Lee Eun Seong, Oh Kyung Taek, Kim Dongin, Youn Yu Seok, Bae You Han
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, 421 Wakara Way, Suite 315, UT 84108, USA.
J Control Release. 2007 Oct 18;123(1):19-26. doi: 10.1016/j.jconrel.2007.08.006. Epub 2007 Aug 16.
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: approximately 80 nm; critical micelle concentration (CMC): 2 microg/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).
以聚（L-乳酸）（PLA；数均分子量3K）-b-聚（乙二醇）（PEG；数均分子量2K）-b-聚（L-组氨酸）（聚组氨酸；数均分子量5K）构建聚合物胶束，作为肿瘤pH特异性抗癌药物载体。通过将聚合物溶液在二甲基亚砜（DMSO）中对pH 8.0的水溶液进行透析形成的胶束（粒径：约80 nm；临界胶束浓度（CMC）：2 μg/ml），被认为在核心具有PLA和聚组氨酸嵌段的花状组装，而PEG嵌段作为外壳。胶束的pH敏感性源于聚组氨酸在略酸性pH下的电离导致胶束核心的变形。然而，核心中存在对pH不敏感的亲脂性PLA嵌段可防止胶束解体并导致肿胀/聚集。荧光探针研究表明，随着pH从7.4降至6.6，胶束中保留的芘的极性增加，表明胶束内环境变为更亲水。考虑到在pH 6.6时尺寸从pH 7.4时的80 nm增加到580 nm，并且胶束溶液的透光率随pH降低而增加，胶束并未解离而是肿胀/聚集。有趣的是，在pH低于6.6时芘极性随后下降表明嵌段共聚物重新自组装，最有可能形成PLA嵌段核心，而聚组氨酸嵌段重新定位到表面。因此，PLA-b-PEG-b-聚组氨酸胶束的这些pH依赖性物理变化为pH（pH 7.2 - 6.5）的微小变化触发胶束中的药物释放提供了一种机制。
