College of Chemistry, Chemical Engineering and Biotechnology, and ‡State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University , Shanghai 201620, People's Republic of China.
ACS Appl Mater Interfaces. 2014 Sep 24;6(18):16416-25. doi: 10.1021/am504849x. Epub 2014 Sep 12.
We report the development of a lactobionic acid (LA)-modified multifunctional dendrimer-based carrier system for targeted therapy of liver cancer cells overexpressing asialoglycoprotein receptors. In this study, generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were sequentially modified with fluorescein isothiocyanate (FI) and LA (or polyethylene glycol (PEG)-linked LA, PEG-LA), followed by acetylation of the remaining dendrimer terminal amines. The synthesized G5.NHAc-FI-LA or G5.NHAc-FI-PEG-LA conjugates (NHAc denotes acetamide groups) were used to encapsulate a model anticancer drug doxorubicin (DOX). We show that both conjugates are able to encapsulate approximately 5.0 DOX molecules within each dendrimer and the formed dendrimer/DOX complexes are stable under different pH conditions and different aqueous media. The G5.NHAc-FI-PEG-LA conjugate appears to have a better cytocompatibility, enables a slightly faster DOX release rate, and displays better liver cancer cell targeting ability than the G5.NHAc-FI-LA conjugate without PEG under similar experimental conditions. Importantly, the developed G5.NHAc-FI-PEG-LA/DOX complexes are able to specifically inhibit the growth of the target cells with a better efficiency than the G5.NHAc-FI-LA/DOX complexes at a relatively high DOX concentration. Our results suggest a key role played by the PEG spacer that affords the dendrimer platform with enhanced targeting and therapeutic efficacy of cancer cells. The developed LA-modified multifunctional dendrimer conjugate with a PEG spacer may be used as a delivery system for targeted liver cancer therapy and offers new opportunities in the design of multifunctional drug carriers for targeted cancer therapy applications.
我们报告了一种乳糖酸（LA）修饰的多功能树状大分子载体系统的开发，用于治疗过度表达唾液酸糖蛋白受体的肝癌细胞的靶向治疗。在这项研究中，通过依次修饰第五代（G5）聚（酰胺-胺）（PAMAM）树状大分子与异硫氰酸荧光素（FI）和 LA（或聚乙二醇（PEG）连接的 LA，PEG-LA），然后乙酰化剩余的树突状大分子末端胺。合成的 G5.NHAc-FI-LA 或 G5.NHAc-FI-PEG-LA 缀合物（NHAc 表示乙酰胺基团）用于包封模型抗癌药物阿霉素（DOX）。我们表明，两种缀合物都能够将大约 5.0 DOX 分子封装在每个树突状大分子内，并且形成的树突状大分子/DOX 复合物在不同 pH 值条件和不同水介质下稳定。在类似的实验条件下，与没有 PEG 的 G5.NHAc-FI-LA 缀合物相比，G5.NHAc-FI-PEG-LA 缀合物具有更好的细胞相容性，能够稍微更快地释放 DOX，并且具有更好的肝癌细胞靶向能力。重要的是，与 G5.NHAc-FI-LA/DOX 复合物相比，开发的 G5.NHAc-FI-PEG-LA/DOX 复合物能够在相对较高的 DOX 浓度下以更高的效率特异性抑制靶细胞的生长。我们的结果表明，PEG 间隔物起到了关键作用，使树突状大分子平台具有增强的靶向性和癌症细胞的治疗效果。开发的具有 PEG 间隔物的 LA 修饰的多功能树突状大分子缀合物可用作靶向肝癌治疗的递送系统，并为用于靶向癌症治疗应用的多功能药物载体的设计提供了新的机会。
