Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China.
Interventional Therapy Department, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
Acta Biomater. 2022 Jan 15;138:453-462. doi: 10.1016/j.actbio.2021.10.048. Epub 2021 Oct 30.
Pancreatic cancer (PC) is the most lethal malignancy due to its high metastatic ability and poor drug permeability. Here, a synergized interventional photothermal-immunotherapy strategy was developed with imaging guidance and temperature monitoring by magnetic resonance imaging (MRI) technique, for the local treatment of metastatic PC. A tumor microenvironment (TME)-responsive nanoplatform was fabricated via coating of DSPE-PEG and indocyanine green (ICG) onto imiquimod (IMQ) loaded amorphous iron oxide nanoparticles (IONs). This unique nanoplatform, IMQ@IONs/ICG, served as a contrast agent for MRI, a drug delivery vehicle for IMQ and ICG, and a catalyst for TME modulation. The biodegradable IMQ@IONs/ICG was also non-toxic, and improved the penetration of the loaded drugs in PC to maximize thermal ablation of the tumor and minimize damage to the surrounding healthy tissue. For the treatment of aggressive, metastatic Panc02-H7 pancreatic tumors in mice, ION-assisted MRI was employed to guide the administration of interventional photothermal therapy (IPTT) and monitor the temperature distribution in target tumor and surrounding tissue during treatment. The local IPTT treatment induced in situ immunogenic cell death (ICD), and, in combination with released IMQ, triggered a strong antitumor immunity, leading to decreased metastases and increased CD8 in spleen and tumors. With precise local treatment and monitoring, treated primary tumors were completely eradicated, mesentery metastases were dramatically reduced, and the survival time was significantly prolonged, without damage to normal tissue and systemic autoimmunity. Overall, this synergistic strategy represents a promising approach to treat PC with significant potential for clinical applications. STATEMENT OF SIGNIFICANCE: Pancreatic cancer (PC) is one of the most lethal malignancies because it is non-permeable to drugs and highly metastatic. In this study, we designed a tumor microenvironment-responsive amorphous iron oxide nanoplatform (ION) to co-deliver photothermal agent (ICG) and toll-like-receptor-7 agonist (IMQ). This biodegradable nanoplatform IMQ@IONs/ICG improved the penetration of the loaded drugs in pancreatic tumor. With MR imaging guidance and temperature monitoring, the precise interventional photothermal therapy on mouse Panc02-H7 orthotopic tumors releases tumor antigens to initiate tumor-special immune responses, amplified by the released IMQ. Our results demonstrate that IMQ@IONs/ICG overcomes the obstacle of drug delivery to pancreatic tumors, and when combined with photothermal therapy, induces a systemic antitumor immunity to control metastatic tumors.
胰腺癌（PC）是最致命的恶性肿瘤，因为它对药物的通透性差，转移能力高。在这里，我们开发了一种协同的介入性光热免疫治疗策略，该策略通过磁共振成像（MRI）技术进行成像指导和温度监测，用于局部治疗转移性 PC。通过将二硬脂酰基磷脂酰乙醇胺（DSPE-PEG）和吲哚菁绿（ICG）涂覆到负载咪喹莫特（IMQ）的无定形氧化铁纳米颗粒（IONs）上，制备了一种肿瘤微环境（TME）响应性纳米平台。这种独特的纳米平台，IMQ@IONs/ICG，可用作 MRI 的造影剂、IMQ 和 ICG 的药物递送载体以及 TME 调节剂的催化剂。可生物降解的 IMQ@IONs/ICG 也没有毒性，并且提高了载药在 PC 中的渗透，以最大限度地进行肿瘤热消融并最大程度地减少对周围健康组织的损害。为了治疗小鼠侵袭性转移性 Panc02-H7 胰腺肿瘤，使用 ION 辅助 MRI 指导介入性光热治疗（IPTT）的给药，并在治疗过程中监测靶肿瘤和周围组织中的温度分布。局部 IPTT 治疗诱导原位免疫原性细胞死亡（ICD），并与释放的 IMQ 结合，引发强烈的抗肿瘤免疫反应，从而减少转移并增加脾脏和肿瘤中的 CD8。通过精确的局部治疗和监测，完全消除了原发性肿瘤，大大减少了肠系膜转移，并显著延长了生存期，而不会损害正常组织和全身自身免疫。总体而言，这种协同策略为治疗 PC 提供了一种很有前途的方法，具有很大的临床应用潜力。
