In vivo studies on the effect of co-encapsulation of CpG DNA and antigen in acid-degradable microparticle vaccines.
In vivo studies on the effect of co-encapsulation of CpG DNA and antigen in acid-degradable microparticle vaccines.
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DOI：
10.1021/mp900038e
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发表时间：
2009-07
影响因子：
4.9
通讯作者：
Engleman EG
中科院分区：
文献类型：
--
作者：
Beaudette TT;Bachelder EM;Cohen JA;Obermeyer AC;Broaders KE;Fréchet JM;Kang ES;Mende I;Tseng WW;Davidson MG;Engleman EG
基于蛋白质的疫苗已被探索作为传统的基于弱化或杀死的整个生物体的疫苗接种策略的更安全的替代方案，并且已研究了它们激活免疫系统对抗某些癌症的能力。为了最佳地刺激T淋巴细胞，基于蛋白质的疫苗应该在适当的免疫刺激信号的背景下将蛋白质抗原递送至抗原呈递细胞，从而模拟实际的病原体。在这份报告中，我们描述了免疫刺激性酸可降解微粒的合成，表征和生物学评价，这是合适的递送载体，用于蛋白质为基础的疫苗和癌症免疫治疗。使用3′结合策略，我们优化了免疫刺激性CpG DNA与我们的疫苗载体的连接，并证明在与内体区室中发现的酸性条件相似的酸性条件下，这些新颗粒能够同时释放模型蛋白抗原和CpG DNA佐剂。我们在体内细胞毒性测定中发现，与与未结合形式的佐剂共施用的颗粒相比，卵清蛋白（模型抗原）和免疫刺激剂在同一颗粒中的共包封导致上级细胞毒性T淋巴细胞活性。此外，我们研究了这些酸可降解颗粒在MO5鼠黑色素瘤模型中诱导保护性免疫的能力，并发现它们在肿瘤逃逸之前是有效的，这似乎是由于体内选择压力导致癌细胞抗原表达丧失所致。
Protein-based vaccines have been explored as a safer alternative to traditional weakened or killed whole organism based vaccination strategies and have been investigated for their ability to activate the immune system against certain cancers. For optimal stimulation of T lymphocytes, protein-based vaccines should deliver protein antigens to antigen presenting cells in the context of appropriate immunostimulatory signals, thus mimicking actual pathogens. In this report, we describe the synthesis, characterization, and biological evaluation of immunostimulatory acid-degradable microparticles, which are suitable delivery vehicles for use in protein-based vaccines and cancer immunotherapy. Using a 3′ conjugation strategy, we optimized the attachment of immunostimulatory CpG DNA to our vaccine carriers and demonstrated that under acidic conditions similar to that found in endosomal compartments, these new particles were capable of simultaneously releasing a model protein antigen and a CpG DNA adjuvant. We found in an in vivo cytotoxicity assay that the co-encapsulation of ovalbumin, a model antigen, and immunostimulatory agent in the same particle led to superior cytotoxic T lymphocyte activity compared to particles co-administered with adjuvant in an unbound form. In addition, we investigated the ability of these acid-degradable particles to induce protective immunity in the MO5 murine melanoma model and found that they were effective until tumor escape, which appeared to result from a loss of antigen expression by the cancer cells due to in vivo selection pressure.
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DOI：
10.1073/pnas.0930644100
发表时间：
2003-04-29
影响因子：
11.1
作者：
Murthy, N;Xu, MC;Fréchet, JMJ
通讯作者：
Fréchet, JMJ
DOI：
10.1073/pnas.0901592106
发表时间：
2009-04-07
影响因子：
11.1
作者：
Broaders, Kyle E.;Cohen, Joel A.;Frechet, Jean M. J.
通讯作者：
Frechet, Jean M. J.
影响因子：
20.3
作者：
Merad, M;Sugie, T;Fong, L
通讯作者：
Fong, L
DOI：
10.1038/nri1957
发表时间：
2006-11
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Marshak-Rothstein A
通讯作者：
Marshak-Rothstein A
影响因子：
64.8
作者：
KRIEG, AM;YI, AK;KLINMAN, DM
通讯作者：
KLINMAN, DM