Kernan Daniel L, Wen Amy M, Pitek Andrzej S, Steinmetz Nicole F
1 Department of Biomedical Engineering, Case Western Reserve University Schools of Medicine and Engineering, Cleveland, OH 44106, USA.
2 Department of Radiology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Exp Biol Med (Maywood). 2017 Aug;242(14):1405-1411. doi: 10.1177/1535370217719222. Epub 2017 Jul 4.
The first-line treatment for non-Hodgkin's lymphoma is chemotherapy. While generally well tolerated, off-target effects and chemotherapy-associated complications are still of concern. To overcome the challenges associated with systemic chemotherapy, we developed a biology-inspired, nanoparticle drug delivery system (nanoDDS) making use of the nucleoprotein components of the tobacco mosaic virus (TMV). Virus-based nanoparticles, including the high-aspect ratio soft nanorods formed by TMV, are growing in popularity as nanoDDS due to their simple genetic and chemical engineerability, size and shape tunability, and biocompatibility. In this study, we used bioconjugation to modify TMV as a multivalent carrier for delivery of the antimitotic drug valine-citrulline monomethyl auristatin E (vcMMAE) targeting non-Hodgkin's lymphoma. We demonstrate successful synthesis of the TMV-vcMMAE; data indicate that the TMV-vcMMAE particles remained structurally sound with all of the 2130 identical TMV coat proteins modified to carry the therapeutic payload vcMMAE. Cell uptake using Karpas 299 cells was confirmed with TMV particles trafficking to the endolysosomal compartment, likely allowing for protease-mediated cleavage of the valine-citrulline linker for the release of the active monomethyl auristatin E component. Indeed, effective cell killing of non-Hodgkin's lymphoma in vitro was demonstrated; TMV-vcMMAE was shown to exhibit an IC of ∼250 nM. This study contributes to the development of viral nanoDDS. Impact statement Due to side effects associated with systemic chemotherapy, there is an urgent need for the development of novel drug delivery systems. We focus on the high-aspect ratio nanotubes formed by tobacco mosaic virus (TMV) to deliver antimitotic drugs targeted to non-Hodgkin's lymphoma. Many synthetic and biologic nanocarriers are in the development pipeline; the majority of systems are spherical in shape. This may not be optimal, because high-aspect ratio filaments exhibit enhanced tumor homing, increased target cell interactions and decreased immune cell uptake, and therefore have favorable properties for drug delivery compared to their spherical counterparts. Nevertheless, the synthesis of high-aspect ratio materials at the nanoscale remains challenging; therefore, we turned toward the nucleoprotein components of TMV as a biologic nanodrug delivery system. This work presents groundwork for the development of plant virus-based vehicles for use in cancer treatment.
非霍奇金淋巴瘤的一线治疗方法是化疗。虽然化疗通常耐受性良好，但脱靶效应和化疗相关并发症仍然令人担忧。为了克服与全身化疗相关的挑战，我们开发了一种受生物学启发的纳米颗粒药物递送系统（nanoDDS），该系统利用烟草花叶病毒（TMV）的核蛋白成分。基于病毒的纳米颗粒，包括由TMV形成的高纵横比软纳米棒，由于其简单的基因和化学可工程性、尺寸和形状可调性以及生物相容性，作为纳米药物递送系统越来越受欢迎。在本研究中，我们使用生物共轭修饰TMV，使其成为用于递送靶向非霍奇金淋巴瘤的抗有丝分裂药物缬氨酸 - 瓜氨酸单甲基澳瑞他汀E（vcMMAE）的多价载体。我们证明了TMV - vcMMAE的成功合成；数据表明，TMV - vcMMAE颗粒结构保持完好，所有2130个相同的TMV衣壳蛋白都经过修饰以携带治疗性有效载荷vcMMAE。使用Karpas 299细胞证实了细胞摄取，TMV颗粒运输到溶酶体区室，这可能允许蛋白酶介导的缬氨酸 - 瓜氨酸连接子裂解，从而释放活性单甲基澳瑞他汀E成分。事实上，已证明在体外对非霍奇金淋巴瘤有有效的细胞杀伤作用；TMV - vcMMAE的IC显示约为250 nM。这项研究为病毒纳米药物递送系统的发展做出了贡献。影响声明由于全身化疗的副作用，迫切需要开发新型药物递送系统。我们专注于由烟草花叶病毒（TMV）形成的高纵横比纳米管来递送靶向非霍奇金淋巴瘤的抗有丝分裂药物。许多合成和生物纳米载体正在研发中；大多数系统是球形的。这可能不是最佳的，因为高纵横比的细丝表现出增强的肿瘤归巢、增加的靶细胞相互作用和减少的免疫细胞摄取，因此与球形对应物相比，具有有利于药物递送的特性。然而，在纳米尺度上合成高纵横比材料仍然具有挑战性；因此，我们转向TMV的核蛋白成分作为生物纳米药物递送系统。这项工作为开发用于癌症治疗的基于植物病毒的载体奠定了基础。
