Core-Corona형 Poly( methacryloyloxymethyl-5-FU) Prodrug 미립자의 제조 및 항암활성

조석형; 김공수; 강종구; 조병호

Polymer(Korea), Vol.18, No.5, 877-885, September, 1994

Export Citation

Core-Corona형 Poly( methacryloyloxymethyl-5-FU) Prodrug 미립자의 제조 및 항암활성

Preparation and Antitumor Activities of Core-Corona Type Poly(methacryloyloxymethyl-5-FU) Prodrug

조석형, 김공수, 강종구, 조병호

초록

고분자 prodrug을 제조하기 위하여 약물이 결합된 모노머 methacryloyl oxymethyl-5-FU(MAOFU)를 합성하였으며 이를 안정제로 사용한 acryloyl terminated polyethylene glycol macromonomer(AtPEGM)와 침전중합으로써 미립자의 고분자 prodrug을 얻었다. 합성한 prodrug의 입자크기는 0.2∼0.25㎛로서 다분산성이었으며, morphology는 core-corona형이었다. 또한 고분자 prodrug은 완충용액중에서 수분산 안정성이 우수하였다. 합성한 prodrug의 in vitro 실험결과 매우 느린 약물방출을 나타내었고 MAOFU 단독으로 중합한 경우보다 친수성 모노머인 acrylamide(AAm)와 공중합한 경우가 약물의 방출속도는 비교적 빨랐으며, 약물방출속도는 prodrug 입자의 친수성에 의존한다. 또한 복수암 유발 마우스에 고분자 prodrug을 투여한 결과 낮은 독성과 생체적합성을 나타냈으며 sarcoma(S)-180 종양세포에 대한 함암활성에서 친수성 모노머가 중합된 prodrug이 비교적 항암활성을 나타낸 반면 MAOFU 단독으로 중합한 것은 항암활성을 나타내지 않았다.

In order to prepare prodrug, methacryloyloxymethyl-5-FU(MAOFU) monomer was synthesized and the poly(MAOFU) prodrug particle were prepared by precipitation polymerization of MAOFU using acryloyl terminated polyethylene glycol macromonomer(AtPEGM) as a stabilizer. The size of prodrug was 0.2∼0.25㎛, and the particle size distribution is polydisperse. The particles have morphology of core-corona type and were dispersable in buffer solution. The release rate of drug from the prodrug copolymerized with acrylamide(AAm) was relatively faster than that of prodrug itself and release rate of drug depends on hydrophilicity of polymer prodrug. The antitumor activity of prodrugs against sarcoma(S)-180 tumor cell in mice was demonstrated and the polymer particles itself showed low toxicity and good biocompatability when they were administrated into mice.

Keywords:antitumor activity;poly(methacryloyloxymethyl-5-FU);prodrug;S-fluoracil

[References]

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Ahmad S, Ozaki S, Nagase T, Iigo M, Hoshi A, Chem. Pharm. Bull., 35, 4137 (1987)
Hashida M, Sato A, Kojima T, Muranishi S, Sezaki H, Tanigawa N, Satomura K, Hikasa Y, Jpn. J. Cancer Res., 72, 226 (1981)
Onishi H, Gawaguchi T, Nagai T, Chem. Pharm. Bull., 35, 3370 (1987)
Ozaky S, Ike Y, Mizuno H, Ishikawa K, Mori H, Bull. Chem. Soc. Jpn., 50, 2406 (1977)
Ozaki S, Watanabe Y, Hoshiko T, Mizuno H, Ishikawa K, Mori H, Bull. Pharm., 32, 733 (1984)
Ozaki S, Watanabe Y, Ogasawara T, Yamauchi Y, Fujiwara K, Hoshi A, Iigo M, Chem. Pharm. Bull., 33, 2832 (1985)
Kita Y, Imaki Y, Takemoto K, J. Polym. Sci. A: Polym. Chem., 18, 427 (1980)
Lee H, Shim HS, Lee MG, Park MK, Kim CK, Yakhak Hoeji, 33, 267 (1989)
Yang F, Zhuo R, Polym. J., 22, 572 (1990)
Tsukuda Y, Ohkawa K, Hibi N, Cancer Res., 47, 4293 (1987)
Ozaki S, Ohnishi J, Watanabe Y, Nohda T, Nagase T, Akiyama T, Uehara N, Hoshi A, Polym. J., 21, 955 (1989)
Kita Y, Imaki Y, Takemoto K, J. Polym. Sci. A: Polym. Chem., 18, 427 (1980)
Endo N, Umemoro N, Kato Y, Hara T, J. Immunol. Methods, 104, 253 (1987)
Ozaki S, Ohnishi J, Akiyama T, Nagase T, Uehara N, Hoshi A, Polym. J., 22, 689 (1990)
Yokeyama M, J. Control. Release, 11, 269 (1989)
Yokeyama M, Cancer Res., 50, 1695 (1990)
Cho SH, Kim KS, Kim YJ, Polym. J., 25, 847 (1993)
Doyle A, Griffiths JB, Newell DG, "Cell and Tissue Culture," 4B; 52, John Wiley and Sons, Porton Down; Salisbury, United Kingdom (1993)
Gawaguchi T, Tsugane A, Higashide K, J. Pharm. Sci., 81, 508 (1992)
Seki T, Gawaguchi T, Endoh H, Pharm. Res., 5, 741 (1988)

[Referenced By]

[1] Hoshi A, Inomata M, Kanzawa F, Iigo M, Kuretani K, J. Pharmacobio Dxn., 3, 208 (1982)

[2] Ahmad S, Ozaki S, Nagase T, Iigo M, Hoshi A, Chem. Pharm. Bull., 35, 4137 (1987)

[3] Hashida M, Sato A, Kojima T, Muranishi S, Sezaki H, Tanigawa N, Satomura K, Hikasa Y, Jpn. J. Cancer Res., 72, 226 (1981)

[4] Onishi H, Gawaguchi T, Nagai T, Chem. Pharm. Bull., 35, 3370 (1987)

[5] Ozaky S, Ike Y, Mizuno H, Ishikawa K, Mori H, Bull. Chem. Soc. Jpn., 50, 2406 (1977)

[6] Ozaki S, Watanabe Y, Hoshiko T, Mizuno H, Ishikawa K, Mori H, Bull. Pharm., 32, 733 (1984)

[7] Ozaki S, Watanabe Y, Ogasawara T, Yamauchi Y, Fujiwara K, Hoshi A, Iigo M, Chem. Pharm. Bull., 33, 2832 (1985)

[8] Kita Y, Imaki Y, Takemoto K, J. Polym. Sci. A: Polym. Chem., 18, 427 (1980)

[9] Lee H, Shim HS, Lee MG, Park MK, Kim CK, Yakhak Hoeji, 33, 267 (1989)

[10] Yang F, Zhuo R, Polym. J., 22, 572 (1990)

[11] Tsukuda Y, Ohkawa K, Hibi N, Cancer Res., 47, 4293 (1987)

[12] Ozaki S, Ohnishi J, Watanabe Y, Nohda T, Nagase T, Akiyama T, Uehara N, Hoshi A, Polym. J., 21, 955 (1989)

[13] Kita Y, Imaki Y, Takemoto K, J. Polym. Sci. A: Polym. Chem., 18, 427 (1980)

[14] Endo N, Umemoro N, Kato Y, Hara T, J. Immunol. Methods, 104, 253 (1987)

[15] Ozaki S, Ohnishi J, Akiyama T, Nagase T, Uehara N, Hoshi A, Polym. J., 22, 689 (1990)

[16] Yokeyama M, J. Control. Release, 11, 269 (1989)

[17] Yokeyama M, Cancer Res., 50, 1695 (1990)

[18] Cho SH, Kim KS, Kim YJ, Polym. J., 25, 847 (1993)

[19] Doyle A, Griffiths JB, Newell DG, "Cell and Tissue Culture," 4B; 52, John Wiley and Sons, Porton Down; Salisbury, United Kingdom (1993)

[20] Gawaguchi T, Tsugane A, Higashide K, J. Pharm. Sci., 81, 508 (1992)

[21] Seki T, Gawaguchi T, Endoh H, Pharm. Res., 5, 741 (1988)