Bluetongue Virus Particles as Nanoreactors for Enzyme Delivery and Cancer Therapy.
Bluetongue Virus Particles as Nanoreactors for Enzyme Delivery and Cancer Therapy.
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蓝舌病毒颗粒作为酶传递和癌症治疗的纳米反应器。
DOI：
10.1021/acs.molpharmaceut.0c01053
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发表时间：
2021-03-01
影响因子：
4.9
通讯作者：
Steinmetz NF
中科院分区：
文献类型：
--
作者：
Thuenemann EC;Le DHT;Lomonossoff GP;Steinmetz NF
通过用酶（或相应的基因）靶向肿瘤细胞，可以减少化疗的副作用，该酶将肿瘤细胞内的无毒前药转化为有毒药物，同时通过旁观者效应杀死周围的肿瘤细胞。病毒是最有效的基因传递载体，因为它们已经进化到可以将自己的核酸转移到细胞中，但它们的效率必须与感染风险、核酸的免疫原性和基因组整合的潜力相平衡。因此，我们测试了无基因组病毒样颗粒 (VLP) 输送单纯疱疹病毒 1 型胸苷激酶 (HSV1-TK) 的有效性，HSV1-TK 是前药转化疗法中最常用的酶。 HSV1-TK 通常作为基因传递，但在 VLP 中，它必须作为蛋白质传递。我们基于蓝舌病毒构建了 VLP 和更小的核心状颗粒 (CLP)，其中 HSV1-TK 与内部衣壳蛋白 VP3 融合。 TK-CLP 和 TK-VLP 可以在植物中大量生产。在更昔洛韦存在的情况下，TK-VLP 可有效杀死人胶质母细胞瘤细胞，IC50 值为 14.8 μM。相反，CLP 是无效的，因为它们仍然被困在内体隔室中，与许多合成纳米颗粒一样。 VLP 是有利的，因为它们可以从内体中逃逸，因此允许 HSV1-TK 接触更昔洛韦磷酸化所需的胞质三磷酸腺苷 (ATP)。因此，TK 蛋白的 VLP 递送策略为使用更昔洛韦等全身性前药治疗癌症提供了一种有前景的新方式。
The side effects of chemotherapy can be reduced by targeting tumor cells with an enzyme (or the corresponding gene) that converts a nontoxic prodrug into a toxic drug inside the tumor cells, also killing the surrounding tumor cells via the bystander effect. Viruses are the most efficient gene delivery vehicles because they have evolved to transfer their own nucleic acids into cells, but their efficiency must be balanced against the risks of infection, the immunogenicity of nucleic acids, and the potential for genomic integration. We therefore tested the effectiveness of genome-free virus-like particles (VLPs) for the delivery of Herpes simplex virus 1 thymidine kinase (HSV1-TK), the most common enzyme used in prodrug conversion therapy. HSV1-TK is typically delivered as a gene, but in the context of VLPs, it must be delivered as a protein. We constructed VLPs and smaller core-like particles (CLPs) based on Bluetongue virus, with HSV1-TK fused to the inner capsid protein VP3. TK-CLPs and TK-VLPs could be produced in large quantities in plants. The TK-VLPs killed human glioblastoma cells efficiently in the presence of ganciclovir, with an IC50 value of 14.8 μM. Conversely, CLPs were ineffective because they remained trapped in the endosomal compartment, in common with many synthetic nanoparticles. VLPs are advantageous because they can escape from endosomes and therefore allow HSV1-TK to access the cytosolic adenosine triphosphate (ATP) required for the phosphorylation of ganciclovir. The VLP delivery strategy of TK protein therefore offers a promising new modality for the treatment of cancer with systemic prodrugs such as ganciclovir.
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影响因子：
16.1
作者：
Karjoo Z;Chen X;Hatefi A
通讯作者：
Hatefi A
影响因子：
2.8
作者：
Park, Ji Hyun;Kim, Hyeon-Young;Yun, Eun Kyoung
通讯作者：
Yun, Eun Kyoung
影响因子：
3
作者：
HEWAT, EA;BOOTH, TF;ROY, P
通讯作者：
ROY, P
DOI：
10.1111/j.1749-6632.1999.tb09538.x
发表时间：
1999-01-01
期刊：
CELL AND MOLECULAR BIOLOGY OF PANCREATIC CARCINOMA: RECENT DEVELOPMENTS IN RESEARCH AND EXPERIMENTAL THERAPY
影响因子：
--
作者：
Howard, BD;Kalthoff, H;Fong, TC
通讯作者：
Fong, TC
影响因子：
5.4
作者：
Kar, AK;Iwatani, N;Roy, P
通讯作者：
Roy, P