Targeted lipid-coated nanoparticles: Delivery of tumor necrosis factor-functionalized particles to tumor cells
Targeted lipid-coated nanoparticles: Delivery of tumor necrosis factor-functionalized particles to tumor cells
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DOI：
10.1016/j.jconrel.2009.03.010
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发表时间：
2009-07-01
影响因子：
10.8
通讯作者：
Kontermann, Roland E.
中科院分区：
文献类型：
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作者：
Messerschmidt, Sylvia K. E.;Musyanovych, Anna;Kontermann, Roland E.
在其表面上展示肿瘤坏死因子的聚合物纳米颗粒（TNF纳米细胞）是能够模拟膜结合的TNF的生物活性的有用的载体系统。因此。TNF纳米细胞是TNF受体1和2的有效激活剂，导致细胞凋亡的显著增强。然而，体内应用受到潜在全身毒性的阻碍。在这里，使用TNF纳米细胞作为模型系统，我们开发了一种程序，以产生靶向脂质包被颗粒（TLP），其中TNF活性被屏蔽。此处产生的TLP由内部单链TNF（scTNF）官能化的聚合物纳米颗粒核心组成，所述核心被赋予用于空间稳定的聚乙二醇（PEG）的脂质包衣和用于靶向的单链Fv（scFv）片段包围。使用针对肿瘤基质标志物成纤维细胞活化蛋白（FAP）的scFv，我们表明TLP和scTNF-TLP特异性结合FAP表达细胞，但不结合FAP阴性细胞。脂质涂层强烈降低了颗粒的非特异性结合和scTNF介导的对FAP阴性细胞的细胞毒性。相反，对于FAP阳性细胞，观察到TO的细胞毒性增加。因此，通过脂质体包封，携带生物活性分子的纳米颗粒，其受到对各种细胞和组织的非选择性摄取和活性。可以转化为对抗原阳性靶细胞显示选择活性的靶细胞特异性复合颗粒。除了安全和靶向递送死亡配体如TNF之外，TLP还应适用于各种诊断和治疗应用，其受益于包埋到颗粒核心中或展示在核心颗粒表面上的试剂的靶向递送。(c)2009 Elsevier B. V.保留所有权利。
Polymeric nanoparticles displaying tumor necrosis factor on their surface (TNF nanocytes) are useful carrier systems capable of mimicking the bioactivity of membrane-bound TNF. Thus. TNF nanocytes are potent activators of TNF receptor 1 and 2 leading to a striking enhancement of apoptosis. However, in vivo applications are hampered by potential systemic toxicity. Here, using TNF nanocytes as a model system, we developed a procedure to generate targeted lipid-coated particles (TLP) in which TNF activity is shielded. The TLPs generated here are composed of an inner single-chain TNF (scTNF)-functionalized, polymeric nanoparticle core surrounded by a lipid coat endowed with polyethylene glycol (PEG) for sterical stabilization and a single-chain Fv (scFv) fragment for targeting. Using a scFv directed against the tumor stroma marker fibroblast activation protein (FAP) we show that TLP and scTNF-TLP specifically bind to FAP-expressing, but not to FAP-negative cells. Lipid coating strongly reduced nonspecific binding of particles and scTNF-mediated cytotoxicity towards FAP-negative cells. In contrast, an increased cytotoxicity of TO was observed for FAP-positive cells. Thus, through liposome encapsulation, nanoparticles carrying bioactive molecules, which are subject to nonselective uptake and activity towards various cells and tissues. can be converted into target cell-specific composite particles exhibiting a selective activity towards antigen-positive target cells. Besides safe and targeted delivery of death ligands such as TNF, TLP should be suitable for various diagnostic and therapeutic applications, which benefit from a targeted delivery of reagents embedded into the particle core or displayed on the core particle surface. (c) 2009 Elsevier B.V. All rights reserved.