School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul 02841, Republic of Korea; Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Republic of Korea; Department of Biomedical Science, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
J Control Release. 2017 Dec 10;267:181-190. doi: 10.1016/j.jconrel.2017.08.032. Epub 2017 Aug 26.
The cell-free approach to foreignizing tumor cells with non-self antigens has received increasing attention as a method to induce cytotoxic T lymphocyte (CTL)-mediated immunological rejection of tumors, because the clinical translation of the conventional CTL-based cancer immunotherapies has been limited by a complicated manufacturing process and autotransplantation. In this study, we prepared matrix metalloproteinase 9 (MMP9)-responsive polymeric conjugates consisting of PEGylated hyaluronic acid (HA) as the targeting moiety and ovalbumin (OVA) as the model foreign antigen. The MMP9-cleavable linker was introduced between PEG and the HA backbone to facilitate the detachment of the PEG corona from the conjugate at the tumor site. From the in vitro cellular uptake study, it was revealed that the conjugate was effectively taken up by the CD44-expressing TC-1 cancer cells in the presence of MMP9 via receptor-mediated endocytosis. When the conjugate was systemically administered into the tumor-bearing mice with endogenous OVA-specific CTLs, the tumor growth was markedly inhibited, which was attributed to the significant antigen presentation on the tumor cells. Overall, the MMP9-responsive conjugates bearing foreign antigens might have the potential as an alternative to CTL-based cancer immunotherapeutics.
无细胞方法将非自身抗原导入肿瘤细胞以诱导细胞毒性 T 淋巴细胞 (CTL) 介导的肿瘤免疫排斥反应，已受到越来越多的关注，因为传统的基于 CTL 的癌症免疫疗法的临床转化受到复杂的制造过程和自体移植的限制。在这项研究中，我们制备了基质金属蛋白酶 9 (MMP9) 响应性聚合物缀合物，其由作为靶向部分的聚乙二醇化透明质酸 (HA) 和卵清蛋白 (OVA) 作为模型外源性抗原组成。MMP9 可切割的连接子被引入到 PEG 和 HA 主链之间，以促进在肿瘤部位从缀合物上脱离 PEG 冠。从体外细胞摄取研究中发现，在 MMP9 存在下，该缀合物通过受体介导的内吞作用被表达 CD44 的 TC-1 癌细胞有效摄取。当将带有内源性 OVA 特异性 CTL 的荷瘤小鼠系统给予缀合物时，肿瘤生长明显受到抑制，这归因于肿瘤细胞上的显著抗原呈递。总的来说，带有外源性抗原的 MMP9 响应性缀合物可能具有替代基于 CTL 的癌症免疫疗法的潜力。
