National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518071, China.
State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China.
J Control Release. 2022 Oct;350:158-174. doi: 10.1016/j.jconrel.2022.08.019. Epub 2022 Aug 18.
DNA nanostructures, with good biosafety, highly programmable assembly, flexible modification, and precise control, are tailored as drug carriers to deliver therapeutic agents for cancer therapy. However, they face considerable challenges regarding their delivery into the brain, mainly due to the blood-brain barrier (BBB). By controlling the acoustic parameters, focused ultrasound combined with microbubbles (FUS/MB) can temporarily, noninvasively, and reproducibly open the BBB in a localized region. We investigated the delivery outcome of pH-responsive DNA octahedra loading Epirubicin (Epr@DNA-Octa) via FUS/MB and its therapeutic efficiency in a mouse model bearing intracranial glioma xenograft. Using FUS/MB to locally disrupt the BBB or the blood-tumor barrier (BTB) and systemic administration of Epr@DNA-Octa (Epr@DNA-Octa + FUS/MB) (2 mg/kg of loaded Epr), we achieved an Epr concentration of 292.3 ± 10.1 ng/g tissue in glioma, a 4.4-fold increase compared to unsonicated animals (p < 0.001). The in vitro findings indicated that Epr released from DNA strands accumulated in lysosomes and induced enhanced cytotoxicity compared to free Epr. Further two-photon intravital imaging of spatiotemporal patterns of the DNA-Octa leakage revealed that the FUS/MB treatment enhanced DNA-Octa delivery across several physiological barriers at microscopic level, including the first extravasation across the BBB/BTB and then deep penetration into the glioma center and engulfment of DNA-Octa into the tumor cell body. Longitudinal in vivo bioluminescence imaging and histological analysis indicated that the intracranial glioma progression in nude mice treated with Epr@DNA-Octa + FUS/MB was effectively retarded compared to other groups. The beneficial effect on survival was most significant in the Epr@DNA-Octa + FUS/MB group, with a 50% increase in median survival and a 73% increase in the maximum survival compared to control animals. Our work demonstrates the potential viability of FUS/MB as an alternative strategy for glioma delivery of anticancer drugs using DNA nanostructures as the drug delivery platform for brain cancer therapy.
DNA 纳米结构具有良好的生物安全性、高度可编程的组装、灵活的修饰和精确的控制，被设计为药物载体，用于递送治疗癌症的治疗剂。然而，它们在递送到大脑方面面临着相当大的挑战，主要是由于血脑屏障（BBB）的存在。通过控制声参数，聚焦超声联合微泡（FUS/MB）可以在局部区域临时、非侵入性和可重复地打开 BBB。我们研究了通过 FUS/MB 递送 pH 响应性 DNA 八面体负载表阿霉素（Epr@DNA-Octa）及其在携带颅内神经胶质瘤异种移植物的小鼠模型中的治疗效果。使用 FUS/MB 局部破坏 BBB 或血肿瘤屏障（BTB），并全身给予 Epr@DNA-Octa（Epr@DNA-Octa + FUS/MB）（负载 Epr 2mg/kg），我们在神经胶质瘤中获得了 292.3±10.1ng/g 组织的 Epr 浓度，与未超声处理的动物相比增加了 4.4 倍（p<0.001）。体外研究结果表明，与游离 Epr 相比，从 DNA 链中释放的 Epr 积累在溶酶体中，并诱导增强的细胞毒性。进一步的双光子活体成像显示，FUS/MB 处理增强了 DNA-Octa 在微观水平上跨越几个生理屏障的传递，包括首次穿过 BBB/BTB 的外渗，然后深入穿透神经胶质瘤中心并将 DNA-Octa 吞噬到肿瘤细胞体中。纵向体内生物发光成像和组织学分析表明，与其他组相比，用 Epr@DNA-Octa + FUS/MB 治疗的裸鼠颅内神经胶质瘤进展得到了有效抑制。在 Epr@DNA-Octa + FUS/MB 组中，中位生存期延长 50%，最大生存期延长 73%，与对照组相比，对生存的有益影响最为显著。我们的工作证明了 FUS/MB 作为一种替代策略的潜力，用于使用 DNA 纳米结构作为药物递送平台递送治疗脑癌的抗癌药物。
