Biological Assessment of Triazine Dendrimer: Toxicological Profiles, Solution Behavior, Biodistribution, Drug Release and Efficacy in a PEGylated, Paclitaxel Construct
Biological Assessment of Triazine Dendrimer: Toxicological Profiles, Solution Behavior, Biodistribution, Drug Release and Efficacy in a PEGylated, Paclitaxel Construct
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DOI：
10.1021/mp100104x
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发表时间：
2010-07-01
影响因子：
4.9
通讯作者：
Simanek, Eric E.
中科院分区：
文献类型：
--
作者：
Lo, Su-Tang;Stern, Stephan;Simanek, Eric E.
第三代三嗪树枝状大分子轴承约9个2 kDa的聚乙二醇链和12个酯连接紫杉醇基团的理化特性，在体外性能，和在体内的毒性和疗效的报告。中性构建体的流体动力学直径随水性溶剂略有变化，范围为15.6至19.4 nm。质谱和光散射表明分子量完全不同，前者类似于与预期一致的40 kDa质量，后者400 kDa质量与十聚体结构和观察到的流体动力学半径一致。HPLC可用于评估纯度以及紫杉醇释放，这在中性和低pH的有机溶剂或水溶液中是不显著的。紫杉醇释放发生在体外人，大鼠和小鼠血浆中，并且是非线性的，在48小时孵育期内的累积释放范围为7 - 20%。该构建体在人肝癌（Hep G2）、猪肾近端小管（LLC-PK 1）和人结肠癌（LS 174 T）细胞中的毒性比紫杉醇低2-3个数量级，但在LS 174 T细胞中显示出与Abraxane相似的细胞毒性。紫杉醇和构建体似乎都诱导半胱天冬酶3依赖性凋亡。该构建体显示出低水平的内毒素，不具有溶血性，并且在体外不诱导血小板聚集，但似乎在体外减少胶原诱导的血小板聚集。此外，树枝状聚合物制剂在体外轻微激活补体系统，这很可能是由于存在痕量（
The physicochemical characteristics, in vitro properties, and in vivo toxicity and efficacy of a third generation triazine dendrimer bearing approximately nine 2 kDa polyethylene glycol chains and twelve ester linked paclitaxel groups are reported. The hydrodynamic diameter of the neutral construct varies slightly with aqueous solvent ranging from 15.6 to 19.4 nm. Mass spectrometry and light scattering suggest radically different molecular weights with the former similar to 40 kDa mass consistent with expectation, and the latter 400 kDa mass consistent with a decameric structure and the observed hydrodynamic radii. HPLC can be used to assess purity as well as paclitaxel release, which is insignificant in organic solvents or aqueous solutions at neutral and low pH. Paclitaxel release occurs in vitro in human, rat, and mouse plasma and is nonlinear, ranging from 7 to 20% cumulative release over a 48 h incubation period. The construct is 2-3 orders of magnitude less toxic than Taxol by weight in human hepatocarcinoma (Hep G2), porcine renal proximal tubule (LLC-PK1), and human colon carcinoma (LS174T) cells, but shows similar cytotoxicity to Abraxane in LS174T cells. Both Taxol and the construct appear to induce caspase 3-dependent apoptosis. The construct shows a low level of endotoxin, is not hemolytic and does not induce platelet aggregation in vitro, but does appear to reduce collagen-induced platelet aggregation in vitro. Furthermore, the dendrimer formulation slightly activates the complement system in vitro due most likely to the presence of trace amounts (