표적항암 약물전달체용 담즙산-히알루론산 유도체의 파클리탁셀 봉입 나노입자

김유미; 임선경; 윤명식; Yu Mi Kim; Sun Kyung Lim; Myeong Sik Yoon

Polymer(Korea), Vol.39, No.6, 967-975, November, 2015

DOI10.7317/pk.2015.39.6.967 Export Citation

표적항암 약물전달체용 담즙산-히알루론산 유도체의 파클리탁셀 봉입 나노입자

Paclitaxel-loaded Nanoparticles of Cholanic Acid-Modified Hyaluronan Oligosaccharide for Tumor-site Specific Delivery

김유미, 임선경, 윤명식^{1, †}

씨제이제일제당 제약연구소
¹호서대학교 제약공학과

Yu Mi Kim, Sun Kyung Lim, and Myeong Sik Yoon^{1, †}

Pharmaceutical Research Institute, CJ Cheiljedang, 522-1, Deokpyeong-ri, Majang-myeon Icheon-si, Gyeonggi-do 467-812, Korea
¹Department of Pharmaceutical Engineering, Hoseo University, 20 Hoseo-ro 79, Baebang, Asan, Chungcheongnam-do 336-795, Korea

E-mail:

초록

본 연구에서는 저분자량의 히알루론산에 5-β-cholanic acid를 conjugation하여 in vivo에서 종양표적성이 있고 투과율이 증가된 자기집합 나노입자를 제조하였다. 주사용으로 적합한 점도를 갖는 히알루론산 분자량은 16000 g/mol이었으며, 자기집합 나노입자를 만들 수 있는 cholanic acid의 히알루론산에 대한 최적 치환율(degree of substitution)은 14% 였다. 최적화된 파클리탁셀의 feed amount를 구하기 위해 파클리탁셀이 봉입된 나노입자의 크기와 안정성을 비교하였고 그 비는 30%가 적합하였다. 파클리탁셀이 봉입된 나노입자를 사용하여 biodistribution을 조사한 결과 HA-CA 나노입자의 혈액 내 long circulation 특성과 생체 내 종양표적 특이성으로 인하여 기존의 나노입자보다 간으로 분포되는 양이 현저히 줄어들었다. 또한 유방암 xenograft 모델을 이용한 항암효율 측정에서도 파클리탁셀이 봉입된 나노입자는 양성대조군보다 종양성장을 더 많이 저해함을 보여주었다.

We have demonstrated that introduction of 5-β-cholanic acid into low molecular weight hyaluronic acid oligosaccharide produces self-assembled nanoparticles with enhanced permeability to a tumor site in vivo. We have found that hyaluronic acid of molecular weight 16000 g/mol has appropriate injectable viscosity. For making self-assembled nanoparticles with the selected hyaluronic acid, the optimal degree of substitution value of cholanic acid was 14%, which was selected by considering the size and stability of nanoparticles after loading with paclitaxel. 30% paclitaxel was selected as the optimal feed amount to make the paclitaxel-loaded hyaluronic acid-cholanic acid nanoparticles. Importantly, the optimal formulation of paclitaxel-loaded nanoparticles showed less liver uptake than the reported formula, along with long circulation as well as tumor-site specific accumulation in the in vivo biodistribution study. In the antitumor efficacy study, the paclitaxel-loaded nanoparticles showed higher efficacy to inhibit tumor growth than a positive control in the breast cancer cell xenograft model.

Keywords:hyaluronic acid oligosaccharide;self-assembled nanoparticle;paclitaxel;site specific delivery;antitumor efficacy

[References]

Toole BP, Nat. Rev. Cancer, 4, 528 (2004)
Choi KY, Saravanakumar G, Park JH, Park KN, Colloids Surf. B: Biointerfaces, 99, 92 (2012)
Luo Y, Prestwich GD, Bioconjugate Chem., 10, 755 (1999)
Na SJ, Chae SY, Lee S, Park K, Kim K, Park JH, Kwon IC, Jeong SY, Lee KC, Int. J. Pharm., 363, 14 (2008)
Yadav AK, Mishra P, Mishra AK, Mishra P, Jain S, Agrawal GP, Biol. Med., 3, 246 (2007)
Teder P, Vandivier RW, Jiang D, Liang J, Cohn L, Pure E, Henson PM, Noble PW, Science, 296, 155 (2002)
Tammi MI, Day AJ, Turley EA, J. Biol. Chem., 277, 4581 (2002)
Toole BP, Wight TN, Tammi MI, J. Biol. Chem., 277, 4593 (2002)
Maharjan AD, Pilling D, Gomer RH, PLoS ONE, 6, 1 (2011)
Yang C, Cao M, Liu H, He Y, Xu J, Du Y, Liu Y, Wang W, Cul L, Hu J, Gao F, J. Biol. Chem., 287, 43094 (2012)
Choi KY, Chung H, Min KH, Yoon HY, Kim K, Park JH, Kwon IC, Jeong SY, Biomaterials, 31, 106 (2010)
Hwang HY, Kim IS, Kwon IC, Kim YH, J. Control. Release, 128, 23 (2008)
Son YJ, Jang J, Cho YW, Chung H, Park R, Kwon IC, Kim I, Park JY, Bae SB, Park CR, Jeong SY, J. Control. Release, 91, 135 (2003)
Kim J, Kim Y, Park K, Lee S, Nam HY, Min KY, Jo HG, Park JH, Choi K, Jeong SY, Park R, Kim I, Kim K, Kwon IC, J. Control. Release, 127, 41 (2008)
Min KH, Park K, Kim Y, Bae SM, Lee S, Jo HG, Park R, Kim I, Jeong SY, Kim K, Kwon IC, J. Control. Release, 127, 208 (2008)
Goodison S, Urquidi V, Tarin D, Mol. Pathol., 52, 189 (1999)
Kaya G, Rodriguez I, Jorcano JL, Vassalli P, Stamenkovic I, Genes Dev., 11, 996 (1997)
Saravanakumar G, Choi KY, Yoon HY, Kim K, Park JH, Kwon IC, Park K, Int. J. Pharm., 394, 154 (2010)
Banerji S, Ni J, Wang S, Clasper S, Su J, Tammi R, Jones M, Jackson DG, J. Cell Biol., 144, 789 (1999)
Zhou B, Weigel JA, Fauss L, Weigel PH, J. Biol. Chem., 275, 37733 (2000)
Kim SC, Kim DW, Shim YH, Bang JS, Oh HS, Kim SW, Seo MH, J. Control. Release, 72, 191 (2001)
Peyron JG, J. Rheumatol., 20, 10 (1993)
Soltes L, Mendichi R, Lath D, Mach M, Bokos D, Biomed. Chromatogr., 16, 459 (2002)

[Referenced By]

[1] Toole BP, Nat. Rev. Cancer, 4, 528 (2004)

[2] Choi KY, Saravanakumar G, Park JH, Park KN, Colloids Surf. B: Biointerfaces, 99, 92 (2012)

[3] Luo Y, Prestwich GD, Bioconjugate Chem., 10, 755 (1999)

[4] Na SJ, Chae SY, Lee S, Park K, Kim K, Park JH, Kwon IC, Jeong SY, Lee KC, Int. J. Pharm., 363, 14 (2008)

[5] Yadav AK, Mishra P, Mishra AK, Mishra P, Jain S, Agrawal GP, Biol. Med., 3, 246 (2007)

[6] Teder P, Vandivier RW, Jiang D, Liang J, Cohn L, Pure E, Henson PM, Noble PW, Science, 296, 155 (2002)

[7] Tammi MI, Day AJ, Turley EA, J. Biol. Chem., 277, 4581 (2002)

[8] Toole BP, Wight TN, Tammi MI, J. Biol. Chem., 277, 4593 (2002)

[9] Maharjan AD, Pilling D, Gomer RH, PLoS ONE, 6, 1 (2011)

[10] Yang C, Cao M, Liu H, He Y, Xu J, Du Y, Liu Y, Wang W, Cul L, Hu J, Gao F, J. Biol. Chem., 287, 43094 (2012)

[11] Choi KY, Chung H, Min KH, Yoon HY, Kim K, Park JH, Kwon IC, Jeong SY, Biomaterials, 31, 106 (2010)

[12] Hwang HY, Kim IS, Kwon IC, Kim YH, J. Control. Release, 128, 23 (2008)

[13] Son YJ, Jang J, Cho YW, Chung H, Park R, Kwon IC, Kim I, Park JY, Bae SB, Park CR, Jeong SY, J. Control. Release, 91, 135 (2003)

[14] Kim J, Kim Y, Park K, Lee S, Nam HY, Min KY, Jo HG, Park JH, Choi K, Jeong SY, Park R, Kim I, Kim K, Kwon IC, J. Control. Release, 127, 41 (2008)

[15] Min KH, Park K, Kim Y, Bae SM, Lee S, Jo HG, Park R, Kim I, Jeong SY, Kim K, Kwon IC, J. Control. Release, 127, 208 (2008)

[16] Goodison S, Urquidi V, Tarin D, Mol. Pathol., 52, 189 (1999)

[17] Kaya G, Rodriguez I, Jorcano JL, Vassalli P, Stamenkovic I, Genes Dev., 11, 996 (1997)

[18] Saravanakumar G, Choi KY, Yoon HY, Kim K, Park JH, Kwon IC, Park K, Int. J. Pharm., 394, 154 (2010)

[19] Banerji S, Ni J, Wang S, Clasper S, Su J, Tammi R, Jones M, Jackson DG, J. Cell Biol., 144, 789 (1999)

[20] Zhou B, Weigel JA, Fauss L, Weigel PH, J. Biol. Chem., 275, 37733 (2000)

[21] Kim SC, Kim DW, Shim YH, Bang JS, Oh HS, Kim SW, Seo MH, J. Control. Release, 72, 191 (2001)

[22] Peyron JG, J. Rheumatol., 20, 10 (1993)

[23] Soltes L, Mendichi R, Lath D, Mach M, Bokos D, Biomed. Chromatogr., 16, 459 (2002)