Tumor pH-responsive flower-like micelles of poly(L-lactic acid)-b-poly (ethylene glycol)-b-poly(L-histidine)

被引:440
作者
Lee, Eun Seong [1 ]
Oh, Kyung Taek [1 ]
Kim, Dongin [1 ]
Youn, Yu Seok [1 ]
Bae, You Han [1 ]
机构
[1] Univ Utah, Dept Pharmaceut & Pharmaceut Chem, Salt Lake City, UT 84108 USA
关键词
poly(L-histidine)-b-PEG-b-poly(L-lactic acid) triblock copolymer; flower-like micelle; tumor pH; triggered drug release;
D O I
10.1016/j.jconrel.2007.08.006
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Polymeric micelles were constructed from poly(L-lactic acid) (PLA; M-n 3K)-b-poly(ethylene glycol) (PEG; M-n 2K)-b-poly(L-histidine) (polyHis; M-n 5K) as a tumor pH-specific anticancer drug carrier. Micelles (particle diameter: similar to 80 nm; critical micelle concentration (CMC): 2 mu g/ml) formed by dialysis of the polymer solution in dimethylsulfoxide (DMSO) against pH 8.0 aqueous solution, are assumed to have a flower-like assembly of PLA and polyHis blocks in the core and PEG block as the shell. The pH-sensitivity of the micelles originates from the deformation of the micellar core due to the ionization of polyHis at a slightly acidic pH. However, the co-presence of pH-insensitive lipophilic PLA block in the core prevented disintegration of the micelles and caused swelling/aggregation. A fluorescence probe study showed that the polarity of pyrene retained in the micelles increased as pH was decreased from 7.4 to 6.6, indicating a change to a more hydrophilic environment in the micelles. Considering that the size increased up to 580 nm at pH 6.6 from 80 nm at pH 7.4 and that the transmittance of micellar solution increased with decreasing pH, the micelles were not dissociated but rather swollen/aggregated. Interestingly, the subsequent decline of pyrene polarity below pH 6.6 suggested re-self-assembly of the block copolymers, most likely forming a PLA block core while polyHis block relocation to the surface. Consequently, these pH-dependent physical changes of the PLA-b-PEG-b-polyHis micelles provide a mechanism for triggered drug release from the micelles triggered by the small change in pH (pH 7.2-6.5). (c) 2007 Elsevier B.V. All rights reserved.
引用
收藏
页码:19 / 26
页数:8
相关论文
共 43 条
[1]   Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: Tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy [J].
Bae, Y ;
Nishiyama, N ;
Fukushima, S ;
Koyama, H ;
Yasuhiro, M ;
Kataoka, K .
BIOCONJUGATE CHEMISTRY, 2005, 16 (01) :122-130
[2]   pH-sensitive cationic polymer gene delivery vehicle:: N-Ac-poly(L-histidine)-graft-poly(L-lysine) comb shaped polymer [J].
Benns, JM ;
Choi, JS ;
Mahato, RI ;
Park, JS ;
Kim, SW .
BIOCONJUGATE CHEMISTRY, 2000, 11 (05) :637-645
[3]   Controlled clustering of superparamagnetic nanoparticles using block copolymers: Design of new contrast agents for magnetic resonance imaging [J].
Berret, JF ;
Schonbeck, N ;
Gazeau, F ;
El Kharrat, D ;
Sandre, O ;
Vacher, A ;
Airiau, M .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128 (05) :1755-1761
[4]   Fluorocarbon associative polymers [J].
Berret, JF ;
Calvet, D ;
Collet, A ;
Viguier, M .
CURRENT OPINION IN COLLOID & INTERFACE SCIENCE, 2003, 8 (03) :296-306
[5]   pH-Tunable rheological properties of a telechelic cationic polyelectrolyte reversible hydrogel [J].
Bossard, Frederic ;
Aubry, Thierry ;
Gotzamanis, Georgios ;
Tsitsilianis, Constantinos .
SOFT MATTER, 2006, 2 (06) :510-516
[6]  
Campbell Robert B., 2006, Anti-Cancer Agents in Medicinal Chemistry, V6, P503, DOI 10.2174/187152006778699077
[7]   EXTRACELLULAR PH DISTRIBUTION IN HUMAN TUMORS [J].
ENGIN, K ;
LEEPER, DB ;
CATER, JR ;
THISTLETHWAITE, AJ ;
TUPCHONG, L ;
MCFARLANE, JD .
INTERNATIONAL JOURNAL OF HYPERTHERMIA, 1995, 11 (02) :211-216
[8]   Doxorubicin loaded pH-sensitive micelle targeting acidic extracellular pH of human ovarian A2780 tumor in mice [J].
Gao, ZG ;
Lee, DH ;
Kim, DI ;
Bae, YH .
JOURNAL OF DRUG TARGETING, 2005, 13 (07) :391-397
[9]   pH-responsive copolymer assemblies for controlled release of doxorubicin [J].
Gillies, ER ;
Fréchet, JMJ .
BIOCONJUGATE CHEMISTRY, 2005, 16 (02) :361-368
[10]   A light scattering study of the association of hydrophobically α- and α,ω-end-capped poly(ethylene oxide) in water [J].
Gourier, C ;
Beaudoin, E ;
Duval, M ;
Sarazin, D ;
Maître, S ;
François, J .
JOURNAL OF COLLOID AND INTERFACE SCIENCE, 2000, 230 (01) :41-52