Laboratory of Biotechnology, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, ENEA, Casaccia Research Center, Via Anguillarese 301, 00123 Rome, Italy.
Laboratory of Biomedical Technologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, ENEA, Casaccia Research Center, Via Anguillarese 301, 00123 Rome, Italy.
Int J Mol Sci. 2021 Sep 29;22(19):10523. doi: 10.3390/ijms221910523.
Medulloblastoma (MB) is a primary central nervous system tumor affecting mainly young children. New strategies of drug delivery are urgent to treat MB and, in particular, the SHH-dependent subtype-the most common in infants-in whom radiotherapy is precluded due to the severe neurological side effects. Plant virus nanoparticles (NPs) represent an innovative solution for this challenge. Tomato bushy stunt virus (TBSV) was functionally characterized as a carrier for drug targeted delivery to a murine model of Shh-MB. The TBSV NPs surface was genetically engineered with peptides for brain cancer cell targeting, and the modified particles were produced on a large scale using plants. Tests on primary cultures of Shh-MB cells allowed us to define the most efficient peptides able to induce specific uptake of TBSV. Immunofluorescence and molecular dynamics simulations supported the hypothesis that the specific targeting of the NPs was mediated by the interaction of the peptides with their natural partners and reinforced by the presentation in association with the virus. In vitro experiments demonstrated that the delivery of Doxorubicin through the chimeric TBSV allowed reducing the dose of the chemotherapeutic agent necessary to induce a significant decrease in tumor cells viability. Moreover, the systemic administration of TBSV NPs in MB symptomatic mice, independently of sex, confirmed the ability of the virus to reach the tumor in a specific manner. A significant advantage in the recognition of the target appeared when TBSV NPs were functionalized with the CooP peptide. Overall, these results open new perspectives for the use of TBSV as a vehicle for the targeted delivery of chemotherapeutics to MB in order to reduce early and late toxicity.
髓母细胞瘤（MB）是一种主要影响幼儿的原发性中枢神经系统肿瘤。迫切需要新的药物输送策略来治疗 MB，特别是 SHH 依赖性亚型——在婴儿中最常见——由于放疗的严重神经副作用而被排除在外。植物病毒纳米颗粒（NPs）为这一挑战提供了一个创新的解决方案。番茄丛矮病毒（TBSV）被功能表征为一种载体，用于将药物靶向递送至 Shh-MB 的鼠模型。TBSV NPs 的表面通过基因工程与用于脑癌细胞靶向的肽结合，并使用植物大规模生产修饰后的颗粒。对 Shh-MB 细胞的原代培养物进行的测试使我们能够确定最有效的肽，这些肽能够诱导 TBSV 的特异性摄取。免疫荧光和分子动力学模拟支持了这样的假设，即 NPs 的特异性靶向是由肽与其天然配体的相互作用介导的，并通过与病毒结合的呈递得到加强。体外实验表明，通过嵌合 TBSV 递送达柔比星可以减少诱导肿瘤细胞活力显著降低所需的化疗药物剂量。此外，TBSV NPs 在有症状的 MB 小鼠中的系统给药，无论性别如何，都证实了病毒以特定方式到达肿瘤的能力。当 TBSV NPs 用 CooP 肽功能化时，在识别靶标方面出现了显著的优势。总的来说，这些结果为使用 TBSV 作为载体将化疗药物靶向递送至 MB 以降低早期和晚期毒性开辟了新的前景。
