Multistage nanovectors: from concept to novel imaging contrast agents and therapeutics.
Multistage nanovectors: from concept to novel imaging contrast agents and therapeutics.
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DOI：
10.1021/ar200077p
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发表时间：
2011-10-18
影响因子：
18.3
通讯作者：
Ferrari, Mauro
中科院分区：
文献类型：
--
作者：
Godin, Biana;Tasciotti, Ennio;Liu, Xuewu;Serda, Rita E.;Ferrari, Mauro
在过去的几十年中，已经合成和制造了各种基于纳米技术的平台，以改善活性化合物向疾病部位的递送。目前在临床中使用的纳米颗粒，以及正在研究的大多数纳米治疗/纳米诊断，在同一实体上提供单一或多个功能。由于许多异质性生物屏障可以阻止治疗剂和成像剂以足够的浓度到达其预期靶点，因此出现了开发多模块纳米组装体的需求，其中具有单独特定功能的不同组分以协同方式起作用。它包括几个纳米组件或“阶段”，每个纳米组件或“阶段”都被设计为通过一个或多个生物屏障。第1阶段介孔硅颗粒（S1 MP）的合理设计和制造在一个非球形的几何形状，使上级血液边集和增加细胞表面粘附。S1 MP的主要任务是有效地运输装载到其多孔结构中的纳米颗粒，并在从给药部位运输到疾病病灶期间保护它们。包括光刻和电化学蚀刻的半导体制造技术允许精细控制和精确再现S1 MP物理特性，例如几何形状和孔隙率。此外，S1 MP可以用带负/正电荷的基团、PEG和其他聚合物、荧光探针、造影剂和生物活性靶向部分（包括抗体、肽、适体和噬菌体）进行化学修饰。有效载荷纳米颗粒，称为阶段2纳米颗粒（S2 NP），可以是任何目前可用的纳米颗粒，例如脂质体、胶束、无机/金属纳米颗粒、树枝状聚合物和碳结构。直径在5-100 nm的近似尺寸范围内。根据S1 MP的物理化学特征（几何形状，孔隙率和表面修饰），各种S2 NPs或纳米颗粒“鸡尾酒”可以加载并有效地传递到疾病部位。正如在这里审查的研究中所示，一旦S2 NPs加载到S1 MP中，各种新的特性出现，这使得新的和改进的成像造影剂和治疗的设计成为可能。例如，将MRI Gd基造影剂装载到半球形和盘形S1 MP上显著增加了磁共振弛豫率（r1），其值比临床上可用的钆基造影剂（104 mM-1 s-1/Gd 3+离子）大50倍。此外，施用单剂量的装载有中性纳米脂质体的MSV，所述中性纳米脂质体含有靶向EphA 2癌蛋白的小干扰RNA（siRNA），使得能够持续EphA 2基因沉默至少21天。因此，在卵巢癌原位小鼠模型中，肿瘤负荷降低。我们设想，MSV平台的多功能性及其新兴特性将能够在癌症治疗诊断学领域内外创建具有广泛临床意义的个性化解决方案。
Over the last few decades a great variety of nanotechnology based platforms have been synthesized and fabricated to improve the delivery of active compounds to a disease site. Nanoparticles currently used in the clinic, and the majority of nanotherapeutics/nanodiagnostics under investigation, accommodate single- or multiple- functionalities on the same entity. Because many heterogeneous biological barriers can prevent therapeutic and imaging agents from reaching their intended targets in sufficient concentrations, there is an emerging requirement to develop a multimodular nanoassembly, in which different components with individual specific functions act in a synergistic manner.The multistage nanovectors (MSVs) were introduced in 2008 as the first system of this type. It comprises several nanocomponents or “stages”, each of which is designed to negotiate one or more biological barriers. Stage 1 mesoporous silicon particles (S1MPs) were rationally designed and fabricated in a nonspherical geometry to enable superior blood margination and to increase cell surface adhesion. The main task of S1MPs is to efficiently transport nanoparticles that are loaded into their porous structure and to protect them during transport from the administration site to the disease lesion. Semiconductor fabrication techniques including photolithography and electrochemical etching allow for the exquisite control and precise reproducibility of S1MP physical characteristics such as geometry and porosity. Furthermore, S1MPs can be chemically modified with negatively/positively charged groups, PEG and other polymers, fluorescent probes, contrast agents, and biologically active targeting moieties including antibodies, peptides, aptamers, and phage.The payload nanoparticles, termed stage 2 nanoparticles (S2NPs), can be any currently available nanoparticles such as liposomes, micelles, inorganic/metallic nanoparticles, dendrimers, and carbon structures, within the approximate size range of 5–100 nm in diameter. Depending upon the physicochemical features of the S1MP (geometry, porosity, and surface modifications), a variety of S2NPs or nanoparticle “cocktails” can be loaded and efficiently delivered to the disease site.As demonstrated in the studies reviewed here, once the S2NPs are loaded into the S1MPs, a variety of novel properties emerge, which enable the design of new and improved imaging contrast agents and therapeutics. For example, the loading of the MRI Gd-based contrast agents onto hemispherical and discoidal S1MPs significantly increased the longitudal relaxivity (r1) to values of up to 50 times larger than those of clinically available gadolinium-based agents (∼4 mM–1s–1/Gd3+ion). Furthermore, administration of a single dose of MSVs loaded with neutral nanoliposomes containing small interfering RNA (siRNA) targeted against the EphA2 oncoprotein enabled sustained EphA2 gene silencing for at least 21 days. As a result, the tumor burden was reduced in an orthotopic mouse model of ovarian cancer.We envision that the versatility of the MSV platform and its emerging properties will enable the creation of personalized solutions with broad clinical implications within and beyond the realm of cancer theranostics.
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影响因子：
13.3
作者：
Serda, Rita E.;Mack, Aaron;van de Ven, Anne L.;Ferrati, Silvia;Dunner, Kenneth, Jr.;Godin, Biana;Chiappini, Ciro;Landry, Matthew;Brousseau, Louis;Liu, Xuewu;Bean, Andrew J.;Ferrari, Mauro
通讯作者：
Ferrari, Mauro
影响因子：
64.8
作者：
Sengupta, S;Eavarone, D;Sasisekharan, R
通讯作者：
Sasisekharan, R
影响因子：
14
作者：
Alvarez, Sara D.;Derfus, Austin M.;Sailor, Michael J.
通讯作者：
Sailor, Michael J.
影响因子：
14
作者：
Decuzzi, Paolo;Ferrari, Mauro
通讯作者：
Ferrari, Mauro
DOI：
10.1007/978-1-60327-295-7_3
发表时间：
2009-01-01
期刊：
THERAPEUTIC APPLICATIONS OF RNAI: METHODS AND PROTOCOLS
影响因子：
--
作者：
Mangala, Lingegowda S.;Han, Hee Dong;Sood, Anil K.
通讯作者：
Sood, Anil K.