Macromolecular Bipill of Gemcitabine and Methotrexate Facilitates Tumor-Specific Dual Drug Therapy with Higher Benefit-to-Risk Ratio
Macromolecular Bipill of Gemcitabine and Methotrexate Facilitates Tumor-Specific Dual Drug Therapy with Higher Benefit-to-Risk Ratio
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DOI：
10.1021/bc400477q
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发表时间：
2014-03-01
影响因子：
4.7
通讯作者：
Jain, Sanyog
中科院分区：
文献类型：
--
作者：
Das, Manasmita;Jain, Roopal;Jain, Sanyog
本研究报告了一种新型大分子双药丸的合成、表征和生物学评价，该双药丸是通过将两种不同的抗癌药物，即吉西他滨（GEM）和甲氨蝶呤（MTX）添加到长循环聚乙二醇（PEG）间隔物的远端而合成的。 GEM 和 MTX 通过 PEG 连接体共价结合不仅改变了组成药物分子的溶解度特征，而且显着提高了它们在血浆存在下的稳定性。体外细胞毒性研究证实，与游离药物同源物（即游离 GEM（24 小时 IC50 0.294 μM）和游离 MTX（24 小时 IC50 0.591 μM）相比，GEM-PEG-MTX 在人乳腺腺癌 MCF-7 细胞系中发挥更高的细胞毒性（24 小时 IC50 0.181 μM）。在化学诱导的乳腺癌大鼠中进行的肿瘤生长抑制研究表明，GEM-PEG-MTX 缀合物优于所有其他药物制剂，包括游离药物、GEM 和 MTX 的物理混合物以及聚乙二醇化 GEM/MTX。对荷瘤大鼠和健康小鼠的毒性研究证实，双药物结合是协同潜在候选药物的治疗指数，同时减轻药物相关副作用的有效手段。
The present study reports the synthesis, characterization, and biological evaluation of a novel macromolecular bipill, synthesized by appending two different anticancer agents, viz., gemcitabine (GEM) and methotrexate (MTX), to the distal ends of a long-circulating poly(ethylene glycol) (PEG) spacer. Covalent conjugation of GEM and MTX via PEG linker not only transformed the solubility profiles of constituent drug molecules, but significantly improved their stability in the presence of plasma. In vitro cytotoxicity studies confirmed that GEM-PEG-MTX exerts higher cytotoxicity (IC50 0.181 mu M at 24 h) in human breast adenocarcinoma MCF-7 cell lines, when compared to free drug congeners, i.e., free GEM (IC50 0.294 mu M at 24 h) and free MTX (IC50 0.591 mu M at 24 h). Tumor growth inhibition studies in chemically induced breast cancer bearing rats established the superiority of GEM-PEG-MTX conjugate over all other pharmaceutical preparations including free drugs, physical mixture of GEM and MTX, and PEGylated GEM/MTX. Toxicity studies in tumor bearing rats as well as healthy mice corroborated that dual drug conjugation is an effective means to synergize the therapeutic indices of potential drug candidates while alleviating drug-associated side effects.