Miyazaki Maiko, Yuba Eiji, Hayashi Hiroshi, Harada Atsushi, Kono Kenji
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
Sciencelin, 1-1-35, Nishiawaji, Higashiyodogawa-ku, Osaka, Osaka 533-0031, Japan.
ACS Biomater Sci Eng. 2019 Nov 11;5(11):5790-5797. doi: 10.1021/acsbiomaterials.9b01278. Epub 2019 Oct 25.
Cancer immunotherapy has gained much attention because of the recent success of immune checkpoint inhibitors. Nevertheless, clinical therapeutic effects of immune checkpoint inhibitors remain limited, probably because most patients have other immune checkpoint molecules or because they lack cancer-specific cytotoxic T lymphocytes. Induction of cancer-specific cytotoxic T lymphocytes requires efficient antigen delivery systems that can convey cancer antigens specifically to antigen presenting cells, promote the endosomal escape of antigen into cytosol, and activate immune cells. Earlier, we reported cytoplasmic delivery systems of antigen using pH-sensitive polymer-modified liposomes. Adjuvant molecules were further incorporated into these liposomes to provide activation properties of cellular immune responses. This study further introduced cell specificity to these liposomal systems using hyaluronic acid-based pH-sensitive polymers, which are recognized by CD44 expressing on antigen presenting cells. pH-Sensitive hyaluronic acid derivative-modified liposomes showed much higher cellular association to antigen presenting cells than to fibroblasts with less CD44 expression. These liposomes achieved the delivery of model antigenic proteins into cytosol of dendritic cells and promoted Th1 cytokine production from the cells. Subcutaneous administration of these liposomes to mice induced antigen-specific cellular immune response in the spleen, leading to tumor regression in tumor-bearing mice. The results show that pH-sensitive hyaluronic acid derivative-modified liposomes are promising as multifunctional antigen carriers having cell-specificity, cytoplasmic antigen delivery performance, and adjuvant property to induce antigen-specific cellular immunity.
由于免疫检查点抑制剂最近取得的成功，癌症免疫疗法备受关注。然而，免疫检查点抑制剂的临床治疗效果仍然有限，这可能是因为大多数患者存在其他免疫检查点分子，或者是因为他们缺乏癌症特异性细胞毒性T淋巴细胞。诱导癌症特异性细胞毒性T淋巴细胞需要高效的抗原递送系统，该系统能够将癌症抗原特异性地传递给抗原呈递细胞，促进抗原从内体逃逸到细胞质中，并激活免疫细胞。早些时候，我们报道了使用pH敏感聚合物修饰的脂质体进行抗原的细胞质递送系统。将佐剂分子进一步掺入这些脂质体中，以提供细胞免疫反应的激活特性。本研究使用基于透明质酸的pH敏感聚合物进一步赋予这些脂质体系统细胞特异性，这种聚合物可被抗原呈递细胞上表达的CD44识别。与CD44表达较少的成纤维细胞相比，pH敏感的透明质酸衍生物修饰的脂质体与抗原呈递细胞的细胞结合能力要高得多。这些脂质体能够将模型抗原蛋白递送至树突状细胞的细胞质中，并促进细胞产生Th1细胞因子。将这些脂质体皮下注射到小鼠体内可诱导脾脏中的抗原特异性细胞免疫反应，从而导致荷瘤小鼠的肿瘤消退。结果表明，pH敏感的透明质酸衍生物修饰的脂质体有望成为具有细胞特异性、细胞质抗原递送性能和佐剂特性以诱导抗原特异性细胞免疫的多功能抗原载体。
