Multicompartment micelles with adjustable poly(ethylene glycol) shell for efficient in vivo photodynamic therapy.
Multicompartment micelles with adjustable poly(ethylene glycol) shell for efficient in vivo photodynamic therapy.
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DOI：
10.1021/nn4028294
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发表时间：
2014-01
期刊：
影响因子：
17.1
通讯作者：
C. Synatschke;Takahiro Nomoto;H. Cabral;M. Förtsch;K. Toh;Yu Matsumoto;K. Miyazaki;A. Hanisch;F. Schacher;A. Kishimura;N. Nishiyama;A. Müller;K. Kataoka
中科院分区：
文献类型：
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作者：
C. Synatschke;Takahiro Nomoto;H. Cabral;M. Förtsch;K. Toh;Yu Matsumoto;K. Miyazaki;A. Hanisch;F. Schacher;A. Kishimura;N. Nishiyama;A. Müller;K. Kataoka
我们描述了聚丁二烯-嵌段-聚(1-甲基-2-乙烯基吡啶甲基硫酸盐)-嵌段-聚甲基丙烯酸(BVqMAA)三嵌段三元共聚物的制备及其作为光动力疗法(PDT)先进药物递送系统的应用。在自组装过程中，一种卟嗪类化合物被引入到疏水核心中，同时作为模型药物和荧光探针。初始胶束电晕由带负电荷的聚甲基丙烯酸甲酯(PMAA)与带正电荷的聚乙二醇-嵌段-聚(L-赖氨酸)(PLL-b-PEG2)两嵌段共聚物通过聚电解质间络合物的方式控制地逐渐转变为聚乙二醇型(PEGO)。在聚乙二醇化程度较高的情况下，观察到了一个分隔的胶束电晕，低温电子显微镜测量表明，胶束电晕具有稳定的瓶刷状球体形态。通过体外细胞实验，我们证实了卟嗪胶束对A549细胞具有PDT活性。电晕组成对其体外PDT活性有很大影响，随着聚乙二醇化程度的增加，PDT活性降低，这与细胞对胶束的摄取有关。此外，还发现聚乙二醇化对体内血液循环和肿瘤聚集的影响。完全聚乙二醇化的胶束在血流中持续24小时，并在实体皮下A549肿瘤中蓄积，而未或仅部分聚乙二醇化的胶束迅速清除，不会在肿瘤组织中积聚。完全聚乙二醇化的胶束显示出有效的肿瘤生长抑制长达20天，在体内证明了PDT的有效性。
We describe the preparation of well-defined multicompartment micelles from polybutadiene-block-poly(1-methyl-2-vinyl pyridinium methyl sulfate)-block-poly(methacrylic acid) (BVqMAA) triblock terpolymers and their use as advanced drug delivery systems for photodynamic therapy (PDT). A porphyrazine derivative was incorporated into the hydrophobic core during self-assembly and served as a model drug and fluorescent probe at the same time. The initial micellar corona is formed by negatively charged PMAA and could be gradually changed to poly(ethylene glycol) (PEG) in a controlled fashion through interpolyelectrolyte complex formation of PMAA with positively charged poly(ethylene glycol)-block-poly(L-lysine) (PLL-b-PEG) diblock copolymers. At high degrees of PEGylation, a compartmentalized micellar corona was observed, with a stable bottlebrush-on-sphere morphology as demonstrated by cryo-TEM measurements. By in vitro cellular experiments, we confirmed that the porphyrazine-loaded micelles were PDT-active against A549 cells. The corona composition strongly influenced their in vitro PDT activity, which decreased with increasing PEGylation, correlating with the cellular uptake of the micelles. Also, a PEGylation-dependent influence on the in vivo blood circulation and tumor accumulation was found. Fully PEGylated micelles were detected for up to 24 h in the bloodstream and accumulated in solid subcutaneous A549 tumors, while non- or only partially PEGylated micelles were rapidly cleared and did not accumulate in tumor tissue. Efficient tumor growth suppression was shown for fully PEGylated micelles up to 20 days, demonstrating PDT efficacy in vivo.