Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, P.R. China.
TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu, University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, Sichuan, 610072, P.R. China.
J Nanobiotechnology. 2023 Jun 10;21(1):186. doi: 10.1186/s12951-023-01953-9.
Targeted chemo-phototherapy has received widespread attention in cancer treatment for its advantages in reducing the side effects of chemotherapeutics and improving therapeutic effects. However, safe and efficient targeted-delivery of therapeutic agents remains a major obstacle. Herein, we successfully constructed an AS1411-functionalized triangle DNA origami (TOA) to codeliver chemotherapeutic drug (doxorubicin, DOX) and a photosensitizer (indocyanine green, ICG), denoted as TOADI (DOX/ICG-loaded TOA), for targeted synergistic chemo-phototherapy. In vitro studies show that AS1411 as an aptamer of nucleolin efficiently enhances the nanocarrier's endocytosis more than 3 times by tumor cells highly expressing nucleolin. Subsequently, TOADI controllably releases the DOX into the nucleus through the photothermal effect of ICG triggered by near-infrared (NIR) laser irradiation, and the acidic environment of lysosomes/endosomes facilitates the release. The downregulated Bcl-2 and upregulated Bax, Cyt c, and cleaved caspase-3 indicate that the synergistic chemo-phototherapeutic effect of TOADI induces the apoptosis of 4T1 cells, causing ~ 80% cell death. In 4T1 tumor-bearing mice, TOADI exhibits 2.5-fold targeted accumulation in tumor region than TODI without AS1411, and 4-fold higher than free ICG, demonstrating its excellent tumor targeting ability in vivo. With the synergetic treatment of DOX and ICG, TOADI shows a significant therapeutic effect of ~ 90% inhibition of tumor growth with negligible systemic toxicity. In addition, TOADI presents outstanding superiority in fluorescence and photothermal imaging. Taken together, this multifunctional DNA origami-based nanosystem with the advantages of specific tumor targeting and controllable drug release provides a new strategy for enhanced cancer therapy.
靶向化疗 - 光疗在癌症治疗中受到广泛关注，因为它具有降低化疗副作用和提高治疗效果的优势。然而，安全有效地输送治疗剂仍然是一个主要障碍。在此，我们成功构建了一种 AS1411 功能化的三角形 DNA 折纸（TOA），以共递送化疗药物（阿霉素，DOX）和光敏剂（吲哚菁绿，ICG），表示为 TOADI（DOX/ICG 负载的 TOA），用于靶向协同化疗 - 光疗。体外研究表明，AS1411 作为核仁素的适体通过高表达核仁素的肿瘤细胞有效地增强了纳米载体的内吞作用超过 3 倍。随后，TOADI 通过近红外（NIR）激光照射触发的 ICG 的光热效应可控地将 DOX 释放到细胞核中，并且溶酶体/内体的酸性环境促进了释放。下调的 Bcl-2 和上调的 Bax、Cyt c 和裂解的 caspase-3 表明，TOADI 的协同化疗 - 光疗作用诱导 4T1 细胞凋亡，导致约 80%的细胞死亡。在 4T1 荷瘤小鼠中，与没有 AS1411 的 TODI 相比，TOADI 在肿瘤区域的靶向积累增加了 2.5 倍，与游离 ICG 相比增加了 4 倍，证明了其在体内的优异肿瘤靶向能力。通过 DOX 和 ICG 的协同治疗，TOADI 显示出对肿瘤生长的约 90%抑制的显著治疗效果，而全身毒性可忽略不计。此外，TOADI 在荧光和光热成像方面表现出卓越的优势。总之，这种具有特异性肿瘤靶向和可控药物释放优势的多功能 DNA 折纸纳米系统为增强癌症治疗提供了新策略。
