Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer
Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer
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DOI：
10.1158/0008-5472.can-04-3921
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发表时间：
2005-06-15
期刊：
影响因子：
11.2
通讯作者：
Baker, JR
中科院分区：
文献类型：
--
作者：
Kukowska-Latallo, JF;Candido, KA;Baker, JR
先前的研究表明，纳米粒子药物递送可能会提高对抗癌药物的治疗反应，并允许同时监测肿瘤对药物的摄取。我们使用直径小于5纳米的改性PAMAM树枝状聚合物作为载体。乙酰化树枝状聚合物与叶酸作为靶向剂结合，然后与甲氨蝶呤或氚以及荧光素或6 - 羧基四甲基罗丹明偶联。将这些偶联物静脉注射到携带过度表达叶酸受体的人KB肿瘤的免疫缺陷小鼠体内。与非靶向聚合物相比，叶酸偶联的纳米粒子在给药后4天内集中在肿瘤和肝脏组织中。预先静脉注射游离叶酸可减弱叶酸靶向聚合物在肿瘤组织中的定位。共聚焦显微镜证实了药物偶联物进入肿瘤细胞内。靶向甲氨蝶呤提高了其抗肿瘤活性，并显著降低了其毒性，使得使用游离药物无法实现的治疗反应成为可能。
Prior studies suggested that nanoparticle drug delivery might improve the therapeutic response to anticancer drugs and allow the simultaneous monitoring of drug uptake by tumors. We employed modified PAMAM dendritic polymers < 5 nm in diameter as carriers. Acetylated dendrimers were conjugated to folic acid as a targeting agent and then coupled to either methotrexate or tritium and either fluorescein or 6-carboxytetramethylrhodamine. These conjugates were injected i.v. into immunodeficient mice bearing human KB tumors that overexpress the folic acid receptor. In contrast to nontargeted polymer, folate-conjugated nanoparticles concentrated in the tumor and liver tissue over 4 days after administration. The tumor tissue localization of the folate-targeted polymer could be attenuated by prior i.v. injection of free folic acid. Confocal microscopy confirmed the internalization of the drug conjugates into the tumor cells. Targeting methotrexate increased its antitumor activity and markedly decreased its toxicity, allowing therapeutic responses not possible with a free drug.