Intracellular delivery of a protein antigen with an endosomal-releasing polymer enhances CD8 T-cell production and prophylactic vaccine efficacy.
Intracellular delivery of a protein antigen with an endosomal-releasing polymer enhances CD8 T-cell production and prophylactic vaccine efficacy.
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DOI：
10.1021/bc100204m
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发表时间：
2010-12-15
影响因子：
4.7
通讯作者：
Stayton, Patrick S.
中科院分区：
文献类型：
--
作者：
Foster, Suzanne;Duvall, Craig L.;Crownover, Emily F.;Hoffman, Allan S.;Stayton, Patrick S.
基于蛋白质的疫苗具有作为感染性疾病和抗癌治疗剂的显著潜力，但由于其产生协调的细胞免疫应答的能力，其临床影响在一些应用中受到限制。在此，评估了掺入聚（丙基丙烯酸）（PPAA）的pH响应性载体以测试蛋白质抗原的改善的胞质递送是否可以增强CD 8+细胞毒性淋巴细胞产生和预防性肿瘤疫苗应答。PPAA通过可还原的二硫键直接与模型卵清蛋白抗原偶联，并在与阳离子聚（甲基丙烯酸二甲氨基乙酯）（PDMAEMA）缩合后在颗粒制剂中进行测试。细胞内运输的研究表明，这两个PPAA含有制剂的控制共轭物相比，稳定的内化和逃避胞吐途径，导致增加的细胞内积累和潜在的访问胞质MHC-1抗原呈递途径。在EG.7-OVA小鼠肿瘤保护模型中，两种含PPAA的载体均强烈抑制肿瘤生长，并导致相对于对照的无肿瘤存活期延长约3.5倍。从机制上讲，这种反应归因于卵清蛋白特异性CD 8 + T淋巴细胞产生增加8倍，抗卵清蛋白IgG产生增加11倍。值得注意的是，这是使用可溶性蛋白质-聚合物缀合物的体内免疫功效的第一个证明的实例之一。这些结果表明，增强蛋白质抗原胞浆递送的载体可以导致更稳健的CD 8 + T细胞反应，并证明了基于pH响应性PPAA的载体在治疗性疫苗应用中的潜力。
Protein-based vaccines have significant potential as infectious disease and anticancer therapeutics, but clinical impact has been limited in some applications by their ability to generate a coordinated cellular immune response. Here, a pH-responsive carrier incorporating poly(propylacrylic acid) (PPAA was evaluated to test whether improved cytosolic delivery of a protein antigen could enhance CD8+ cytotoxic lymphocyte generation and prophylactic tumor vaccine responses. PPAA was directly conjugated to the model ovalbumin antigen via reducible disulfide linkages and was also tested in a particulate formulation after condensation with the cationic poly(dimethylaminoethyl methacrylate) (PDMAEMA). Intracellular trafficking studies revealed that both PPAA-containing formulations were stably internalized compared to control conjugates and evaded exocytotic pathways, leading to increased intracellular accumulation and potential access to the cytosolic MHC-1 antigen presentation pathway. In an EG.7-OVA mouse tumor protection model, both PPAA-containing carriers robustly inhibited tumor growth and led to an approximately 3.5 fold increase in the longevity of tumor free survival relative to controls. Mechanistically this response was attributed to the 8-fold increase in production of ovalbumin-specific CD8+ T-lymphocytes and an 11-fold increase in production of anti-ovalbumin IgG. Significantly, this is one of the first demonstrated examples of in vivo immunotherapeutic efficacy using soluble protein-polymer conjugates. These results suggest that carriers enhancing cytosolic delivery of protein antigens could lead to more robust CD8+ T-cell response and demonstrate the potential of pH-responsive PPAA-based carriers for therapeutic vaccine applications.
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影响因子：
64.8
作者：
Houde, M;Bertholet, S;Desjardins, M
通讯作者：
Desjardins, M
DOI：
10.1016/j.jconrel.2008.10.004
发表时间：
2009-02-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Convertine AJ;Benoit DS;Duvall CL;Hoffman AS;Stayton PS
通讯作者：
Stayton PS
影响因子：
56.9
作者：
KOVACSOVICSBANKOWSKI, M;ROCK, KL
通讯作者：
ROCK, KL
影响因子：
5.8
作者：
Johnston, D;Reynolds, SR;Bystryn, JC
通讯作者：
Bystryn, JC
影响因子：
14
作者：
Bennewitz, NL;Babensee, JE
通讯作者：
Babensee, JE