Lai Ping-Shan, Lou Pei-Jen, Peng Cheng-Liang, Pai Chin-Ling, Yen Wei-Nen, Huang Ming-Yi, Young Tai-Horng, Shieh Ming-Jium
Department of Chemistry and Center of Nanoscience and Nanotechnology, National Chung-Hsing University, Taichung, Taiwan.
J Control Release. 2007 Sep 11;122(1):39-46. doi: 10.1016/j.jconrel.2007.06.012. Epub 2007 Jun 22.
Coupling anticancer drugs to synthetic polymers is a promising approach to improve the efficacy and reduce the side effects of these drugs. The pH-activated polymer has been demonstrated to be a successful drug delivery vehicle system, whereas the photochemical internalization (PCI) was invented for site-specific delivery of membrane impermeable macromolecules from endocytic vesicles into the cytosol. In this study, doxorubicin (DOX) was conjugated to polyamidoamine (PAMAM) dendrimers via pH-sensitive and -insensitive linkers and was combined with different PCI strategies to evaluate the cytotoxic effects. Our results showed that both PCI strategies significantly improved the cytotoxicity of free DOX on Ca9-22 cells at higher concentrations. The 'light after' PCI treatment was efficient in releasing DOX from the PAMAM-hyd-DOX conjugates, resulted in more nuclear accumulation of DOX and more cell death through synergistic effects. On the other hand, antagonism was observed when 'light before' PCI combined with PAMAM-hyd-DOX conjugate. The distribution of PAMAM-amide-DOX was mainly cytosolic with or without PCI treatments. Both PCI strategies failed to improve the cytotoxicity of PAMAM-amide-DOX conjugates. Our results provide invaluable information in the future design of drug-polymer complexes for multi-modality cancer treatments.
将抗癌药物与合成聚合物偶联是一种很有前景的方法，可提高这些药物的疗效并降低其副作用。pH激活聚合物已被证明是一种成功的药物递送载体系统，而光化学内化（PCI）则是为将膜不可渗透的大分子从内吞小泡特异性递送至细胞质中而发明的。在本研究中，阿霉素（DOX）通过对pH敏感和不敏感的连接子与聚酰胺胺（PAMAM）树枝状大分子偶联，并与不同的PCI策略相结合，以评估细胞毒性作用。我们的结果表明，两种PCI策略在较高浓度下均显著提高了游离DOX对Ca9-22细胞的细胞毒性。“光照后”PCI处理有效地从PAMAM-hyd-DOX偶联物中释放出DOX，导致更多的DOX在细胞核中积累，并通过协同作用导致更多细胞死亡。另一方面，当“光照前”PCI与PAMAM-hyd-DOX偶联物联合使用时，观察到拮抗作用。无论有无PCI处理，PAMAM-酰胺-DOX的分布主要在细胞质中。两种PCI策略均未能提高PAMAM-酰胺-DOX偶联物的细胞毒性。我们的结果为未来用于多模式癌症治疗的药物-聚合物复合物设计提供了宝贵信息。
