Ge Wei, Li Yuan, Li Zeng-Shan, Zhang Shan-Hong, Sun Yu-Jing, Hu Pei-Zhen, Wang Xiao-Ming, Huang Yang, Si Shao-Yan, Zhang Xiu-Min, Sui Yan-Fang
State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
Cancer Immunol Immunother. 2009 Feb;58(2):201-8. doi: 10.1007/s00262-008-0539-9. Epub 2008 Jun 4.
Previous studies have shown that there are profuse lymphatic tissues under the intestinal mucous membrane. Moreover, vaccine administered orally can elicit both mucous membrane and system immune response simultaneously, accordingly induce tumor-specific cytotoxic T lymphocyte. As a result, the oral route is constituted the preferred immune route for vaccine delivery theoretically. However, numerous vaccines especially protein/peptide vaccines remain poorly available when administered by this route. Nanoemulsion has been shown as a useful vehicle can be developed to enhance the antitumor immune response against antigens encapsulated in it and it is good for the different administration routes. Of particular interest is whether the protein vaccine following peroral route using nanoemulsion as delivery carrier can induce the same, so much as stronger antitumor immune response to following conventional ways such as subcutaneous (sc.) or not. Hence, in the present study, we encapsulated the MAGE1-HSP70 and SEA complex protein in nanoemulsion as nanovaccine NE (MHS) using magnetic ultrasound method. We then immuned C57BL/6 mice with NE (MHS), MHS alone or NE (-) via po. or sc. route and detected the cellular immunocompetence by using ELISpot assay and LDH release assay. The therapeutic and tumor challenge assay were examined then. The results showed that compared with vaccination with MHS or NE (-), the cellular immune responses against MAGE-1 could be elicited fiercely by vaccination with NE (MHS) nanoemulsion. Furthermore, encapsulating MHS in nanoemulsion could delay tumor growth and defer tumor occurrence of mice challenged with B16-MAGE-1 tumor cells. Especially, the peroral administration of NE (MHS) could induce approximately similar antitumor immune responses to the sc. administration, but the MHS unencapsulated with nanoemulsion via po. could induce significantly weaker antitumor immune responses than that via sc., suggesting nanoemulsion as a promising carrier can exert potent antitumor immunity against antigen encapsulated in it and make the tumor protein vaccine immunizing via po. route feasible and effective. It may have a broad application in tumor protein vaccine.
先前的研究表明，肠道黏膜下存在丰富的淋巴组织。此外，口服疫苗可同时引发黏膜免疫和全身免疫反应，从而诱导肿瘤特异性细胞毒性T淋巴细胞。因此，理论上口服途径是疫苗递送的首选免疫途径。然而，许多疫苗尤其是蛋白质/肽疫苗经此途径给药时效果不佳。纳米乳剂已被证明是一种有用的载体，可用于增强针对包裹其中的抗原的抗肿瘤免疫反应，且适用于不同的给药途径。特别值得关注的是，以纳米乳剂为递送载体经口服途径给予蛋白质疫苗，是否能诱导与皮下注射等传统方式相同甚至更强的抗肿瘤免疫反应。因此，在本研究中，我们采用磁超声法将MAGE1-HSP70和SEA复合蛋白包裹在纳米乳剂中制成纳米疫苗NE（MHS）。然后，我们通过口服或皮下途径用NE（MHS）、单独的MHS或NE（-）免疫C57BL/6小鼠，并使用ELISpot分析和LDH释放分析检测细胞免疫能力。随后进行了治疗和肿瘤攻击试验。结果表明，与接种MHS或NE（-）相比，接种NE（MHS）纳米乳剂能强烈引发针对MAGE-1的细胞免疫反应。此外，将MHS包裹在纳米乳剂中可延缓接种B16-MAGE-1肿瘤细胞小鼠的肿瘤生长并推迟肿瘤发生。特别是，口服NE（MHS）可诱导与皮下注射大致相似的抗肿瘤免疫反应，但未用纳米乳剂包裹的MHS经口服给药诱导的抗肿瘤免疫反应明显弱于经皮下给药，这表明纳米乳剂作为一种有前景的载体，可对包裹其中的抗原发挥强大的抗肿瘤免疫作用，使肿瘤蛋白疫苗经口服途径免疫可行且有效。它可能在肿瘤蛋白疫苗中有广泛应用。
