Enhanced recognition ability, cell uptake capacity, and biostability are characteristics attributed to aptamer-based targeted anticancer agents, and are possibly associated with increased accumulation at the tumor site, improved therapeutic efficacy and reduced negative side effects. Herein, a phosphorothioate backbone modification strategy was applied to regulate the biomedical properties of pancreatic cancer cell–targeting aptamer for efficient in vivo drug delivery. Specifically, the CD71- targeting aptamer XQ-2d was modified into a fully thio-substituted aptamer S-XQ-2d, improving the plasma stability of S-XQ-2d and mitomycin C (MMC)-functionalized S-XQ-2d (MFSX), thus considerably prolonging their half-life in mice. Moreover, the binding and uptake capacities of S-XQ-2d were significantly enhanced. MFSX showed the same level of cytotoxicity as that of MMC against targeted cancer cells, but lower toxicity to non-targeted cells, highlighting its specificity and biosafety. Brief mechanistic studies demonstrated that XQ-2d and S-XQ-2d had different interaction modes and internalization pathways with the targeted cells.
基于适配体的靶向抗癌药物具有增强的识别能力、细胞摄取能力和生物稳定性，这些特性可能与其在肿瘤部位的积累增加、疗效提升及负面副作用减少相关。本文采用硫代磷酸骨架修饰策略调控靶向胰腺癌细胞的适配体生物医学特性，以实现高效的体内药物递送。具体而言，将靶向CD71的适配体XQ-2d修饰为全硫代取代的适配体S-XQ-2d，从而显著提升了S-XQ-2d及其功能化修饰产物丝裂霉素C-MFSX的血浆稳定性，并大幅延长了其在小鼠体内的半衰期。此外，S-XQ-2d的结合与摄取能力也显著增强。MFSX对靶向癌细胞的细胞毒性与丝裂霉素C相当，但对非靶向细胞的毒性较低，突显了其特异性和生物安全性。初步机制研究表明，XQ-2d与S-XQ-2d在靶细胞中的相互作用模式和内化途径存在差异。
Regulating the properties of XQ-2d for targeted delivery of therapeutic agents to pancreatic cancers
肿瘤(癌症)患者之家