Zhao Yongmei, Liu Tianqing, Ardana Aditya, Fletcher Nicholas L, Houston Zachary H, Blakey Idriss, Thurecht Kristofer J
School of Pharmacy, Nantong University, Nantong 226019 China.
QIMR Berghofer Medical Research, 300 Herston Rd, Brisbane, QLD 4006 Australia.
ACS Omega. 2022 May 10;7(20):17119-17127. doi: 10.1021/acsomega.2c00620. eCollection 2022 May 24.
Multidrug resistance (MDR) is a problem that is often associated with a poor clinical outcome in chemotherapeutic cancer treatment. MDR may potentially be overcome by utilizing synergistic approaches, such as combining siRNA gene therapy and chemotherapy to target different mechanisms of apoptosis. In this study, a strategy is presented for developing multicomponent nanomedicines using orthogonal and compatible chemistries that lead to effective nanotherapeutics. Hyperbranched polymers were used as drug carriers that contained doxorubicin (DOX), attached via a pH-sensitive hydrazone linkage, and ataxia-telangiectasia mutated (ATM) siRNA, attached via a redox-sensitive disulfide group. This nanomedicine also contained cyanine 5 (Cy5) as a diagnostic tracer as well as in-house developed bispecific antibodies that allowed targeting of the epidermal growth factor receptor (EGFR) present on tumor tissue. Highly efficient coupling of siRNA was achieved with 80% of thiol end-groups on the hyperbranched polymer coupling with siRNA. This attachment was reversible, with the majority of siRNA released under reducing conditions as desired. In cellular studies, the nanomedicine exhibited increased DNA damage and cancer cell inhibition compared to the individual treatments. Moreover, the nanomedicine has great potential to suppress the metabolism of cancer cells including both mitochondrial respiration and glycolytic activity, with enhanced efficacy observed when targeted to the cell surface protein EGFR. Our findings indicated that co-delivery of ATM siRNA and DOX serves as a more efficient therapeutic avenue in cancer treatment than delivery of the single species and offers a potential route for synergistically enhanced gene therapy.
多药耐药性（MDR）是一个在癌症化疗中常与不良临床结果相关的问题。利用协同方法，如将siRNA基因治疗与化疗相结合以针对不同的细胞凋亡机制，有可能克服MDR。在本研究中，提出了一种使用正交且兼容的化学方法开发多组分纳米药物的策略，该策略可产生有效的纳米治疗剂。超支化聚合物用作药物载体，其包含通过pH敏感的腙键连接的阿霉素（DOX）和通过氧化还原敏感的二硫键连接的共济失调毛细血管扩张突变（ATM）siRNA。这种纳米药物还包含作为诊断示踪剂的花菁5（Cy5）以及内部开发的双特异性抗体，该抗体可靶向肿瘤组织上存在的表皮生长因子受体（EGFR）。siRNA实现了高效偶联，超支化聚合物上80%的硫醇端基与siRNA偶联。这种连接是可逆的，大部分siRNA在所需的还原条件下释放。在细胞研究中，与单独治疗相比，该纳米药物表现出增加的DNA损伤和癌细胞抑制作用。此外，该纳米药物具有极大的潜力抑制癌细胞的代谢，包括线粒体呼吸和糖酵解活性，当靶向细胞表面蛋白EGFR时观察到疗效增强。我们的研究结果表明，与单一药物递送相比，共递送ATM siRNA和DOX在癌症治疗中是一种更有效的治疗途径，并为协同增强基因治疗提供了一条潜在途径。
