar
  34. 34.
    Y.Y. Yang, T.S. Chung, X.L. Bai, W.K. Chan, Chem. Eng. Sci. 55, 2223 (2000)CrossRefGoogle Scholar
  35. 35.
    X.S. Luan, M. Skupin, J. Siepmann, Int. J. Pharm. 324, 168 (2006)CrossRefGoogle Scholar
  36. 36.
    T.W. Chung, Y.Y. Huang, Y.Z. Liu, Int. J. Pharm. 212, 161 (2001)CrossRefGoogle Scholar
  37. 37.
    Y.Y. Yang, H.H. Chia, T.S. Chung, J. Control Release 69, 81 (2000)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Xiaolan Zhang
    • 1
  • Changsheng Liu
    • 1
  • Yuan Yuan
    • 1
  • Shiyu Zhang
    • 1
  • Xiaoqian Shan
    • 1
  • Yan Sheng
    • 1
  • Feng Xu
    • 1
  1. 1.Key Laboratory for Ultrafine Materials of Ministry of Education, Engineering Research Center for Biomedical Materials of Ministry of EducationEast China University of Science and TechnologyShanghaiChina

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