Effects of branching architecture and linker on the activity of hyperbranched polymer-drug conjugates.
Effects of branching architecture and linker on the activity of hyperbranched polymer-drug conjugates.
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DOI：
10.1021/bc800526z
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发表时间：
2009-05-20
影响因子：
4.7
通讯作者：
Kannan RM
中科院分区：
文献类型：
--
作者：
Perumal O;Khandare J;Kolhe P;Kannan S;Lieh-Lai M;Kannan RM
药物从超支化聚合物-药物缀合物的释放和随后的活性受到支化结构和连接体的影响。为了理解这些作用，我们使用超支化多元醇和G4-OH聚酰胺胺（PAMAM）树状聚合物与甲基泼尼松龙（MP）作为模型药物。使用谷氨酸（GA）或琥珀酸（SA）间隔基将药物缀合至树枝状聚合物或多元醇。药物有效载荷是最高的多元醇，而在树枝状聚合物的情况下，实现了更高的有效载荷与GA比SA间隔。在A549肺上皮细胞中聚合物缀合物的细胞摄取高于游离药物，并且缀合物主要定位于胞质溶胶中。如通过抑制前列腺素合成所测量的，聚合物缀合的MP的抗炎活性对于MP-SA-树枝状聚合物缀合物最高，其次是MP-GA-多元醇缀合物，然后是MP-GA-树枝状聚合物缀合物。这项研究表明，分支结构和间隔影响药物的有效载荷和药物-纳米聚合物缀合物的药理活性，这可能会显着影响这些纳米器件的体内功效。这对这些纳米器件的最终体内功效具有关键影响。以甲基强的松龙为模型药物，研究了支化结构和间隔基对药物-聚合物偶联物载药量和药理活性的影响。与完全支化的G4 OH树枝状聚合物相比，不完全支化的多元醇的载药量和抗炎活性更高。类似地，在树枝状聚合物缀合物中，与谷氨酸间隔基相比，琥珀酸间隔基的载药量和抗炎活性更高。
Drug release from hyperbranched polymer-drug conjugates and the subsequent activity are influenced by the branching architecture and the linker. To gain an understanding of these effects, we used hyperbranched polyol and G4-OH Polyamidoamine (PAMAM) dendrimer with methyl prednisolone (MP) as the model drug. The drug was conjugated to dendrimer or polyol using a glutaric acid (GA), or a succinic acid (SA) spacer. Drug payload was the highest with polyol, while in the case of dendrimer, a higher payload was achieved with the GA than the SA spacer. Cell uptake of the polymer conjugates in A549 lung epithelial cells was higher than the free drug and the conjugates largely localized in the cytosol. The anti-inflammatory activity of polymer conjugated-MP, as measured by inhibition of prostaglandin synthesis, was the highest for MP-SA-dendrimer conjugate followed by MP-GA-polyol conjugate, and then MP-GA-dendrimer conjugate. This study suggests that the branching architecture and spacer influence the drug payload and pharmacological activity of a drug-nanopolymer conjugate, which may significantly influence the in vivo efficacy of these nanodevices. This has key implications in the eventual in vivo efficacy of these nanodevices. The influence of branching architecture and spacer on drug loading and pharmacological activity of drug-polymer conjugates is reported using methyl prednisolone as a model drug. The drug loading and anti-inflammatory activity was higher with imperfectly branched polyol in comparison to perfectly branched G4OH dendrimer. Similarly the drug loading and anti-inflammatory activity was higher with succinic acid spacer compared to glutaric acid spacer in dendrimer conjugates.
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