Henri Justin L, Nakhjavani Maryam, McCoombe Scott, Shigdar Sarah
School of Medicine, Deakin University, Geelong, VIC, 3220, Australia.
School of Medicine, Deakin University, Geelong, VIC, 3220, Australia; Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC, 3220, Australia.
Biochimie. 2023 Jan;204:108-117. doi: 10.1016/j.biochi.2022.09.005. Epub 2022 Sep 22.
Despite medical advances in treatment strategies over the past 30-years, epithelial ovarian cancer (EOC) continues to be defined by poor patient survival rates and aggressive, drug resistant relapse. Traditional approaches to cancer chemotherapy are typically limited by severe off-target effects on healthy tissue and aggressive drug-resistant recurrence. Recent shifts towards targeted therapies offer the possibility of circumventing the obstacles experienced by these treatments. While antibodies are the pioneering agents in such targeted therapies, several intrinsic characteristics of antibodies limits their clinical translation and efficacy. In contrast, oligonucleotide chemical antibodies, known as aptamers, are ideal for this application given their small size and lack of immunogenicity. This study explored the efficacy of a DNA aptamer, designed to target a well-established cancer biomarker, EpCAM, to deliver a chemotherapeutic drug. The results from this study support evidence that EpCAM aptamers can bind to epithelial ovarian cancer; and offers a valid alternative as a targeting ligand with tuneable specificity and sensitivity. It also supports the growing body of evidence that aptamers show great potential for application-specific, post-SELEX engineering through rational modifications. Through in vitro assays, these aptamers demonstrated cytotoxicity in both monolayer and tumoursphere assays, as well as in tumourigenic enriching assays. Further experimentation based on the results achieved in this project might aid in the development of novel cancer therapeutics and guide the novel designs of drugs for targeted drug delivery.
尽管在过去30年里治疗策略取得了医学进展，但上皮性卵巢癌（EOC）仍然以患者生存率低和侵袭性、耐药性复发为特征。传统的癌症化疗方法通常受到对健康组织严重的脱靶效应和侵袭性耐药复发的限制。最近向靶向治疗的转变为规避这些治疗所面临的障碍提供了可能性。虽然抗体是此类靶向治疗中的先驱药物，但抗体的一些固有特性限制了它们的临床转化和疗效。相比之下，被称为适配体的寡核苷酸化学抗体因其小尺寸和缺乏免疫原性而非常适合此应用。本研究探索了一种DNA适配体的疗效，该适配体旨在靶向一种成熟的癌症生物标志物EpCAM，以递送一种化疗药物。这项研究的结果支持了EpCAM适配体可以与上皮性卵巢癌结合的证据；并提供了一种有效的替代方案，作为具有可调节特异性和敏感性的靶向配体。它还支持越来越多的证据表明，适配体通过合理修饰在SELEX后工程中显示出巨大的应用潜力。通过体外试验，这些适配体在单层和肿瘤球试验以及肿瘤富集试验中均表现出细胞毒性。基于本项目取得的结果进行进一步的实验可能有助于开发新型癌症治疗方法，并指导靶向药物递送药物的新设计。
