NCE-Polymer Chemistry Group, Piramal Healthcare Ltd., Goregaon, Mumbai 400063, India.
J Biomed Nanotechnol. 2013 May;9(5):776-89. doi: 10.1166/jbn.2013.1582.
Many polymer based drug delivery nanosystems are currently being explored for delivering cytotoxic agents to the tumors. However, very few strategies delineate the comparative carrier ability of nanosystems, in similar experimental settings. As a result, it remains unclear how to optimally design polymer based multicomponent prodrug systems for delivery applications. The present study is aimed to design polymeric prodrug conjugate carriers for the comparative cellular delivery ability of anticancer drug doxorubicin hydrochloride (DOX) using linear poly(ethylene glycol) (PEG), hyperbranched poly(amido amine) (PAMAM) G4 dendrimer, and PAMAM G4 dendrimer-PEG conjugate using MCF-7 cells. Furthermore, the cellular targetability and in vitro anticancer activity of DOX conjugates is evaluated using transferrin (Tf) as a targeting ligand. Interestingly, conjugation of DOX to PAMAM G4-OH dendrimer significantly influences the cytotoxicity of DOX leading to -4 fold decrease in the IC50 dose when compared to pegylated DOX. This study establishes the rational and comparative structural activity relationship of polymeric prodrug carriers for delivery of anticancer drugs. The schematic representation of design of prodrug conjugates with varied polymeric architecures is as shown below (Fig. 1).
许多基于聚合物的药物传递纳米系统目前正在被探索用于向肿瘤递送细胞毒性药物。然而，很少有策略能够在相似的实验条件下描绘纳米系统的比较载体能力。因此，如何为递药应用最优地设计基于聚合物的多组分前药系统仍然不清楚。本研究旨在设计聚合物前药偶联载体，以比较线性聚乙二醇（PEG）、超支化聚（酰胺-胺）（PAMAM）G4 树枝状大分子和 PAMAM G4 树枝状大分子-PEG 对盐酸阿霉素（DOX）的细胞内递送能力，使用 MCF-7 细胞。此外，还使用转铁蛋白（Tf）作为靶向配体评估 DOX 缀合物的细胞靶向性和体外抗癌活性。有趣的是，DOX 与 PAMAM G4-OH 树枝状大分子的缀合显著影响 DOX 的细胞毒性，导致与 PEG 化 DOX 相比，IC50 剂量降低了 4 倍。该研究建立了用于抗癌药物递药的聚合物前药载体的合理和比较结构活性关系。具有不同聚合物结构的前药缀合物的设计示意图如下所示（图 1）。
