화학공학소재연구정보센터
Macromolecular Research, Vol.18, No.2, 153-161, February, 2010
Design of a Multifunctional Heparin-based Nanoparticle System for Anticancer Drug Delivery
E-mail:
A ligand-mediated nanoparticulate drug carrier composed of heparin-based copolymers was designed to achieve targeted drug delivery for chemotherapy. Novel amphiphilic copolymers composed of heparin with antitumor activities and poly(beta-benzyl-L-aspartate) (PBLA) with the potential capacity for serving as pH-responsive drug release reservoirs were synthesized by conjugating PBLA as a hydrophobic segment to the hydrophilic heparin backbone. To introduce folate ligands for tumor targeting to the heparin/PBLA copolymers, folate-conjugated heparin/PBLA copolymers were prepared with various compositions by varying the feed molar ratio of PBLA, amine-terminated folate (or folate-conjugated PEG) to heparin. The synthesis and composition of the heparin-based copolymers were confirmed by H-1 NMR and colorimetric methods, respectively. Heparin-based amphiphilic copolymeric nanoparticles were prepared by micelle formation in an aqueous solution. The properties of the micelles were described by the critical micelle concentration (CMC), size and size distribution. The CMC values of heparin-based copolymers decreased with increasing concentration of the PBLA hydrophobic segments in the copolymers. The conjugation of folate (or folate-conjugated PEG) with hydrophilic nature into heparin/PBLA copolymers affected the free chain-micelle equilibrium, leading to an increase in the CMC values. The particle size of the heparin-based copolymers determined by light scattering measurements ranged from 100 to 130 nm, depending on the molecular weight and composition of the copolymers. Field emission scanning electron microscopy showed that the heparin-based copolymeric particles had a sub-micron size with spherical shape.
  1. Jain RK, Adv. Drug Deliv. Rev., 46, 149 (2001)
  2. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ, Adv. Drug Deliv. Rev., 46, 3 (2000)
  3. Wu J, Liu Q, Lee RJ, Int. J. Pharm., 316, 148 (2006)
  4. Maeda H, Sawa T, Konno T, J. Control. Release, 74, 47 (2001)
  5. Kukowska-Latallo JF, Candido KA, Cao ZY, Nigavekar SS, Majoros IJ, Thomas TP, Balogh LP, Khan MK, Baker JR, Cancer Res., 65, 5317 (2005)
  6. Molema G, Acta Biochim. Pol., 52, 301 (2005)
  7. Agarwal A, Saraf S, Asthana A, Gupta U, Gajbhiye V, Jain NK, Int. J. Pharm., 350, 3 (2008)
  8. de Wolf FA, Brett GM, Pharmacol. Rev., 52, 207 (2000)
  9. Kim SY, Cho SH, Lee YM, Chu LY, Macromol. Res., 15(7), 646 (2007)
  10. Park JS, Cho YW, Macromol. Res., 15(6), 513 (2007)
  11. Xiao SY, Tong CY, Liu XM, Yu DM, Liu QL, Xue CG, Tang DY, Zhao ZL, Chin. Sci. Bull., 51, 1693 (2006)
  12. Lee ES, Na K, Bae YH, J. Control. Release, 91, 103 (2003)
  13. Yu MK, Lee DY, Kim YS, Park KS, Park SA, Son DH, Lee GY, Nam JH, Kim SY, Kim IS, Park RW, Byun Y, Pharm. Res., 24, 705 (2007)
  14. Park EK, Kim SY, Lee SB, Lee YM, J. Control. Release, 109, 158 (2005)
  15. Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, Zurawski VR, Kamen BA, Cancer Res., 52, 3396 (1992)
  16. Campbell IG, Jones TA, Foulkes WD, Trowsdale J, Cancer Res., 51, 5329 (1991)
  17. Lee RJ, Low PS, J. Biol. Chem., 269, 3198 (1994)
  18. Mohapatra S, Mallick SK, Maiti TK, Ghosh SK, Pramanik P, Nanotechnology, 18, 385102 (2007)
  19. Linhardt RJ, Hudson CS, J. Med. Chem., 46, 2551 (2003)
  20. Linhardt RJ, Chem. Ind., 2, 45 (1991)
  21. Niers TMH, Klerk CPW, DiNisio M, Van Noorden CJF, Buller HR, Reitsma PH, Richel DJ, Crit. Rev. Oncol. Hematol., 61, 195 (2007)
  22. Bobek V, Kovarik J, Biomed. Pharmacother., 58, 213 (2004)
  23. Smorenburg SM, Van Noorden CJ, Pharmacol. Rev., 53, 93 (2001)
  24. Folkman J, EXS, 79, 1 (1997)
  25. Meyer T, Hart IR, Eur. J. Cancer, 34, 214 (1998)
  26. Lee AYY, Thromb. Res., 120, S121 (2007)
  27. Siragusa S, Oncology Rev., 1, 36 (2007)
  28. ten Cate-Hoek AJ, Prins MH, Thromb. Res., 122, 584 (2007)
  29. Park K, Kim K, Kwon IC, Kim SK, Lee S, Lee DY, Byun Y, Langmuir, 20(26), 11726 (2004)
  30. Park KS, Lee GY, Kim YS, Yu M, Park RW, Kim IS, Kim SY, Byun Y, J. Control. Release, 114, 300 (2006)
  31. Lee GY, Kim SK, Byun Y, J. Control. Release, 123, 46 (2007)
  32. Thorpe PE, Derbyshire EJ, Andrade SP, Press N, Knowles PP, King S, Watson GJ, Yang YC, Bette MR, Cancer Res., 53, 3000 (1993)
  33. Daly WH, Poche D, Tetrahedron Lett., 29, 5859 (1988)
  34. Konoto T, Kojima Y, Kawai T, Macromol. Chem., 179, 1861 (1978)
  35. Shukla S, Wu G, Chatterjee M, Yang WL, Sekido M, Diop LA, Muller R, Sudimack JJ, Lee RJ, Barth RF, Tjarks W, Bioconjugate Chem., 14, 158 (2003)
  36. Smith PK, Mallia AK, Hermanson GT, Anal. Biochem., 109, 466 (1980)
  37. Wilhelm M, Zhao CL, Wang Y, Xu R, Winnik MA, Mura JL, Riess G, Croucher MD, Macromolecules, 24, 1033 (1991)
  38. Allen C, Maysinger D, Eisenberg A, Biointerfaces, 16, 3 (1999)
  39. Rapoport N, Prog. Polym. Sci, 32, 962 (2007)
  40. Shin IG, Kim SY, Lee YM, Cho CS, Sung YK, J. Control. Release, 51, 1 (1998)
  41. Kim SY, Shin IG, Lee YM, Cho CS, Sung YK, J. Control. Release, 51, 13 (1998)
  42. Astafieva I, Zhong XF, Eisenberg A, Macromolecules, 26(26), 7339 (1993)
  43. Huh KM, Lee SC, Cho YW, Lee JH, Jeong JH, Park KN, J. Control. Release, 101, 59 (2005)