Preparation and cytotoxic activity of poly(ethylene glycol)-modified poly(amidoamine) dendrimers bearing adriamycin
Preparation and cytotoxic activity of poly(ethylene glycol)-modified poly(amidoamine) dendrimers bearing adriamycin
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DOI：
10.1016/j.biomaterials.2007.12.017
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发表时间：
2008-04-01
期刊：
影响因子：
14
通讯作者：
Harada, Atsushi
中科院分区：
文献类型：
--
作者：
Kono, Kenji;Kojima, Chie;Harada, Atsushi
我们已经开发了聚（酰胺基胺）（PAMAM）树枝状聚合物，在所有树枝状聚合物链末端具有聚（乙二醇）（PEG）接枝。为了获得PEG修饰的树枝状聚合物与抗癌药物的缀合位点，我们制备了PAMAM G4树枝状聚合物，其在树枝状聚合物的每个链末端具有谷氨酸（Glu）残基; PEG链连接到Glu残基的氨基。然后，我们使用酰胺键[PEG-Glu（ADR）-G4]或腙键[PEG-Glu（NHN-ADR）-G4]将抗癌药物阿霉素与Glu残基的侧链结合。对于通过酰胺键承载阿霉素的树枝状聚合物，阿霉素仅在pH 7.4和5.5下轻微释放。虽然在pH 7.4时通过腙键连接阿霉素的树枝状聚合物的释放水平可以忽略不计，但在pH 5.5时诱导了显著程度的阿霉素释放，这对应于晚期内体的pH。这些阿霉素轴承树枝状大分子显示出低得多的毒性HeLa细胞比游离阿霉素。然而，与PEG-Glu（ADR）-G4相比，PEG-Glu（NHN-ADR）-G4表现出高7倍的细胞毒性，这表明pH敏感的腙连接对于高细胞毒性的重要性。此外，PEG修饰的树枝状聚合物表现出与阿霉素耐药SBC-3/ADR 100细胞及其亲本阿霉素敏感SBC-3细胞相当的毒性水平。(c)2007爱思唯尔有限公司保留所有权利。
We have developed poly(amidoamine) (PAMAM) dendrimers that have poly(ethylene glycol) (PEG) grafts at all dendrimer chain ends. To obtain PEG-modified dendrimers with sites for conjugation of anticancer drugs for this study, we prepared PAMAM G4 dendrimers that have a glutamic acid (Glu) residue at every chain end of dendrimer; PEG chains were attached to amino groups of Glu residues. We then combined the anticancer drug adriamycin to side chains of the Glu residues using an amide bond, [PEG-Glu(ADR)-G4], or hydrazone bond, [PEG-Glu(NHN-ADR)-G4]. For the dendrimers bearing adriamycin through amide linkage, adriamycin was released only slightly at pH 7.4 and 5.5. Although a negligible level of release occurred at pH 7.4 for dendrimers with adriamycin via hydrazone linkage, a remarkable extent of adriamycin release was induced at pH 5.5, which corresponds to the pH of late endosome. These adriamycin-bearing dendrimers showed much lower toxicity to HeLa cells than did free adriamycin. However, compared to PEG-Glu(ADR)-G4, PEG-Glu(NHN-ADR)-G4 exhibited 7 times higher cytotoxicity, suggesting the importance of pH-sensitive hydrazone linkage for high cytotoxicity. Furthermore, the PEG-modified dendrimers exhibited an equivalent level of toxicity to that of adriamycin-resistant SBC-3/ADR100 cells and their parent adriamycin-sensitive SBC-3 cells. (c) 2007 Elsevier Ltd. All rights reserved.