Università Vita-Salute San Raffaele, Milano, I-20132, Italy; Istituto di Ricerca Urologica, Divisione di Oncologia Sperimentale, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy.
Università degli Studi di Milano-Bicocca, NanoBioLab, Dipartimento di Biotecnologie e Bioscienze, Piazza Della Scienza 2, 20126 Milan, Italy.
Pharmacol Res. 2016 Sep;111:619-641. doi: 10.1016/j.phrs.2016.07.007. Epub 2016 Jul 18.
Conventional chemotherapeutics have been employed in cancer treatment for decades due to their efficacy in killing the malignant cells, but the other side of the coin showed off-target effects, onset of drug resistance and recurrences. To overcome these limitations, different approaches have been investigated and suicide gene therapy has emerged as a promising alternative. This approach consists in the introduction of genetic materials into cancerous cells or the surrounding tissue to cause cell death or retard the growth of the tumor mass. Despite promising results obtained both in vitro and in vivo, this innovative approach has been limited, for long time, to the treatment of localized tumors, due to the suboptimal efficiency in introducing suicide genes into cancer cells. Nanoparticles represent a valuable non-viral delivery system to protect drugs in the bloodstream, to improve biodistribution, and to limit side effects by achieving target selectivity through surface ligands. In this scenario, the real potential of suicide genes can be translated into clinically viable treatments for patients. In the present review, we summarize the recent advances of inorganic nanoparticles as non-viral vectors in terms of therapeutic efficacy, targeting capacity and safety issues. We describe the main suicide genes currently used in therapy, with particular emphasis on toxin-encoding genes of bacterial and plant origin. In addition, we discuss the relevance of molecular targeting and tumor-restricted expression to improve treatment specificity to cancer tissue. Finally, we analyze the main clinical applications, limitations and future perspectives of suicide gene therapy.
传统的化疗药物在癌症治疗中已经使用了几十年，因为它们在杀死恶性细胞方面非常有效，但另一方面也显示出了脱靶效应、耐药性的产生和复发。为了克服这些局限性，已经研究了不同的方法，自杀基因治疗已经成为一种有前途的替代方法。这种方法包括将遗传物质引入癌细胞或周围组织，以导致细胞死亡或减缓肿瘤体积的生长。尽管在体外和体内都取得了有希望的结果，但由于将自杀基因引入癌细胞的效率不理想，这种创新方法长期以来仅限于治疗局限性肿瘤。纳米粒子是一种有价值的非病毒递送系统，可以保护药物在血液中的稳定性，改善生物分布，并通过表面配体实现靶向选择性来限制副作用。在这种情况下，自杀基因的真正潜力可以转化为对患者具有临床可行性的治疗方法。在本综述中，我们总结了无机纳米粒子作为非病毒载体在治疗效果、靶向能力和安全问题方面的最新进展。我们描述了目前用于治疗的主要自杀基因，特别强调了细菌和植物来源的毒素编码基因。此外，我们还讨论了分子靶向和肿瘤限制表达的重要性，以提高对癌症组织的治疗特异性。最后，我们分析了自杀基因治疗的主要临床应用、局限性和未来展望。
