Macromolecular delivery of 5-aminolaevulinic acid for photodynamic therapy using dendrimer conjugates
Macromolecular delivery of 5-aminolaevulinic acid for photodynamic therapy using dendrimer conjugates
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DOI：
10.1158/1535-7163.mct-06-0359
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发表时间：
2007-03-01
影响因子：
5.7
通讯作者：
MacRobert, Alexander J.
中科院分区：
文献类型：
--
作者：
Battah, Sinan;Balaratnam, Sherina;MacRobert, Alexander J.
5-氨基乙酰丙酸（5-ALA）给药后细胞内卟啉的产生已广泛用于光动力治疗。然而，5-ALA的细胞摄取受到其亲水性的限制，因此正在寻求改进的递送方式。高度支化的聚合物药物载体被称为树枝状聚合物，因为它们具有能够掺入高药物有效载荷的明确结构，所以呈现出有希望的药物递送新方法。在这项工作中，树枝状聚合物共轭物进行了研究，其中纳入18个氨基乙酰丙酸残基通过酯键连接到一个多足芳香族核心。在转化的PAM 212鼠角质形成细胞和A431人表皮样癌细胞系中研究了树枝状聚合物在细胞内递送和释放5-ALA以代谢为光敏剂原卟啉IX的能力。在最佳浓度为0.1 mmol/L时，该树枝状聚合物的合成效率明显高于5-ALA。细胞内卟啉荧光水平与光暴露后的细胞光毒性表现出良好的相关性，以及最小的暗毒性。树枝状聚合物的细胞摄取主要通过巨胞饮途径通过内吞途径发生。总之，大分子树枝状衍生物能够有效地将5-ALA递送至细胞用于持续卟啉合成。
Intracellular porphyrin generation following administration of 5-aminolaevulinic acid (5-ALA) has been widely used in photodynamic therapy. However, cellular uptake of 5-ALA is limited by its hydrophilicity, and improved means of delivery are therefore being sought. Highly branched polymeric drug carriers known as dendrimers present a promising new approach to drug delivery because they have a well-defined structure capable of incorporating a high drug payload. In this work, a dendrimer conjugate was investigated, which incorporated 18 aminolaevulinic acid residues attached via ester linkages to a multipodent aromatic core. The ability of the dendrimer to deliver and release 5-ALA intracellularly for metabolism to the photosensitizer, protoporphyrin IX, was studied in the transformed PAM 212 murine keratinocyte and A431 human epidermoid carcinoma cell lines. Up to an optimum concentration of 0.1 mmol/L, the dendrimer was significantly more efficient compared with 5-ALA for porphyrin synthesis. The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure, together with minimal dark toxicity. Cellular uptake of the dendrimer occurs through endocytic routes predominantly via a macropinocytosis pathway. In conclusion, macromolecular dendritic derivatives are capable of delivering 5-ALA efficiently to cells for Sustained porphyrin synthesis.