In Vitro Antitumor Activity of BCNU-Loaded PLGA Wafer Containing Additives

첨가제 함유 BCNU/PLGA웨이퍼의 in vitro 항암 활성

  • Lee, Jin-Soo (Department of Advanced Organic Materials Engineering, Chonbuk National University) ;
  • An, Tae-Kun (Department of Advanced Organic Materials Engineering, Chonbuk National University) ;
  • Shin, Phil-Kyung (Department of Polymer Engineering, Pukyong National University) ;
  • Chae, Ghang-Soo (Department of Advanced Organic Materials Engineering, Chonbuk National University) ;
  • Jeong, Je-Kyo (Research Center, Samchundang Pharm. Co. Ltd.) ;
  • Lee, Bong (Department of Advanced Organic Materials Engineering, Chonbuk National University) ;
  • Cho, Sun-Hang (Biomaterials Laboratories, Korea Research Institute of Chemical Technology) ;
  • Khang, Gil-Son (Department of Advanced Organic Materials Engineering, Chonbuk National University) ;
  • Lee, Hai-Bang (Biomaterials Laboratories, Korea Research Institute of Chemical Technology)
  • 이진수 (전북대학교 유기신물질공학과) ;
  • 안태군 (전북대학교 유기신물질공학과) ;
  • 신필경 (부경대학교 고분자공학과) ;
  • 채강수 (전북대학교 유기신물질공학과) ;
  • 정제교 (삼천당제약 중앙연구소) ;
  • 이봉 (부경대학교 고분자공학과) ;
  • 조선행 (한국화학연구원 생체의료고분자팀) ;
  • 강길선 (전북대학교 유기신물질공학과) ;
  • 이해방 (한국화학연구원 생체의료고분자팀)
  • Published : 2003.05.01

Abstract

We fabricated the 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine)-loaded PLGA wafers containing poly(N-vinylpyrrolidone) (PVP) or tedium chloride (NaCl) in order to control the release profile of drug in special shape (3 in diameter, 1 mm in thickness) by direct compression method. In vitro release profiles of BCNU could be controlled by additives contained in the wafers. Initial release amount, release rate and duration of BCNU could be controlled with presence of PVP or NaCl. In vitro antitumor activity accessed using 9L gliosarcoma cell line has been evaluated by assaying the viability of cells treated with BCNU released from the wafers containing additives resulting in continuous growth inhibition of 9L gliosarcoma tumor cells. Specially, the continuous growth inhibition of BCNU-loaded PLGA wafers containing additives was more effective than that of non-additive BCNU-loaded PLGA wafers. The cytotoxic effect of the drug from the wafers containing NaCl as compared to wafers containing PVP was more enhanced.

약물의 방출 경향을 제어할 목적으로 폴리비닐피롤리돈 (PVP) 또는 염화나트륨을 함유한 항암제 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine)/poly(L-lactide-co-glycolide) (PLGA) 웨이퍼를 직접 압축성형 방법에 의해 직경 3 mm와 두께 1 mm의 조건으로 제조하였다. 생체외 방출실험에서 BCNLT/PLGA 웨이퍼로부터 약물 방출거동은 웨이퍼에 함유된 첨가제에 의해 조절할 수 있었다. BCNU의 초기 방출량과 방출속도 및 기간은 염화나트륨 또는 PVP의 첨가에 외해 변화하였다. 9L gliosarcoma세포를 이용한 생체 외 항암 활성 실험에서 첨가제가 함유된 웨이퍼로부터 방출된 BCNU를 처리한 세포의 생존율을 분석하여 평가했고, 그 결과 지속적으로 9L gliosarcoma세포의 성장을 억제함을 확인하였다. 9L gliosarcoma세포에 대한 첨가제 함유 BCNU/PLGA 웨이퍼로부터 방출된 BCNU 약효 검색을 통하여 웨이퍼로부터 BCNU가 지속적으로 방출되어 9L gliosarcoma세포의 생존과 증식을 효과적으로 억제함을 확인하였다. 특히, 첨가제 함유 BCNU/PLGA 웨이퍼의 지속적인 성장 억제는 첨가제를 함유하지 않은 웨이퍼의 것보다 더욱 효과적이었다. 또한 염화나트륨 함유 BCNU/PLGA 웨이퍼가 PVP 함유 BCNU/PLCA 웨이퍼보다 세포 증식 억제 효과가 뛰어남을 보였다.

Keywords

References

  1. Biomaster. Res. v.4 D.S.Moon;G.Khang;H.S.Seong;J.M.Rhee;J.S.Lee;H.B.Lee
  2. J. Neurosurg. v.68 P.L.Komblith;M.Walker
  3. J. Neurosurg. Sci. v.28 P.Paoletti;G.Hollenbeck;H.Brem;S.Grossman;M.Clovin;R.Langer
  4. Drug Dev. Ind. Pharm. v.16 M.Chasin;G.Hollenbeck;H.Brem;S.Grossman;M.Colvin;R.Langer https://doi.org/10.3109/03639049009058548
  5. J. Control. Rel. v.16 C.S.Reinhard;M.L.Randomsky;W.M.Saltzman;J.Hilton;H.Brem https://doi.org/10.1016/0168-3659(91)90010-B
  6. J. Neurosurg. v.68 P.L.Kornblith;M.Walke
  7. Cancer Res. v.49 M.B.Yang;R.J.Tarmargo;H.Brem
  8. J. Control. Rel. v.42 W.Dang;T.Daviau;P.Ying;Y.Zhao;D.Nowotnik;C.S.Clow:B.Tyler;H.Brem https://doi.org/10.1016/0168-3659(96)01371-5
  9. Cancer Control v.5 P.Sampath;H.Brem https://doi.org/10.1177/107327489800500204
  10. Polymer(Korea) v.24 no.5 J.C.Cho;G.Khang;H.S.Choi;J.M.Rhee;H.B.Lee
  11. Korea Polymer J. v.8 no.6 G.Khang;H.S.Choi;J.M.Rhee;S.C.Yoon;J.C.Cho;H.B.Lee
  12. Biomater.Res. v.4 no.3 W.I.Son;D.I.Yun;G.Khang;B.S.Kim;H.B.Lee
  13. Lancet v.345 H.Brem;S.Piantadosi;P.Burger;M.Walker;R.Selker;N.Vick;K.Black;M.Sisti;S.Brem;G.Mohr;P.Muller;R.Morawetz;S.Schold https://doi.org/10.1016/S0140-6736(95)90755-6
  14. Cancer Chemother. Pharmacol. v.39 E.P.Sipos;B.Tyler;S.Piantadosi;P.C.Burger;H.Brem https://doi.org/10.1007/s002800050588
  15. Polymer(Korea) v.25 H.S.Choi;S.W.Kim;D.I.Yun;G.Khang;J.M.Rhee;Y.S.Kim;H.B.Lee
  16. Polymer(Korea) v.25 S.A.Seo;H.S.Choi;D.H.Lee;G.Khang;J.M.Rhee;H.B.Lee
  17. Int. J. Pharm. v.239 no.1-2 S.A.Seo;H.S.Choi;G.Khang;J.M.Rhee;H.B.Lee https://doi.org/10.1016/S0378-5173(02)00074-1
  18. Surg. Neurol. v.53 H.H.Engelhard https://doi.org/10.1016/S0090-3019(00)00211-1
  19. Polymer(Korea) v.26 T.K.An;H.J.Kang;D.S.Moon;J.S.Lee;H.S.Seong;J.K.Jeong;G.Khang;H.B.Lee
  20. Korean J. Otolaryngol. v.41 H.J.Kim;I.S.Park;H.J.Lim
  21. Methods of Tissue Engineering v.67 Cell-synthetic Surface Interaction: Physicochemical Surface Modification, Section II. Methods for Cell Delivery Vehicles G.Khang;H.B.Lee;A.Atala(ed.)R.Lanza(ed.)
  22. Polymer Sci. Tech. v.10 no.5 G.Khang;I.Jo;J.H.Lee;I.Lee;H.B.Lee
  23. Polymer Sci. Tech. v.10 no.6 G.Khang;J.H.Lee;H.B.Lee
  24. J. Pharm. Sci. v.55 T.L.Loo;R.L.Dion;R.L.Dixon;D.P.Rall https://doi.org/10.1002/jps.2600550509
  25. Macromol. Chem. Symp v.14 no.3 H.S.Seong;D.S.Moon;G.Khang;H.B.Lee
  26. Polymer(Korea) v.26 H.S.Seong;D.S.Moon;G.Khang;H.B.Lee
  27. Polymer(Korea) v.26 T.K.An;H.J.Kang;J.S.Lee;H.S.Seong;J.K.Jeong;G.Khang;Y.K.Hong;H.B.Lee
  28. Macromol. Chem. Symp. v.15 no.4 T.K.An;J.S.Lee;S.H.Cho;G.Khang;J.M.Rhee;H.B.Lee
  29. Encyclopedic Handbook of Biomaterials and Bioengineering Synthesis and Properties of Biodegradable Lactic/Glycolic Acid Polymers X.S.Wu;Wise(et al.)(ed.)
  30. Pharm.Res. v.17 D.F.Emerich;S.R.Winn;Y.Hu;J.Marsh;P.Snodgrass;D.LaFreniere;T.Wiens;B.P.Hasler;R.T.Bartus https://doi.org/10.1023/A:1007576405039
  31. Bio-Med. Master. Eng. v.9 G.Khang;J.C.Cho;J.W.Lee;J.M.Rhee;H.B.Lee
  32. Polymer Preprints v.40 H.B.Lee;G.Khang;J.C.Cho;J.M.Rhee;J.S.Lee
  33. Korea Polymer J v.8 no.2 G.Khang;J.H.Lee;J.W.Lee;J.C.Cho;H.B.Lee
  34. Int.J.Pharm. v.234 H.S.Choi;G.Khang;H.Shin;J.M.Rhee;H.B.Lee https://doi.org/10.1016/S0378-5173(01)00968-1
  35. Macromol. Res. v.10 S.A.Seo;H.S.Choi;G.Khang;J.M.Rhee;H.B.Lee https://doi.org/10.1007/BF03218313
  36. J. Biomater. Sci. Polym. Ed. v.13 S.J.Lee;G.Khang;Y.M.Lee;H.B.Lee https://doi.org/10.1163/156856202317414375
  37. Polymer Sci. Tech. v.12 G.Khang;I.Lee;J.M.Rhee;H.B.Lee
  38. Drug. Dev. Ind. pharm. v.22 M.Iwata;H.Ueda https://doi.org/10.3109/03639049609065953
  39. Chin Pharm.j. v.30 W.G.Lu;Y.Zhang;Q.M.Xiong;Y.C.Bao;Q.H.Chen
  40. Indian Drugs v.32 K.P.Chowdary;K.V.Ramesh
  41. J.Natl.Cancer Inst. v.82 P.Skehan;R.Sterng;D.Scudiero;A.Monks;J.McMahon;D.Vistica;J.T.Warren;H.Bikesch;S.Denney;M.R.Boyd https://doi.org/10.1093/jnci/82.13.1107
  42. J. Pharm. Sci. v.55 T.L.Loo;R.L.Dion;R.L.Dixon;D.P.Rall https://doi.org/10.1002/jps.2600550509
  43. Acta Pharm.Scand v.23 K.Fredrikson;P.Lundgren
  44. J. Pharm. Sci. v.56 S.Leigh;J.E.Carless;B.W.Burt https://doi.org/10.1002/jps.2600560721
  45. Int. J. Pharm. v.149 I.S.Moussa;L.H.Cartilier https://doi.org/10.1016/S0378-5173(97)04864-3
  46. Int. J. Pharm. v.158 P.Shivanand;O.L.Sprockel
  47. Int. J. Pharm. v.88 S.Trikkonen;P.Paronen https://doi.org/10.1016/0378-5173(92)90302-I
  48. Int. J. Pharm. v.92 S.Trikkonen;PlParonen https://doi.org/10.1016/0378-5173(93)90263-F
  49. J. Pharmacol. v.33 C.McDonald;C.Richardson https://doi.org/10.1111/j.2042-7158.1981.tb13698.x