Strathclyde Institute of Pharmacy and Biomedical Sciences, John Arbuthnott Building, 161 Cathedral Street, Glasgow G4 0RE, United Kingdom.
J Inorg Biochem. 2011 Sep;105(9):1115-22. doi: 10.1016/j.jinorgbio.2011.05.017. Epub 2011 May 27.
Aquated cisplatin was added to half-generation PAMAM dendrimers and the resultant complexes were purified by centrifuge. The drug-dendrimer complexes were then characterised by 1-D and diffusion (1)H NMR and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis-{Pt(NH(3))(2)} molecules per dendrimer; G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'-GMP at temperatures of 60°C for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tumour size by 33% compared to an untreated control group. The G6.5 cisplatin-dendrimer complex was administered at two doses (6 and 8 mg/kg equivalent of cisplatin). Both were well tolerated by the mice. The lower dose displayed comparable activity to cisplatin with a tumour volume reduction of 32%, but the higher dose was significantly more active than free cisplatin with a tumour reduction of 45%.
水合顺铂被添加到半代 PAMAM 树枝状大分子中，所得复合物通过离心进行纯化。然后通过一维和扩散 (1)H NMR 和 ICP-AES 对药物-树枝状大分子复合物进行表征。结合的药物量发现与树枝状大分子的大小成正比：G3.5，每个树枝状大分子有 22 个顺式-{Pt(NH(3))(2)}分子；G4.5，37 个；G5.5，54 个；G6.5，94 个，这仅代表每个树枝状大分子上可用结合位点的一小部分（分别为 68%、58%、42%和 37%）。药物释放研究表明，即使在 60°C 下与 5'-GMP 长时间孵育，一些药物仍与树枝状大分子结合（分别释放药物的百分比为 18%、30%、35%和 63%）。药物的结合被发现降低了树枝状大分子的半径。最后，使用 A2780、A2780cis 和 A2780cp 卵巢癌细胞系的体外测定来确定树枝状大分子对药物细胞毒性的影响。游离树枝状大分子没有细胞毒性，而药物-树枝状大分子复合物表现出中等活性。体内活性通过 A2780 肿瘤异种移植进行检查。顺铂在其最大耐受剂量 6mg/kg 下，与未治疗的对照组相比，肿瘤体积减少了 33%。G6.5 顺铂-树枝状大分子复合物以两种剂量（相当于顺铂的 6 和 8mg/kg）给药。两种剂量都被小鼠耐受良好。低剂量与顺铂的活性相当，肿瘤体积减少 32%，但高剂量比游离顺铂更有效，肿瘤体积减少 45%。
