Fornaguera Cristina, Torres-Coll Antoni, Olmo Laura, Garcia-Fernandez Coral, Guerra-Rebollo Marta, Borrós Salvador
Grup d'Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Universitat Ramon Llull (URL) Spain
RSC Adv. 2023 Oct 13;13(43):29986-30001. doi: 10.1039/d3ra05830a. eCollection 2023 Oct 11.
Non-small cell lung cancer (NSCLC) is one of the leading causes of worldwide death, mainly due to the lack of efficient and safe therapies. Currently, NSCLC standard of care for consist on the use of traditional chemotherapeutics, non-selectively distributed through the whole body, thus causing severe side effects while not achieving high efficacy outcomes. Consequently, the need of novel therapies, targeted to modify specific subcellular routes aberrantly expressed only in tumor cells is still urgent. In this context, the delivery of siRNAs that can know-down overexpressed oncogenes, such as mTOR, could become the promised targeted therapy. However, siRNA effective delivery remains a challenge due to its compromised stability in biological fluids and its inability to cross biological and plasmatic membranes. Therefore, polymeric nanoparticles that efficiently encapsulate siRNAs and are selectively targeted to tumor cells could play a pivotal role. Accordingly, we demonstrate in this work that oligopeptide end-modified poly(beta aminoester) (OM-pBAE) polymers can efficiently complex siRNA in small nanometric particles using very low polymer amounts, protecting siRNA from nucleases attack. These nanoparticles are stable in the presence of serum, advantageous fact in terms of use. We also demonstrated that they efficiently transfect cells , in the presence of serum and are able to knock down target gene expression. Moreover, we demonstrated their antitumor efficacy by encapsulating mTOR siRNA, as a model antisense therapy, which showed specific lung tumor cell growth inhibition and . Finally, through the addition of anisamide functionalization to the surface of the nanoparticles, we proved that they become selective to lung tumor cells, while not affecting healthy cells. Therefore, our results are a first step in the discovery of a tumor cell-targeted efficient silencing nanotherapy for NSCLC patients survival improvement.
非小细胞肺癌（NSCLC）是全球主要死因之一，主要原因是缺乏高效且安全的治疗方法。目前，NSCLC的标准治疗方案是使用传统化疗药物，这些药物在全身非选择性分布，因此在未取得高效治疗效果的同时还会引发严重的副作用。因此，迫切需要针对仅在肿瘤细胞中异常表达的特定亚细胞途径进行修饰的新型疗法。在这种背景下，能够下调如mTOR等过表达癌基因的小干扰RNA（siRNA）的递送可能成为有前景的靶向治疗方法。然而，由于siRNA在生物流体中的稳定性受损以及其无法穿过生物膜和质膜，其有效递送仍然是一个挑战。因此，能够有效封装siRNA并选择性靶向肿瘤细胞的聚合物纳米颗粒可能发挥关键作用。相应地，我们在这项工作中证明，寡肽末端修饰的聚（β-氨基酯）（OM-pBAE）聚合物可以使用非常低的聚合物量在小纳米颗粒中有效地使siRNA形成复合物，保护siRNA免受核酸酶攻击。这些纳米颗粒在血清存在下是稳定的，这在使用方面是一个有利的事实。我们还证明，它们在血清存在下能够有效地转染细胞，并能够下调靶基因表达。此外，我们通过封装mTOR siRNA作为模型反义疗法证明了它们的抗肿瘤功效，该疗法显示出对肺肿瘤细胞生长的特异性抑制。最后，通过在纳米颗粒表面添加茴香酰胺功能化，我们证明它们对肺肿瘤细胞具有选择性，同时不影响健康细胞。因此，我们的结果是发现一种针对肿瘤细胞的高效沉默纳米疗法以改善NSCLC患者生存率的第一步。
