A Novel Micellar PEGylated Hyperbranched Polyester as a Prospective Drug Delivery System for Paclitaxel (original) (raw)

Abstract

A hyperbranched aliphatic polyester has been functionalized with PEG chains to afford a novel water-soluble BH40-PEG polymer which exhibits unimolecular micellar properties, and is therefore appropriate for application as a drug-delivery system. The solubility of the anticancer drug paclitaxel was enhanced by a factor of 35, 110, 230, and 355 in aqueous solutions of BH40-PEG of 10, 30, 60, and 90 mg Á mL À1 , respectively. More than 50% of the drug is released at a steady rate and release is almost complete within 10 h. The toxicity of BH40-PEG was assessed in vitro with A549 human lung carcinoma cells and found to be nontoxic for 3 h incubation up to a 1.75 mg Á mL À1 concentration while LD 50 was 3.5 mg Á mL À1. Finally, it was efficiently internalized in cells, primarily in the absence of foetal bovine serum, while confocal microscopy revealed the preferential localization of the compound in cell nuclei. Paclitaxel is a microtubule stabilizing agent and a chemotherapeutic agent that has shown substantial clinical efficacy for ovarian, breast, colon, head and neck, and non-small cell lung cancers. [50,51] In its commercial form, paclitaxel is formulated as a 1:1 mixture of Cremophor EL, a polyethoxylated castor oil, and ethanol, which is diluted in normal saline or dextrose solution to a final paclitaxel concentration of 5% for administration. [52] This formulation can even cause hypersensitivity reactions mainly because of the cytotoxicity of the amphiphilic compounds and the organic solvent. [53] Therefore, several attempts have been made to increase the poor paclitaxel solubility (0.3 mg Á mL À1) using various formulations [54-60] or prodrug conjugates. [61,62] It is our intention to develop alternative paclitaxel delivery vehicles by the use of biodegradable unimolecular micelles and extend this investigation (work in progress) by preparing hyperbranched polymers of varying degrees of PEGylation in an attempt to find the optimum loading. This PEGylation process coupled with the introduction of targeting ligands [63,64] and molecular transporting moieties, [65,66] will render the systems more effective drug-delivery systems compared with the one described, for the first time, in this manuscript. The work involved is extremely broad to be covered in one publication. The scope of the present manuscript is to present our initial albeit quite promising results.

Loading...

Loading Preview

Sorry, preview is currently unavailable. You can download the paper by clicking the button above.

References (79)

  1. G. R. Newkome, C. N. Moorefield, F. Vo ¨gtle, ''Dendrimers and Dendrons. Concepts, Syntheses, Perspectives'', Wiley-VCH, Weinheim 2001; see also references therein.
  2. J. M. J. Fre ´chet, D. A. Tomalia, ''Dendrimers and Other Den- dritic Polymers'', in: Polymer Science, J. Wiley & Sons, Chiche- ster 2001; see also references therein.
  3. A. W. Bosman, H. M. Janssen, E. W. Meijer, Chem. Rev. 1999, 99, 1665.
  4. A. D. Schlu ¨ter, J. P. Rabe, Angew. Chem. Int. Ed. 2000, 39, 864.
  5. F. Vo ¨gtle, C. A. Schalley, ''Dendrimers'', in: Topics in Current Chemistry, F. Vo ¨gtle, Ed., Springer, Berlin-Heidelberg 1998, Vol. 197; 2000, Vol. 210; 2001, Vol. 212; 2001, Vol. 217.
  6. N. Ardoin, D. Astruc, Bull. Soc. Chim. Fr. 1995, 132, 875.
  7. Z. Sideratou, D. Tsiourvas, C. M. Paleos, Langmuir 2000, 16, 1766.
  8. C. M. Paleos, D. Tsiourvas, Z. Sideratou, L.-A. Tziveleka, Bio- macromolecules 2004, 5, 524.
  9. H. Cordes, U. Boas, P. Olsen, P. M. H. Heegaard, Biomacromo- lecules 2007, 8, 3578.
  10. F. Vo ¨gtle, S. Gestermann, R. Hesse, H. Schwierz, B. Windisch, Prog. Polym. Sci. 2000, 25, 987.
  11. C. C. Lee, J. A. MacKay, J. M. J. Fre ´chet, F. C. Szoka, Nat. Biotechnol. 2005, 23, 1517.
  12. A. Sunder, M.-F. Quincy, R. Mu ¨lhaupt, H. Frey, Angew. Chem. Int. Ed. 1999, 38, 2928.
  13. R. Haag, Chem. Eur. J. 2001, 7, 327.
  14. A. Sunder, R. Mu ¨lhaupt, H. Frey, Macromolecules 2000, 33, 309.
  15. A. Sunder, R. Mu ¨lhaupt, R. Haag, H. Frey, Adv. Mater 2000, 12, 235.
  16. M. Kra ¨mer, J.-F. Stumbe ´, H. Tu ¨rk, S. Krause, A. Komp, L. Delineau, S. Prokhorova, H. Kautz, R. Haag, Angew. Chem. Int. Ed. 2002, 41, 4252.
  17. A. Sunder, M. Kra ¨mer, R. Hanselmann, R. Mu ¨hlaupt, H. Frey, Angew. Chem. Int. Ed. 1999, 38, 3552.
  18. R. Haag, M. Kra ¨mer, J.-F. Stumbe ´, S. Krause, A. Komp, S. Prokhorova, Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 2002, 43, 328.
  19. H. Frey, R. Haag, Rev. Mol. Biotechnol. 2002, 90, 257.
  20. C. Siegers, M. Biesalski, R. Haag, Chem. Eur. J. 2004, 10, 2831.
  21. M. Liu, J. M. J. Fre ´chet, Pharm. Sci. Technol. Today 1999, 2, 393.
  22. N. Malik, R. Wiwattanapatapee, R. Klopsch, K. Lorenz, H. Frey, J. W. Weener, E. W. Meijer, W. Paulus, R. Duncan, J. Controlled Release 2000, 65, 133.
  23. S.-E. Stiriba, H. Frey, R. Haag, Angew. Chem. Int. Ed. 2002, 41, 1329.
  24. O. L. P. De Jesu ´s, H. R. Ihre, L. Cagne, J. M. J. Fre ´chet, F. C. Szoka, Jr., Bioconjugate Chem. 2002, 13, 453.
  25. U. Boas, P. M. H. Heegaard, Chem. Soc. Rev. 2004, 33, 43.
  26. A. E. Beezer, A. S. H. King, I. K. Martin, J. C. Mitchel, L. J. Twyman, C. F. Wain, Tetrahedron 2003, 59, 3873.
  27. E. R. Gillies, J. M. J. Fre ´chet, Drug Discovery Today 2005, 10, 35.
  28. C. M. Paleos, D. Tsiourvas, Z. Sideratou, Mol. Pharm. 2007, 4, 169.
  29. H. L. Crampton, E. E. Simanek, Polym. Int. 2007, 56, 489.
  30. U. Gupta, H. B. Agashe, A. Asthana, N. K. Jain, Nanomedicine: Nanotechnology, Biology and Medicine 2006, 2, 66.
  31. R. Haag, F. Kratz, Angew. Chem. Int. Ed. 2006, 45, 1198.
  32. M. Mammen, S. K. Choi, G. M. Whitesides, Angew. Chem. Int. Ed. 1998, 37, 2754.
  33. P. I. Kitov, D. R. Bundle, J. Am. Chem. Soc. 2003, 125, 16271.
  34. D. D. Lasic, D. Needham, Chem. Rev. 1995, 95, 2601; see also references therein.
  35. T. M. Allen, S. Zalipsky, Polym. Mater. Sci. Eng. 1997, 76, 497.
  36. D. Needham, D. H. Kim, Colloid Surf. B 2000, 18, 183.
  37. M. Silvander, P. Hansson, K. Edwards, Langmuir 2000, 16, 3696.
  38. T. Kaasgaard, O. G. Mouritsen, K. Jørgensen, Int. J. Pharm. 2001, 214, 63.
  39. M. Liu, K. Kono, J. M. J. Fre ´chet, J. Polym. Sci., Part A: Polym. Chem. 1999, 37, 3492.
  40. M. Liu, K. Kono, J. M. J. Fre ´chet, J. Controlled Release 2000, 65, 121.
  41. Z. Sideratou, D. Tsiourvas, C. M. Paleos, J. Colloid Interface Sci. 2001, 242, 272.
  42. A. Pantos, D. Tsiourvas, Z. Sideratou, C. M. Paleos, S. Giatrellis, G. Nounesis, Langmuir 2004, 20, 6165.
  43. L.-A. Tziveleka, C. Kontoyianni, Z. Sideratou, D. Tsiourvas, C. M. Paleos, Macromol. Biosci. 2006, 6, 161.
  44. U. Gupta, H. B. Agashe, A. Astahana, N. K. Jain, Biomacromo- lecules 2006, 7, 649.
  45. E. Malmstro ¨m, M. Johansson, A. Hult, Macromolecules 1995, 28, 1698.
  46. E. Za ˘gar, M. Zi ˘gon, S. Podzimek, Polymer 2006, 47, 166.
  47. E. Za ˘gar, M. Zi ˘gon, Macromolecules 2002, 35, 9913.
  48. R. Duncan, L. Izzo, Adv. Drug Delivery Rev. 2005, 57, 2215.
  49. W. Amass, A. Amass, B. Tighe, Polym. Int. 1998, 47, 89.
  50. B. R. Goldspiel, Pharmacotherapy 1997, 17 (5 II Suppl.), 110S.
  51. T.-H. Wang, H.-S. Wang, Y.-K. Soong, Cancer 2000, 88, 2619.
  52. A. K. Singla, A. Garg, D. Aggarwal, Int. J. Pharm. 2002, 235, 179.
  53. J. Szebeni, F. M. Muggia, C. R. Alving, J. Natl. Cancer Inst. 1998, 90, 300.
  54. J. Wu, Q. Liu, R. J. Lee, Int. J. Pharm. 2006, 316, 148.
  55. T. Ooya, J. Lee, K. Park, Bioconjugate Chem. 2004, 15, 1221.
  56. S. C. Lee, K. M. Huh, J. Lee, Y. W. Cho, R. E. Galinsky, K. Park, Biomacromolecules 2007, 8, 202.
  57. D. Le Garrec, S. Gori, L. Luo, D. Lessard, D. C. Smith, M.-A. Yessine, M. Ranger, J.-C. Lexoux, J. Controlled Release 2004, 99, 83.
  58. P. Crosasso, M. Ceruti, P. Brusa, S. Arpicco, F. Dosio, L. Cattel, J. Controlled Release 2000, 63, 19.
  59. Z. Zhang, S.-S. Feng, Biomaterials 2006, 27, 262.
  60. T. Ooya, K. M. Huh, M. Saitoh, E. Tamiya, K. Park, Sci. Technol. Adv. Mater. 2005, 6, 452.
  61. I. J. Majoros, A. Myc, T. Thomas, C. B. Mehta, J. R. Baker, Jr., Biomacromolecules 2006, 7, 572.
  62. J. J. Khandare, S. Jayant, A. Singh, P. Chandna, Y. Wang, N. Vorsa, T. Minko, Bioconjugate Chem. 2006, 17, 1464.
  63. K. Petrak, Drug Discovery Today 2005, 10, 1667.
  64. R. V. J. Chari, Acc. Chem. Res. 2008, DOI 10.1021/ar700108g.
  65. J. B. Rothbard, T. C. Jessop, P. A. Wender, Adv. Drug Delivery Rev. 2005, 57, 495.
  66. S. Futaki, Adv. Drug Delivery Rev. 2005, 57, 547.
  67. M. Ornatska, S. Peleshanko, K. L. Genson, B. Rybak, K. N. Bergman, V. V. Tsukruk, J. Am. Chem. Soc. 2004, 126, 9675.
  68. T. C. McIlvaine, J. Biol. Chem. 1921, 49, 183.
  69. T. Hikita, A. Mochizuki, K. Takeuchi, M. Asai, M. Ueda, Macro- molecules 2002, 35, 6202.
  70. R. P. Houghton, A. W. Mulvaney, J. Organometallic Chem. 1996, 518, 21.
  71. S. C. Kim, J. Yu, J. W. Lee, E.-S. Park, S.-C. Chi, J. Pharm. Biomed. Anal. 2005, 39, 170.
  72. I. Tsogas, Z. Sideratou, D. Tsiourvas, T. A. Theodossiou, C. M. Paleos, ChemBioChem 2007, 8, 1865.
  73. I. Tsogas, T. Theodossiou, Z. Sideratou, C. M. Paleos, H. Collet, J. C. Rossi, B. Romestand, A. Commeyras, Biomacromolecules 2007, 8, 3263.
  74. G. R. Newkome, C. N. Moorefield, G. R. Baker, M. J. Saunders, S. H. Grossman, Angew. Chem. Int. Ed. Engl. 1991, 30, 1178.
  75. J. M. J. Fre ´chet, Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 4782.
  76. J. Zou, Y. Zhao, S. Wenfang, J. Phys. Chem. B 2006, 110, 2638.
  77. M. R. Radowski, A. Shukla, H. von Berlepsch, C. Bo ¨ttcher, G. Pickaert, H. Rehage, R. Haag, Angew. Chem. Int. Ed. 2007, 46, 1265.
  78. A. Malliaris, Int. Rev. Phys. Chem. 1988, 7, 95.
  79. S. K. Dordunoo, H. M. Burt, Int. J. Pharm. 1996, 133, 191.