Li Lin, Wei Pengyao, Kong Tong, Yuan Bo, Fu Pan, Li Yong, Wang Yuhui, Zheng Jianping, Wang Kaizhe
Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, Ningbo Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering of Chinese Academy of Sciences, Ningbo, 315300, P. R. China.
Cancer Care Centre, St George Hospital, Kogarah, NSW, 2217, Australia.
Nanoscale Horiz. 2025 Apr 22;10(5):873-884. doi: 10.1039/d4nh00652f.
Triple-negative breast cancer (TNBC) is highly invasive with a poor prognosis, and chemotherapy remains the clinical treatment of choice. Paclitaxel is a commonly used first-line chemotherapy drug, but its untargeted distribution poses clinical challenges. Inspired by antibody-drug conjugates, we develop a precisely structured framework nucleic acid-programmed aptamer-paclitaxel conjugate (FAPC) with chemically well-defined paclitaxel loading dosing, enabling the regulation of receptor-aptamer affinity to facilitate tumor-targeted chemotherapy. Utilizing framework nucleic acids as a precise addressing scaffold, we organize the AS1411 aptamer with accurate intermolecular spacing and find that an inter-aptamer spacing of 19.04 nm could enhance the affinity of the FAPC for tumor cells. Then, the multifunctional FAPC can disrupt actin reorganization to achieve cytotoxicity in tumor cells. Furthermore, the AS1411-specifically modified FAPC further enhances the structure-dependent selective accumulation of drugs at tumor sites in a human xenograft model of triple-negative breast cancer, subsequently leading to significantly improved antitumor efficacy and reduced toxicity. The FAPC provides a precisely programmable platform for efficient targeted delivery of chemotherapeutic agents to malignancies.
三阴性乳腺癌（TNBC）具有高度侵袭性且预后较差，化疗仍然是临床治疗的首选。紫杉醇是常用的一线化疗药物，但其非靶向分布带来了临床挑战。受抗体 - 药物偶联物的启发，我们开发了一种结构精确的框架核酸编程适配体 - 紫杉醇偶联物（FAPC），其紫杉醇负载剂量化学定义明确，能够调节受体 - 适配体亲和力以促进肿瘤靶向化疗。利用框架核酸作为精确的寻址支架，我们以精确的分子间距组织AS1411适配体，发现19.04 nm的适配体间间距可增强FAPC对肿瘤细胞的亲和力。然后，多功能FAPC可破坏肌动蛋白重组以在肿瘤细胞中实现细胞毒性。此外，AS1411特异性修饰的FAPC进一步增强了药物在三阴性乳腺癌人异种移植模型中肿瘤部位的结构依赖性选择性积累，随后显著提高了抗肿瘤疗效并降低了毒性。FAPC为将化疗药物高效靶向递送至恶性肿瘤提供了一个精确可编程的平台。
