Nascimento Ana Vanessa, Singh Amit, Bousbaa Hassan, Ferreira Domingos, Sarmento Bruno, Amiji Mansoor M
CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, Portugal; Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Portugal; Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, USA; I3S, Instituto de Investigação e Inovação em Saúde and INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Portugal.
Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, USA.
Acta Biomater. 2017 Jan 1;47:71-80. doi: 10.1016/j.actbio.2016.09.045. Epub 2016 Sep 30.
Efficiency of chemotherapy is often limited by low therapeutic index of the drug as well as emergence of inherent and acquired drug resistance in cancer cells. As a common strategy to overcome drug resistance, higher doses of chemo-agents are administered. However, adverse side effects are usually increased as a consequence. A potentially effective approach is to combine chemotherapy with other therapeutic strategies such as small interfering RNAs (siRNAs) that allow the use of lower yet efficient doses of the anticancer drugs. We previously developed epidermal growth factor receptor (EGFR)-targeted chitosan (CS) nanoparticles as a versatile delivery system for silencing the essential mitotic checkpoint gene Mad2, and induce cell death. Here, we tested this system as a single therapy and in combination with cisplatin in cisplatin sensitive and resistant lung cancer models, and characterized its in vivo efficacy and safety. Combination treatment resulted in significant improvement in tumor inhibition that was strikingly more effective in cisplatin-resistant tumors. Importantly, effective cisplatin dosage was dramatically reduced in the co-therapy regimen resulting in negligible toxic effects from the drug as confirmed by parameters such as body weight gain, biochemical markers of hepatic and renal function, and histopathology of liver/kidney/spleen tissues. Overall, we demonstrate that the combination of Mad2 siRNA-loaded CS nanoparticles strategy with chemotherapeutic agents such as cisplatin constitutes an efficient and safe approach for the treatment of drug resistant tumors.
Lung cancer remains one of the leading killers in the United States and around the world. Platinum agents, including cisplatin, are the first line treatment in lung cancer, including non-small cell lung cancer (NSCLC), which is the predominant form of lung cancer. In this study, we have evaluated Mad2 cell-cycle checkpoint gene silencing using small interfering RNA (siRNA) delivered systemically using epidermal growth factor receptor-targeted chitosan nanoparticles in drug sensitive and resistant models of NSCLC. Our results show that Mad2 gene silencing using targeted chitosan nanoparticles has tremendous potential in overcoming platinum resistance in NSCLC.
化疗的效率常常受到药物治疗指数低以及癌细胞中固有和获得性耐药性出现的限制。作为克服耐药性的常见策略，会给予更高剂量的化疗药物。然而，结果通常是副作用增加。一种潜在有效的方法是将化疗与其他治疗策略相结合，如小干扰RNA（siRNA），这使得可以使用更低但有效的抗癌药物剂量。我们之前开发了表皮生长因子受体（EGFR）靶向的壳聚糖（CS）纳米颗粒，作为一种通用的递送系统，用于沉默关键的有丝分裂检查点基因Mad2，并诱导细胞死亡。在此，我们在顺铂敏感和耐药肺癌模型中测试了该系统作为单一疗法以及与顺铂联合使用的效果，并对其体内疗效和安全性进行了表征。联合治疗导致肿瘤抑制有显著改善，在顺铂耐药肿瘤中效果尤为显著。重要的是，在联合治疗方案中，有效顺铂剂量大幅降低，从体重增加、肝肾功能生化标志物以及肝/肾/脾组织的组织病理学等参数证实，药物的毒性作用可忽略不计。总体而言，我们证明了负载Mad2 siRNA的CS纳米颗粒策略与顺铂等化疗药物联合使用，是一种治疗耐药肿瘤的高效且安全方法。
肺癌在美国和全球仍然是主要杀手之一。包括顺铂在内的铂类药物是肺癌（包括非小细胞肺癌（NSCLC），肺癌的主要形式）的一线治疗药物。在本研究中，我们评估了在NSCLC的药物敏感和耐药模型中，使用表皮生长因子受体靶向的壳聚糖纳米颗粒全身递送小干扰RNA（siRNA）对Mad2细胞周期检查点基因的沉默作用。我们的结果表明，使用靶向壳聚糖纳米颗粒沉默Mad2基因在克服NSCLC铂耐药性方面具有巨大潜力。
