Department of Chemistry, Shands Cancer Center, UF Genetics Institute, University of Florida, Gainesville, Florida 32611-7200, United States.
J Am Chem Soc. 2011 Aug 31;133(34):13380-6. doi: 10.1021/ja201285y. Epub 2011 Aug 5.
Chemotherapy strategies thus far reported can result in both side effects and drug resistance. To address both of these issues at the cellular level, we report a molecular engineering strategy, which employs polymeric aptamers to induce selective cytotoxicity inside target cells. The polymeric aptamers, composed of both multiple cell-based aptamers and a high ratio of dye-labeled short DNA, exploit the target recognition capability of the aptamer, enhanced cell internalization via multivalent effects, and cellular disruption by the polymeric conjugate. Importantly, the polymer backbone built into the conjugate is cytotoxic only inside cells. As a result, selective cytotoxicity is achieved equally in both normal cancer cells and drug-resistant cells. Control assays have confirmed the nontoxicity of the aptamer itself, but they have also shown that the physical properties of the polymer backbone contribute to target cell cytotoxicity. Therefore, our approach may shed new light on drug design and drug delivery.
迄今为止报道的化疗策略可能会导致副作用和耐药性。为了解决细胞水平上的这两个问题，我们报告了一种分子工程策略，该策略使用聚合适体在靶细胞内诱导选择性细胞毒性。聚合适体由多个基于细胞的适体和高比例的染料标记短 DNA 组成，利用适体的靶识别能力、通过多价效应增强细胞内化以及聚合物缀合物引起的细胞破坏。重要的是，聚合物主链在缀合物中仅在细胞内具有细胞毒性。因此，在正常癌细胞和耐药细胞中均能实现同等的选择性细胞毒性。对照实验证实了适体本身的非毒性，但也表明聚合物主链的物理性质有助于靶细胞的细胞毒性。因此，我们的方法可能为药物设计和药物输送提供新的思路。
