Minhang Hospital & School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers , Fudan University , Shanghai 201199 , China.
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy , The University of Rhode Island , Kingston , Rhode Island 02881 , United States.
ACS Nano. 2019 Sep 24;13(9):10242-10260. doi: 10.1021/acsnano.9b03466. Epub 2019 Aug 19.
Cancer photodynamic therapy (PDT) represents an attractive local treatment in combination with immunotherapy. Successful cancer PDT relies on image guidance to ensure the treatment accuracy. However, existing nanotechnology for co-delivery of photosensitizers and image contrast agents slows the clearance of PDT agents from the body and causes a disparity between the release profiles of the imaging and PDT agents. We have found that the photosensitizer Chlorin e6 (Ce6) is inherently bound to immunoglobulin G (IgG) in a nanomolarity range of affinity. Ce6 and IgG self-assemble to form the nanocomplexes termed Chloringlobulin ( e6 + immuno G). Chloringlobulin enhances the Ce6 concentration in the tumor without changing its elimination half-life in blood. Utilizing the immune checkpoint inhibitor antiprogrammed death ligand 1 (PD-L1) (αPD-L1) to prepare αPD-L1 Chloringlobulin, we have demonstrated a combination of Ce6-based red-light fluorescence image-guided surgery, stereotactic PDT, and PD-L1 blockade therapy of mice bearing orthotopic glioma. In mice bearing an orthotopic colon cancer model, we have prepared another Chloringlobulin that allows intraoperative fluorescence image-guided PDT in combination with PD-L1 and cytotoxic T lymphocyte antigen 4 (CTLA-4) dual checkpoint blockade therapy. The Chloringlobulin technology shows great potential for clinical translation of combinatorial intraoperative fluorescence image-guided PDT and checkpoint blockade therapy.
癌症光动力疗法（PDT）结合免疫疗法代表了一种有吸引力的局部治疗方法。成功的癌症 PDT 依赖于图像引导以确保治疗的准确性。然而，现有的用于共递送光敏剂和成像对比剂的纳米技术会减缓 PDT 剂从体内的清除速度，并导致成像和 PDT 剂的释放曲线之间出现差异。我们发现，光敏剂 Chlorin e6（Ce6）在纳米摩尔亲和力范围内与免疫球蛋白 G（IgG）固有结合。Ce6 和 IgG 自组装形成称为 Chloringlobulin（e6+immuno G）的纳米复合物。Chloringlobulin 增强了肿瘤中的 Ce6 浓度，而不会改变其在血液中的消除半衰期。利用免疫检查点抑制剂抗程序性死亡配体 1（PD-L1）（αPD-L1）制备αPD-L1 Chloringlobulin，我们已经证明了基于 Ce6 的红光荧光图像引导手术、立体定向 PDT 以及 PD-L1 阻断疗法联合治疗荷瘤原位胶质瘤的小鼠。在荷瘤原位结肠癌模型的小鼠中，我们制备了另一种 Chloringlobulin，允许术中荧光图像引导 PDT 与 PD-L1 和细胞毒性 T 淋巴细胞抗原 4（CTLA-4）双重检查点阻断疗法联合使用。Chloringlobulin 技术在将组合式术中荧光图像引导 PDT 和检查点阻断疗法进行临床转化方面具有巨大的潜力。
