Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR 97201, United States.
Department of Clinical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, United States.
Theranostics. 2018 Jan 1;8(3):767-784. doi: 10.7150/thno.21209. eCollection 2018.
Fluorescence image-guided surgery combined with intraoperative therapeutic modalities has great potential for intraoperative detection of oncologic targets and eradication of unresectable cancer residues. Therefore, we have developed an activatable theranostic nanoplatform that can be used concurrently for two purposes: (1) tumor delineation with real-time near infrared (NIR) fluorescence signal during surgery, and (2) intraoperative targeted treatment to further eliminate unresected disease sites by non-toxic phototherapy. The developed nanoplatform is based on a single agent, silicon naphthalocyanine (SiNc), encapsulated in biodegradable PEG-PCL (poly (ethylene glycol)--poly(ɛ-caprolactone)) nanoparticles. It is engineered to be non-fluorescent initially via dense SiNc packing within the nanoparticle's hydrophobic core, with NIR fluorescence activation after accumulation at the tumor site. The activatable nanoplatform was evaluated and in two different murine cancer models, including an ovarian intraperitoneal metastasis-mimicking model. Furthermore, fluorescence image-guided surgery mediated by this nanoplatform was performed on the employed animal models using a Fluobeam 800 imaging system. Finally, the phototherapeutic efficacy of the developed nanoplatform was demonstrated . Our data suggest that the intracellular environment of cancer cells is capable of compromising the integrity of self-assembled nanoparticles and thus causes disruption of the tight dye packing inside the hydrophobic cores and activation of the NIR fluorescence. Animal studies demonstrated accumulation of activatable nanoparticles at the tumor site following systemic administration, as well as release and fluorescence recovery of SiNc from the polymeric carrier. It was also validated that the developed nanoparticles are compatible with the intraoperative imaging system Fluobeam® 800, and nanoparticle-mediated image-guided surgery provides successful resection of cancer tumors. Finally, studies revealed that combinatorial phototherapy mediated by the nanoparticles could efficiently eradicate chemoresistant ovarian cancer tumors. The revealed properties of the activatable nanoplatform make it highly promising for further application in clinical image-guided surgery and combined phototherapy, facilitating a potential translation to clinical studies.
荧光引导手术联合术中治疗方法在术中检测肿瘤靶标和消除不可切除的癌症残留方面具有巨大潜力。因此，我们开发了一种可激活的治疗性纳米平台，可同时用于两个目的：(1)在手术过程中使用实时近红外 (NIR) 荧光信号进行肿瘤描绘，(2)通过非毒性光疗进行术中靶向治疗，以进一步消除未切除的疾病部位。所开发的纳米平台基于一种单一组分，硅萘酞菁 (SiNc)，封装在可生物降解的 PEG-PCL（聚乙二醇-聚（ε-己内酯））纳米粒子中。它最初通过纳米粒子疏水性核心内的 SiNc 密集堆积而表现为非荧光，在积累在肿瘤部位后实现 NIR 荧光激活。在两种不同的小鼠癌症模型中评估了这种可激活的纳米平台，包括卵巢腹腔转移模拟模型。此外，使用 Fluobeam 800 成像系统在使用的动物模型上进行了基于该纳米平台的荧光引导手术。最后，展示了所开发的纳米平台的光疗功效。我们的数据表明，癌细胞的细胞内环境能够破坏自组装纳米粒子的完整性，从而导致疏水性核心内的染料紧密堆积的破坏和 NIR 荧光的激活。动物研究表明，在系统给药后，可激活的纳米粒子在肿瘤部位积聚，并且 SiNc 从聚合物载体中释放并恢复荧光。还验证了所开发的纳米粒子与术中成像系统 Fluobeam® 800 兼容，并且基于纳米粒子的图像引导手术成功切除了癌症肿瘤。最后，研究表明，纳米粒子介导的组合光疗可以有效地根除耐药性卵巢癌肿瘤。所揭示的可激活纳米平台的特性使其非常有希望进一步应用于临床图像引导手术和联合光疗，从而有可能转化为临床研究。
