College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.
Biomater Sci. 2020 Feb 21;8(4):1106-1116. doi: 10.1039/c9bm01704f. Epub 2020 Jan 29.
In this study, we sought to design a bionanomaterial that could exert anticancer effects against primary tumors and protect against rechallenged tumors via photodynamic immunotherapy. As a biomaterial, we used an amphiphilic phenylalanine derivative of poly-gamma glutamic acid, which forms nanoparticles by self-assembly. For anticancer effects, we co-entrapped hydrophobic chlorin e6 and monophosphoryl lipid A in the core of the plain amphiphilic phenylalanine nanoparticles (AN), to generate M/C/AN. For comparison, we used plain AN and chlorin e6-loaded AN (C/AN). In vitro studies showed that B16F10 cancer cells treated with C/AN or M/C/AN generated reactive oxygen species and exhibited an enhanced surface display of calreticulin upon exposure to 660 nm light irradiation. C/AN and M/C/AN exerted similar photodynamic anticancer effects; however, M/C/AN, but not C/AN, induced in vitro dendritic cell maturation. Our biodistribution study revealed that C/AN and M/C/AN showed higher accumulation at the tumor tissues compared to that seen in the free chlorin e6-treated group. In B16F10 tumor-bearing mice, the intravenous injection of C/AN or M/C/AN showed similar photodynamic anticancer effects against primary tumors. However, the growth of rechallenged tumors was more significantly inhibited in the M/C/AN group compared to the C/AN group. At day 40 after inoculation of the primary tumor, M/C/AN-treated mice showed 100% survival, whereas the other groups showed 0% survival. In the tumor microenvironment, higher infiltration of CD8+ T cells was observed in the M/C/AN group compared to the other groups. Our results suggest that AN co-loaded with a photosensitizer and an immune stimulant may hold great potential for use in photodynamic immunotherapy to inhibit both primary and metastatic tumors.
在这项研究中，我们试图设计一种仿生材料，通过光动力免疫疗法对原发性肿瘤发挥抗癌作用，并防止再挑战肿瘤。作为一种生物材料，我们使用聚-γ-谷氨酸的亲脂性苯丙氨酸衍生物，它通过自组装形成纳米颗粒。为了发挥抗癌作用，我们将疏水性氯己定和单磷酰脂质 A 共包封在普通亲脂性苯丙氨酸纳米颗粒（AN）的核心中，生成 M/C/AN。为了比较，我们使用了普通的 AN 和负载氯己定的 AN（C/AN）。体外研究表明，用 C/AN 或 M/C/AN 处理的 B16F10 癌细胞在暴露于 660nm 光照射时会产生活性氧，并显示出钙网蛋白的增强表面表达。C/AN 和 M/C/AN 发挥了相似的光动力抗癌作用；然而，只有 M/C/AN 而非 C/AN 诱导体外树突状细胞成熟。我们的生物分布研究表明，与游离氯己定处理组相比，C/AN 和 M/C/AN 在肿瘤组织中的积累更高。在 B16F10 荷瘤小鼠中，静脉注射 C/AN 或 M/C/AN 对原发性肿瘤均表现出相似的光动力抗癌作用。然而，与 C/AN 组相比，M/C/AN 组再挑战肿瘤的生长受到更显著的抑制。在接种原发性肿瘤后第 40 天，M/C/AN 治疗组的小鼠 100%存活，而其他组均为 0%存活。在肿瘤微环境中，与其他组相比，M/C/AN 组观察到更多的 CD8+T 细胞浸润。我们的结果表明，共载光敏剂和免疫刺激剂的 AN 可能具有很大的潜力用于光动力免疫疗法，以抑制原发性和转移性肿瘤。
