Arista-Romero Maria, Cascante Anna, Fornaguera Cristina, Borrós Salvador
Grup d'Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Universitat Ramon Llull (URL), Via Augusta 390, 08017 Barcelona, Spain.
Sagetis Biotech SL, Via Augusta 394, 08017 Barcelona, Spain.
Pharmaceutics. 2021 Nov 19;13(11):1959. doi: 10.3390/pharmaceutics13111959.
Bladder cancer is the 10th most diagnosed cancer, with almost 10 M cancer deaths last year worldwide. Currently, chemotherapy is widely used as adjuvant therapy after surgical transurethral resection. Paclitaxel (PTX) is one of the most promising drugs, but cancer cells acquire resistance, causing failure of this treatment and increasing the recurrence of the disease. This poor chemotherapeutic response has been associated with the overexpression of the protein survivin. In this work, we present a novel dual nano-treatment for bladder cancer based on the hypothesis that the inhibition of survivin in cancer cells, using a siRNA gene therapy strategy, could decrease their resistance to PTX. For this purpose, two different polymeric nanoparticles were developed to encapsulate PTX and survivin siRNA independently. PTX nanoparticles showed sizes around 150 nm, with a paclitaxel loading of around 1.5%, that produced sustained tumor cell death. In parallel, siRNA nanoparticles, with similar sizes and loading efficiency of around 100%, achieved the oligonucleotide transfection and knocking down of survivin expression that also resulted in tumor cell death. However, dual treatment did not show the synergistic effect expected. The root cause of this issue was found to be the cell cycle arrest produced by nuclear survivin silencing, which is incompatible with PTX action. Therefore, we concluded that although the vastly reported role of survivin in bladder cancer, its silencing does not sensitize cells to currently applied chemotherapies.
膀胱癌是全球第十大最常被诊断出的癌症，去年全球癌症死亡人数近1000万。目前，化疗被广泛用作经尿道手术切除后的辅助治疗。紫杉醇（PTX）是最有前景的药物之一，但癌细胞会产生耐药性，导致这种治疗失败并增加疾病的复发率。这种较差的化疗反应与存活素蛋白的过度表达有关。在这项研究中，我们基于一种假设提出了一种新型的膀胱癌双重纳米治疗方法，即使用小干扰RNA（siRNA）基因治疗策略抑制癌细胞中的存活素，可能会降低它们对PTX的耐药性。为此，我们开发了两种不同的聚合物纳米颗粒，分别用于包裹PTX和存活素siRNA。PTX纳米颗粒的尺寸约为150纳米，紫杉醇负载量约为1.5%，能产生持续的肿瘤细胞死亡。与此同时，尺寸相似且负载效率约为100%的siRNA纳米颗粒实现了寡核苷酸转染并敲低了存活素的表达，这也导致了肿瘤细胞死亡。然而，双重治疗并未显示出预期的协同效应。发现该问题的根本原因是细胞核存活素沉默导致的细胞周期停滞，这与PTX的作用不相容。因此，我们得出结论，尽管存活素在膀胱癌中的作用已被大量报道，但其沉默并不会使细胞对目前应用的化疗药物敏感。
