Prophylactic anti-tumor effects in a B cell lymphoma model with DNA vaccines delivered on polyethylenimine (PEI) functionalized PLGA microparticles
Prophylactic anti-tumor effects in a B cell lymphoma model with DNA vaccines delivered on polyethylenimine (PEI) functionalized PLGA microparticles
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DOI：
10.1016/j.jcornel.2006.04.006
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发表时间：
2006-07-20
影响因子：
10.8
通讯作者：
Roy, Krishnendu
中科院分区：
文献类型：
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作者：
Kasturi, Sudhir Pai;Qin, Hong;Roy, Krishnendu
特异于恶性B细胞表达的免疫球蛋白高变区的独特型序列为B细胞淋巴瘤提供了治疗靶点。已经描述了克隆肿瘤免疫球蛋白（IG）的单链片段的有效方法，所述单链片段包含与促炎趋化因子融合的重链和轻链IG（sFv）。由质粒DNA（pDNA）编码的肿瘤相关的免疫原性差的自身抗原已经通过趋化因子融合而具有免疫原性，从而靶向差异表达趋化因子受体的抗原呈递细胞（APC）。在这里，我们提出了一种注射（肠胃外）的方法，使用合成的聚合物为基础的阳离子微粒制剂，以提高这种趋化因子/自身抗原表达质粒构建体的效力。支化和线性聚乙烯亚胺（PEI）的共轭聚（D，L丙交酯-共-乙交酯）（PLGA）微粒使用碳二亚胺化学，然后有效加载质粒DNA。除了赋予这些阳离子微粒显著的缓冲能力之外，流式细胞术研究表明，这些装载DNA的微粒显著上调吞噬性RAW 264.7细胞中的CD 80和MHC II类标志物，表明了内在的佐剂效应。在Balb/c小鼠中皮内注射这些制剂在用2.5倍最小致死剂量的肿瘤攻击后诱导显著保护。与注射盐水的对照或空白微粒相比，长期存活率是显著的（p < 0.05）。进一步的研究表明，肌内递送可能提供比皮内注射更好的保护，并且与基因枪介导的施用类似。我们的结论是，基于这些有前途的体内结果，这种表面功能化的微粒提供了一个有吸引力的策略，以提高自身抗原为基础的癌症DNA疫苗的效力。(c)2006年爱思唯尔B. V.保留所有战斗。
Idiotypic sequences, specific to the hypervariable regions of immumoglobulins expressed by malignant B cells offer a therapeutic target in B cell lymphoma. Efficient approaches have been described to clone a single chain fragment of the tumor immunoglobulin (Ig) comprising of heavy and light Ig chains (sFv) fused with proinflammatory chemokines. Tumor associated, poorly immunogenic self antigens encoded by plasmid DNA (pDNA) have been rendered immunogenic by chemokine fusion, thereby targeting to antigen presenting cells (APCs) which differentially express chemokine receptors. Here we present an injectable (parenteral) approach using synthetic polymer based cationic microparticle formulations for enhancing the potency of such chemokine/self antigen expressing plasmid construct. Branched and linear polyethyleneimine (PEI) were conjugated on poly (D, L lactide-co-glycolide) (PLGA) microparticles using carbodiimide chemistry followed by efficient loading of plasmid DNA. In addition to imparting significant buffering ability to these cationic microparticles, flow cytometry studies indicate that these DNA loaded microparticles significantly up regulate CD80 and MHC class II markers in phagocytic RAW264.7 cells, indicating intrinsic adjuvant effects. Intradermal injections in Balb/c mice with these formulations induced significant protection upon tumor challenge with 2.5 times the minimal lethal dose. Long term survival rates were significant (p < 0.05) in comparison with saline injected controls or blank microparticles. Further studies indicated that intramuscular delivery might provide better protection compared to intradermal injections and perform similar to gene gun mediated administration. We conclude, based on these promising in vivo results, that such surface-functionalized microparticles offer an attractive strategy to improve the potency of self antigen-based cancer DNA vaccines. (c) 2006 Elsevier B.V. All fights reserved.