Boosting Oncolytic Adenovirus Potency with Magnetic Nanoparticles and Magnetic Force
Boosting Oncolytic Adenovirus Potency with Magnetic Nanoparticles and Magnetic Force
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DOI：
10.1021/mp100123t
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发表时间：
2010-07-01
影响因子：
4.9
通讯作者：
Plank, Christian
中科院分区：
文献类型：
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作者：
Tresilwised, Nittaya;Pithayanukul, Pimolpan;Plank, Christian
溶瘤腺病毒在癌症治疗中是最有前途的创新药物之一。我们研究了溶瘤腺病毒dl520在体外和体内肿瘤内注射时与磁性纳米颗粒和磁场引导的多药耐药(MDR)癌细胞感染相关联，从而提高其疗效的可能性。该病毒通过自组装与具有约10 nm磁铁矿核心的核壳纳米粒子复合，并由含有68质量%3-[2-(全氟烷基)乙硫基]丙酸锂和32质量%25 kDa支化聚乙烯亚胺的壳层稳定。优化的病毒结合在50%胎牛血清中足够稳定，当纳米粒子与病毒的比例为每物理病毒粒子(VP)含铁5fg或以上时。根据磁感应迁移率的测量，每个病毒颗粒中有3600到4500个磁铁矿纳米微晶。电子和原子力显微镜的超微结构分析显示，结构完整的病毒被磁性颗粒包围，偶尔会连接几个病毒颗粒。当在磁场影响下进行感染时，在给定病毒剂量下细胞对病毒的摄取比纳米磁性病毒增强10倍。与非磁性病毒相比，在相同的输入病毒剂量下，Vuris内化增加导致溶瘤效力增加10倍，杀灭50%的靶细胞所需的剂量(IC50值)和病毒后代形成增加4个数量级。此外，与非磁性病毒的6天相比，感染后两天内出现了完全的溶瘤效应。绘制磁性和非磁性病毒的靶细胞活性与内化病毒颗粒的关系图显示，与磁性纳米颗粒结合后，病毒固有的溶瘤生产力保持不变。因此，我们得出结论，磁力促进溶瘤作用的机制主要是由于促进了磁性病毒复合体的内化，从而增强了病毒后代的形成。在小鼠异种移植瘤模型中，通过瘤内注射和施加梯度磁场，磁性病毒复合体表现出比腺病毒单独的更强的溶瘤作用。我们认为，他的方法将有助于体内给药肿瘤供血血管，以提高肿瘤内初次感染循环的有效性。为了系统应用，需要对磁腺病毒复合体进行进一步的修饰，以屏蔽和重定向整个磁性病毒复合体。
Oncolytic adenoviruses rank among the most promising innovative agents in cancer therapy. We examined the potential of boosting the efficacy of the oncolytic adenovirus dl520 by associating it with magnetic nanoparticles and magnetic-field-guided infection in multidrug-resistant (MDR) cancer cells in vitro and upon intratumoral injection in vivo. The virus was complexed by self-assembly with core-shell nanoparticles having a magnetite core of about 10 nm and stabilized by a shell containing 68 mass % lithium 3-[2-(perfluoroalkyl)ethylthio]propionate) and 32 mass % 25 kDa branched polyethylenimine. Optimized virus binding, sufficiently stable in 50% fetal calf serum, was found at nanoparticle-to-virus ratios of 5 fg of Fe per physical virus particle (VP) and above. As estimated from magnetophoretic mobility measurements, 3,600 to 4,500 magnetite nano-crystallites were assciated per virus particle. Ultrastructural analysis by electron and atomic force microscopy showed structurally intact viruses surrounded by magnetic particles that occasionally bridged several virus particles. Viral uptake into cells at a given virus dose was enhanced 10-fold compard to nanmagnetic virus when infections were carried out under the influence of a magnetic field. Increased vuris internalization resulted in a 10-fold enhancement of the oncolytic potency in terms of the dose required for killing 50% of the target cells (IC50 value) and an enhancement of 4 orders of magnitude in virus progeny formation at equal input virus doses compared to nonmagnetic viruses. Furthermore, the full oncolytic effect developed within two days postinfection compared with six days in a nonmagnetic virus as a reference. Plotting target cell viability versus internalized virus particles for magnetic and nonmagnetic virus showed that the inherent oncolytic productivity of the virus remained unchanged upon association with magnetic nanoparticles. Hence, we conclede that the mechanism of boosting the oncolytic effect by magnetic force is mainly due to the improved internalization of magnetic virus complexes resulting in potentiated virus progeny formation. Upon intratumoral injection and application of a gradient magnetic field in a murine xenograft model, magnetic virus complexes exhibited a stronger oncolytic effect than adenovirus alone. We propose that his approacg would be useful during in vivo administration to tumor-feeding blood vessels to boost the efficacy of the primary infection cycle within the tumor. For systemic application, further modification of magnetic adenovirus complexes for shielding and retargeting of the whole magnetic virus complex entity is needed.