Formulation and evaluation of oral microparticulate ovarian cancer vaccines.
Formulation and evaluation of oral microparticulate ovarian cancer vaccines.
复制标题
口服微粒卵巢癌疫苗的配制和评价。
DOI：
10.1016/j.vaccine.2012.05.073
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发表时间：
2012
期刊：
影响因子：
5.5
通讯作者：
D'Souza,MartinJ
中科院分区：
文献类型：
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作者：
Tawde,SupritaA;Chablani,Lipika;Akalkotkar,Archana;D'Souza,Cherilyn;Chiriva-Internati,Maurizio;Selvaraj,Periasamy;D'Souza,MartinJ
卵巢癌是美国女性癌症相关死亡的第五大原因。定制的免疫治疗策略可以作为控制卵巢癌复发或进展和避免化疗严重不良反应的替代方法。本研究利用小鼠卵巢癌细胞系ID8的全细胞裂解液，利用喷雾干燥机制备了微颗粒疫苗。这些颗粒设计用于口服给药，使用肠内聚合物，如甲基丙烯酸共聚物，Eudragit®FS30D和羟丙基甲基纤维素醋酸琥珀酸酯。这些颗粒通过m细胞靶向配体，在小肠Peyer's斑块中通过微折叠细胞（m细胞）被摄取。在疫苗制剂中加入白细胞介素（IL-2和IL-12）以进一步增强免疫应答。所得粒子尺寸为1.58±0.62μm，电荷为12.48±2.32mV。通过口服方式给药C57BL/6雌性小鼠，评价疫苗的效果。在疫苗接种结束时，用活肿瘤细胞刺激小鼠。与未接种疫苗的小鼠相比，接种疫苗的小鼠在肿瘤攻击后3周内肿瘤体积显著（约6倍）减慢（p<0.001）。免疫组血清IgG抗体水平明显高于未接种组（p<0.05）。IgG1滴度（Th2反应指标）和IgG2a滴度（Th1反应指标）分析显示，单独疫苗组出现Th1和Th2混合免疫反应，而白细胞介素疫苗组出现Th2反应。此外，免疫小鼠不同淋巴器官的CD8+ t细胞、CD4+ t细胞和b细胞数量均升高。因此，通过喷雾干燥配制的全细胞裂解液疫苗微粒在口服时可引发体液和细胞免疫反应。该疫苗有可能成为残留肿瘤或高复发概率患者的有效治疗方法。
Ovarian cancer is the fifth most leading cause of cancer related deaths in women in the US. Customized immunotherapeutic strategies may serve as an alternative method to control the recurrence or progression of ovarian cancer and to avoid severe adverse effects of chemotherapy. In this study, a microparticulate vaccine using whole cell lysate of a murine ovarian cancer cell line, ID8 was prepared with the use of a spray dryer. These particles were designed for oral delivery using enteric polymers such as methacrylic copolymer, Eudragit®FS30D and hydroxyl propyl methyl cellulose acetate succinate. These particles were targeted for uptake via microfold cell (M-cell) in Peyer's patches of small intestine using M-cell targeting ligand, Aleuria aurantia lectin. The interleukins (ILs) such as IL-2 and IL-12 were added to the vaccine formulation to further enhance the immune response. The particles obtained were of 1.58±0.62μm size with a charge of 12.48±2.32mV. The vaccine efficacy was evaluated by administering the particles via oral route to C57BL/6 female mice. At the end of vaccination, mice were challenged with live tumor cells. Vaccinated mice showed significant (around six-fold) retardation of tumor volume in comparison to non-vaccinated animals for 3 weeks after the tumor challenge (p<0.001). The serum IgG antibody levels were found to be elevated in case of vaccinated animals in comparison to non-vaccinated group (p<0.05). Analysis of IgG1 titers (indicative of Th2 response) and IgG2a titers (indicative of Th1 response) showed a mixed Th1 and Th2 immune response in case vaccine alone and Th2 response in case of vaccine with interleukins group. Moreover, CD8+ T-cell, CD4+ T-cell and B-cell populations in different lymphatic organs were elevated in case of vaccinated mice. Thus, whole cell lysate vaccine microparticles formulated by spray drying could trigger humoral as well as cellular immune response when administered orally. Such vaccine could potentially be an effective treatment for patients with residual tumor or high tumor-relapse probability.