Institute of Cytology of the Russian Academy of Sciences (RAS), Tikhoretsky Ave. 4, 194064 St. Petersburg, Russia; I.P. Pavlov State Medical University of St. Petersburg, Lev Tolstoy str. 6/8, 197022 St. Petersburg, Russia; A.L. Polenov Russian Research Scientific Institute of Neurosurgery, Mayakovsky str. 12, 191014 St. Petersburg, Russia; Technische Universität München, Klinikum rechts der Isar, Ismaniger Str. 22, 81675 Munich, Germany.
Research Institute of Highly Pure Biopreparations, Pudozhskaya str. 12, 191014 St. Petersburg, Russia.
J Control Release. 2015 Dec 28;220(Pt A):329-340. doi: 10.1016/j.jconrel.2015.10.051. Epub 2015 Oct 29.
Nanovaccines based on superparamagnetic iron oxide nanoparticles (SPIONs) provide a novel approach to induce the humoral and cell-based immune system to fight cancer. Herein, we increased the immunostimulatory capacity of SPIONs by coating them with recombinant heat shock protein 70 (Hsp70) which is known to chaperone antigenic peptides. After binding, Hsp70-SPIONs deliver immunogenic peptides from tumor lysates to dendritiс cells (DCs) and thus stimulate a tumor-specific, CD8+ cytotoxic T cell response. We could show that binding activity of Hsp70-SPIONs to the substrate-binding domain (SBD) is highly dependent on the ATPase activity of its nucleotide-binding domain NBD), as shown by (31)P NMR spectroscopy. Immunization of C6 glioma-bearing rats with DCs pulsed with Hsp70-SPIONs and tumor lysates resulted in a delayed tumor progression (as measured by MRI) and an increased overall survival. In parallel an increased IFNγ secretion were detected in the serum of these animals and immunohistological analysis of subsequent cryosections of the glioma revealed an enhanced infiltration of memory CD45RO+ and cytotoxic CD8+ T cells. Taken together the study demonstrates that magnetic nanocarriers such as SPIONs coated with Hsp70 can be applied as a platform for boosting anti-cancer immune responses.
基于超顺磁性氧化铁纳米粒子（SPIONs）的纳米疫苗为诱导体液和基于细胞的免疫系统对抗癌症提供了一种新方法。在此，我们通过用重组热休克蛋白 70（Hsp70）涂覆 SPIONs 来提高其免疫刺激性，已知 Hsp70 可伴侣抗原肽。结合后，Hsp70-SPION 将来自肿瘤裂解物的免疫原性肽递送至树突状细胞（DC），从而刺激肿瘤特异性 CD8+细胞毒性 T 细胞反应。我们可以证明 Hsp70-SPION 与底物结合域（SBD）的结合活性高度依赖于其核苷酸结合域 NBD 的 ATP 酶活性，如 31P NMR 光谱所示。用 DC 脉冲与 Hsp70-SPION 和肿瘤裂解物免疫 C6 神经胶质瘤荷瘤大鼠导致肿瘤进展延迟（通过 MRI 测量）和总生存期延长。同时，这些动物的血清中检测到 IFNγ 分泌增加，并且对随后的神经胶质瘤冷冻切片进行免疫组织化学分析显示记忆性 CD45RO+和细胞毒性 CD8+T 细胞的浸润增强。总之，该研究表明，用 Hsp70 涂覆的磁性纳米载体（如 SPIONs）可作为增强抗癌免疫反应的平台。
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