Dpto. Química en Ciencias Farmacéuticas, Facultad de Farmacia, UCM, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain.
Grupo de Medicina Regenerativa, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), Madrid, Spain.
Acta Biomater. 2019 Jan 1;83:372-378. doi: 10.1016/j.actbio.2018.11.006. Epub 2018 Nov 7.
A Trojan-horse strategy for cancer therapy employing tumor-tropic mesenchymal stem cells transfected with a non-viral nanovector is here presented. In this sense, ultrasound-responsive mesoporous silica nanoparticles were coated with a polycation (using two different molecular weights), providing them with gene transfection capabilities that were evaluated using two different plasmids. First, the expression of Green Fluorescent Protein was analyzed in Decidua-derived Mesenchymal Stem Cells after incubation with the silica nanoparticles. The most successful nanoparticle was then employed to induce the expression of two suicide genes: cytosine deaminase and uracil phosphoribosyl transferase, which allow the cells to convert a non-toxic pro-drug (5-fluorocytosine) into a toxic drug (5-Fluorouridine monophosphate). The effect of the production of the toxic final product was also evaluated in a cancer cell line (NMU cells) co-cultured with the transfected vehicle cells, Decidua-derived Mesenchymal Stem Cells. STATEMENT OF SIGNIFICANCE: Cell-mediated cancer therapy has recently attracted great interest. Tumor-homing cells can exert anticancer effects through innate capacities, via transfection with a therapeutic gene or acting as vehicles of therapeutic nanoparticles. In this work, an ultrasound-responsive mesoporous silica nanoparticle (capable of carrying an anticancer drug) is engineered to act as a non-viral transfection agent for tumor-tropic human placental mesenchymal stem cells. The successful transfection of the vehicle cells is evaluated employing different expression plasmids. After transfection with two suicide genes, the vehicle cells are capable of converting a non-toxic pro-drug into a highly toxic molecule, which can also kill surrounding cancer cells in an in vitro co-culture model. This work opens the gate for a plethora of strategies in which both genes and drug-loaded nanoparticles can be transported towards tumor tissues by easily available human mesenchymal stem cells.
本文提出了一种利用转染非病毒纳米载体的肿瘤趋向性间充质干细胞的特洛伊木马策略治疗癌症。在这种情况下，超声响应介孔硅纳米粒子被涂覆有聚阳离子（使用两种不同的分子量），赋予它们基因转染能力，并用两种不同的质粒进行了评估。首先，在与硅纳米粒子孵育后，分析了蜕膜来源的间充质干细胞中绿色荧光蛋白的表达。然后，使用最成功的纳米粒子诱导两种自杀基因的表达：胞嘧啶脱氨酶和尿嘧啶磷酸核糖转移酶，使细胞能够将非毒性前药（5-氟胞嘧啶）转化为毒性药物（5-氟尿苷单磷酸）。还评估了与转染载体细胞（蜕膜来源的间充质干细胞）共培养的癌细胞系（NMU 细胞）中产生有毒终产物的效果。
细胞介导的癌症治疗最近引起了极大的兴趣。肿瘤归巢细胞可以通过先天能力发挥抗癌作用，例如通过转染治疗基因或作为治疗性纳米粒子的载体。在这项工作中，设计了一种超声响应介孔硅纳米粒子（能够携带抗癌药物）作为肿瘤趋向性人胎盘间充质干细胞的非病毒转染剂。使用不同的表达质粒评估载体细胞的成功转染。在转染两个自杀基因后，载体细胞能够将非毒性前药转化为高度毒性分子，该分子也可以在体外共培养模型中杀死周围的癌细胞。这项工作为许多策略开辟了道路，其中基因和载药纳米粒子都可以通过易于获得的人骨髓间充质干细胞运输到肿瘤组织。
