Kallu Jyothi, Banerjee Tuhina, Sulthana Shoukath, Darji Saloni, Higginbotham Ryan, Fletcher Christina, Gerasimchuk Nikolay N, Santra Santimukul
Department of Chemistry, Pittsburg State University, 1701 S. Broadway Street, Pittsburg, Kansas 66762, United States.
Department of Chemistry, Missouri State University, 901 S. National Ave, Springfield, Missouri 65897, United States.
Nanotheranostics. 2019 Feb 11;3(1):120-134. doi: 10.7150/ntno.28468. eCollection 2019.
K-RAS is the most common mutated oncogene associated with Non-Small-Cell Lung Cancer (NSCLC). So far, there are no promising chemotherapies for the direct inhibition of K-RAS, and considered to be undruggable. In this work, we have introduced a new platinum-based cyanoximate complex, Pt(MCO) as an anti-cancer drug to enhance the therapeutic efficacy of Hsp90 inhibitor drug, ganetespib for the combination therapy of NSCLC. We have synthesized polyacrylic acid (PAA)-coated magnetic nanoparticles (MNPs) and used as drug delivery system. These MNPs were decorated with folic acid in order to target folate receptor-expressing NSCLC. The individual and combination of drugs as well as an optical dye DiI were co-encapsulated successfully inside the PAA-coating of MNPs to evaluate synergistic treatment option for NSCLC. The magnetic resonance (MR) and optical imaging modalities assisted for the monitoring drug loading and NSCLC treatment. To evaluate the therapeutic efficacy of these customized MNPs, various cell-based assays including cell viability, apoptosis and necrosis, cell migration, comet and ROS experiments were performed. Results showed minimal toxicity for functional MNPs with no therapeutic drug and more than 60% cell death within 48 h of treatment, when single drug was encapsulated. Importantly, more than 90% cells were dead when both drugs were delivered. Overall, the results indicated that the Pt(MCO) drug enhances the therapeutic efficacy of ganetespib by more than 30% toxicity towards the targeted treatment of NSCLC, while showed minimal toxicity to the normal healthy tissues. We successfully developed new dual-modal magnetic nanomedicines for the rapid and controlled release of combination of drugs for the effective treatment of NSCLC. The MR and fluorescence modalities help monitoring the delivery of drugs, where the new platinum-based drug Pt(MCO) synergizes the therapeutic efficacy of ganetespib.
K-RAS是与非小细胞肺癌（NSCLC）相关的最常见的突变致癌基因。到目前为止，尚无用于直接抑制K-RAS的有前景的化疗方法，并且认为其难以成药。在这项工作中，我们引入了一种新的基于铂的肟腈配合物Pt(MCO)作为抗癌药物，以增强热休克蛋白90（Hsp90）抑制剂药物ganetespib对NSCLC联合治疗的疗效。我们合成了聚丙烯酸（PAA）包覆的磁性纳米颗粒（MNP）并用作药物递送系统。这些MNP用叶酸修饰，以靶向表达叶酸受体的NSCLC。将药物的单独使用和联合使用以及一种光学染料DiI成功地共包封在MNP的PAA涂层内，以评估NSCLC的协同治疗方案。磁共振（MR）和光学成像方式有助于监测药物负载和NSCLC治疗。为了评估这些定制MNP的治疗效果，进行了各种基于细胞的试验，包括细胞活力、凋亡和坏死、细胞迁移、彗星实验和活性氧（ROS）实验。结果显示，对于没有治疗药物的功能性MNP毒性最小，当包封单一药物时，在治疗48小时内细胞死亡超过60%。重要的是，当两种药物都递送时，超过90%的细胞死亡。总体而言，结果表明Pt(MCO)药物对NSCLC的靶向治疗毒性增强了ganetespib的治疗效果30%以上，同时对正常健康组织显示出最小的毒性。我们成功开发了新型双模态磁性纳米药物，用于快速和可控地释放联合药物，以有效治疗NSCLC。MR和荧光方式有助于监测药物递送，其中新型基于铂的药物Pt(MCO)增强了ganetespib的治疗效果。
