Carboxylated polyamidoamine dendron-bearing lipid-based assemblies for precise control of intracellular fate of cargo and induction of antigen-specific immune responses.
Carboxylated polyamidoamine dendron-bearing lipid-based assemblies for precise control of intracellular fate of cargo and induction of antigen-specific immune responses.
复制标题
DOI：
10.1039/d0bm01813a
复制
发表时间：
2021-03
影响因子：
6.6
通讯作者：
E. Yuba;Y. Sugahara;Yuta Yoshizaki;Takeyuki Shimizu;M. Kasai;K. Udaka;K. Kono
中科院分区：
文献类型：
--
作者：
E. Yuba;Y. Sugahara;Yuta Yoshizaki;Takeyuki Shimizu;M. Kasai;K. Udaka;K. Kono
为了建立先进的药物，如癌症免疫治疗，必须开发精确递送生物活性分子的高性能载体，以靶向细胞的细胞器并在那里释放其内容物。从抗原递送的观点来看，内体是重要的靶细胞器，因为它们含有与免疫应答相关的受体和各种类型的蛋白质。为了获得用于精确内体递送的载体，本研究合成了一种新型的具有pH敏感末端基团的聚酰胺胺树枝状脂质。使用这些pH敏感的树枝状基脂质和蛋黄磷脂酰胆碱制备脂质体。研究了它们的pH响应特性和作为内体递送载体的性能。pH敏感的树枝状脂质基脂质体保留水溶性分子在中性pH值，但在弱酸性条件下释放它们。特别是，含有CHexDL-G1 U的脂质体表现出响应于非常弱酸性pH的高度敏感的特性。这些基于树枝状脂质的脂质体释放内容物，特别是在内体中。内容物释放的时间可以通过选择用于脂质体制备的pH敏感的树枝状脂质来控制。通过给予含有模型抗原蛋白的CHexDL-G1 U修饰的脂质体，在荷瘤小鼠中诱导了显著的肿瘤消退。此外，CHexDL-G1 U修饰的脂质体诱导WT 1肿瘤抗原肽特异性辅助T细胞增殖。结果表明，基于树突状脂质的脂质体可用作癌症免疫治疗的有效疫苗。
For the establishment of advanced medicines such as cancer immunotherapy, high performance carriers that precisely deliver biologically active molecules must be developed to target organelles of the cells and to release their contents there. From the viewpoint of antigen delivery, endosomes are important target organelles because they contain immune-response-related receptors and proteins of various types. To obtain carriers for precision endosome delivery, a novel type of polyamidoamine dendron-based lipid having pH-sensitive terminal groups was synthesized for this study. Liposomes were prepared using these pH-sensitive dendron-based lipids and egg yolk phosphatidylcholine. Their pH-responsive properties and performance as an endosome delivery carrier were investigated. pH-Sensitive dendron lipid-based liposomes retained water-soluble molecules at neutral pH but released them under weakly acidic conditions. Particularly, liposomes containing CHexDL-G1U exhibited highly sensitive properties responding to very weakly acidic pH. These dendron lipid-based liposomes released the contents specifically in the endosome. The timing of content release can be controlled by selecting pH-sensitive dendron lipids for liposome preparation. Significant tumor regression was induced in tumor-bearing mice by the administration of CHexDL-G1U-modified liposomes containing the model antigenic protein. Furthermore, CHexDL-G1U-modified liposomes induced WT1 tumor antigenic peptide-specific helper T cell proliferation. The results demonstrate that dendron lipid-based liposomes are useful as a potent vaccine for cancer immunotherapy.