Biodegradable Hyaluronic Acid Modified with Tetraglycine-L-octaarginine as a Safe Adjuvant for Mucosal Vaccination
Biodegradable Hyaluronic Acid Modified with Tetraglycine-L-octaarginine as a Safe Adjuvant for Mucosal Vaccination
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DOI：
10.1021/acs.molpharmaceut.8b01110
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发表时间：
2019-03-01
影响因子：
4.9
通讯作者：
Sakuma，Shinji
中科院分区：
文献类型：
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作者：
Ukawa，Masami;Tanishita，Sohei;Sakuma，Shinji
我们一直在探索用细胞穿透肽修饰的聚合物作为黏膜疫苗佐剂的潜在用途，并已经开发出不可降解的聚(N-乙烯基乙酰胺-共丙烯酸)(PNVA-co-AA)，将d-八精氨酸(一种典型的细胞穿透肽)接枝到PNVA上。我们以前的小鼠感染实验表明，用流感病毒抗原和d-八精氨酸连接的PNVA-co-AA混合疫苗进行4次鼻腔接种，每隔7天分别在体循环中诱导免疫球蛋白G和分泌免疫球蛋白A，免疫小鼠对同源病毒感染有很好的保护作用。在本研究中，我们从临床应用的角度出发，设计了新型的可生物降解的含细胞穿透肽的聚合物。以单糖比例为30%的四甘氨酸-L-辛精氨酸修饰葡萄糖醛酸制得透明质酸。在上述接种方案下，透明质酸衍生物表现出与PNVA-co-AA相同的佐剂活性，无论是辛精氨酸还是四甘氨酸-d-辛精氨酸。我们进一步发现，间隔7天接种4次和间隔28天接种2次之间的体液免疫水平没有差异。用较少的接种次数用后一种方案诱导的鼻腔内免疫球蛋白A，在临床上是可行的，表现出超越病毒亚型的交叉反应。体外毒性研究表明，透明质酸衍生物的毒性远低于相应的PNVA-co-AA衍生物，且聚合物及其代谢物均不表现出遗传毒性。我们的结果表明，四甘氨酸-L-八精氨酸连接的透明质酸将是一种临床上有价值的安全的粘膜疫苗佐剂。
We have been investigating the potential use of polymers modified with cell-penetrating peptides as an adjuvant for mucosal vaccination and have already developed nondegradable poly(N-vinylacetamide-co-acrylic acid) (PNVA-co-AA) with whichd-octaarginine, a typical cell-penetrating peptide, was grafted. Our previous murine infection experiments demonstrated that immunoglobulin G (IgG) and immunoglobulin A (IgA) were induced in systemic circulation and secreted on nasal mucosa, respectively, through 4-time nasal inoculations with a mixture of influenza viral antigens andd-octaarginine-linked PNVA-co-AA at 7-day intervals, and that immunized mice were perfectly protected from homologous virus infection. In the present study, we designed novel biodegradable polymers bearing cell-penetrating peptides from a perspective of clinical application. Hyaluronic acid whose glucuronic acid was modified with tetraglycine-l-octaarginine at a monosaccharide unit ratio of 30% was successfully developed. The hyaluronic acid derivative exhibited adjuvant activities identical to PNVA-co-AA bearing eitherd-octaarginine or tetraglycine-d-octaarginine under the above-mentioned inoculation schedule. We further found that there was no difference in humoral immunity between the 4-time inoculations at 7-day intervals and the 2-time inoculations at 28-day intervals. Intranasal IgA induced through the latter schedule with a smaller number of inoculations, which is clinically practical, exhibited cross-reactivity beyond the subtype of viral strains. In vitro toxicity studies demonstrated that the hyaluronic acid derivative was much less toxic than the corresponding PNVA-co-AA derivatives, and that both the polymers and their metabolites did not exhibit genotoxicity. Our results suggested that tetraglycine-l-octaarginine-linked hyaluronic acid would be a clinically valuable and safe adjuvant for mucosal vaccination.