School of Chemical Engineering, Purdue University, West Lafayette, IN 47907, USA.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Biotechnol Adv. 2014 Sep-Oct;32(5):1037-50. doi: 10.1016/j.biotechadv.2014.05.006. Epub 2014 Jun 9.
Tumor cells exhibit drug resistant phenotypes that decrease the efficacy of chemotherapeutic treatments. The drug resistance has a genetic basis that is caused by an abnormal gene expression. There are several types of drug resistance: efflux pumps reducing the cellular concentration of the drug, alterations in membrane lipids that reduce cellular uptake, increased or altered drug targets, metabolic alteration of the drug, inhibition of apoptosis, repair of the damaged DNA, and alteration of the cell cycle checkpoints (Gottesman et al., 2002; Holohan et al., 2013). siRNA is used to silence the drug resistant phenotype and prevent this drug resistance response. Of the listed types of drug resistance, pump-type resistance (e.g., high expression of ATP-binding cassette transporter proteins such as P-glycoproteins (Pgp; also known as multi-drug resistance protein 1 or MDR1, encoded by the ATP-Binding Cassette Sub-Family B Member 1 (ABCB1) gene)) and apoptosis inhibition (e.g., expression of anti-apoptotic proteins such as Bcl-2) are the most frequently targeted for gene silencing. The co-delivery of siRNA and chemotherapeutic drugs has a synergistic effect, but many of the current projects do not control the drug release from the nanocarrier. This means that the drug payload is released before the drug resistance proteins have degraded and the drug resistance phenotype has been silenced. Current research focuses on cross-linking the carrier's polymers to prevent premature drug release, but these carriers still rely on environmental cues to release the drug payload, and the drug may be released too early. In this review, we studied the release kinetics of siRNA and chemotherapeutic drugs from a broad range of carriers. We also give examples of carriers used to co-deliver siRNA and drugs to drug-resistant tumor cells, and we examine how modifications to the carrier affect the delivery. Lastly, we give our recommendations for the future directions of the co-delivery of siRNA and chemotherapeutic drug treatments.
肿瘤细胞表现出降低化疗疗效的耐药表型。耐药性具有遗传基础，是由异常基因表达引起的。有几种类型的耐药性：降低细胞内药物浓度的外排泵、改变膜脂质从而减少细胞摄取、增加或改变药物靶点、药物代谢改变、抑制细胞凋亡、修复受损 DNA 以及改变细胞周期检查点（Gottesman 等人，2002 年；Holohan 等人，2013 年）。siRNA 用于沉默耐药表型并防止这种耐药反应。在所列出的耐药类型中，泵型耐药（例如，ATP 结合盒转运蛋白的高表达，如 P 糖蛋白（Pgp；也称为多药耐药蛋白 1 或 MDR1，由 ATP 结合盒亚家族 B 成员 1（ABCB1）基因编码）和细胞凋亡抑制（例如，抗凋亡蛋白的表达，如 Bcl-2）是最常针对基因沉默的靶点。siRNA 和化疗药物的共递呈具有协同作用，但许多当前项目无法控制纳米载体中药物的释放。这意味着在耐药蛋白降解和耐药表型被沉默之前，药物有效载荷就已经被释放了。当前的研究重点是交联载体的聚合物以防止过早释放药物，但这些载体仍然依赖于环境线索来释放药物有效载荷，并且药物可能过早释放。在这篇综述中，我们研究了广泛的载体中 siRNA 和化疗药物的释放动力学。我们还给出了用于将 siRNA 和药物共递送至耐药肿瘤细胞的载体的示例，并研究了载体的修饰如何影响递送。最后，我们为 siRNA 和化疗药物联合治疗的未来发展方向提出了建议。
