Chattopadhyay Sourav, Sarkar Shashanka Shekhar, Saproo Sheetanshu, Yadav Sheetal, Antil Deepika, Das Bodhisatwa, Naidu Srivatsava
Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab, India.
Front Bioeng Biotechnol. 2023 Jun 6;11:1188652. doi: 10.3389/fbioe.2023.1188652. eCollection 2023.
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with resistance to apoptosis being a major driver of therapeutic resistance and aggressive phenotype. This study aimed to develop a novel gene therapy approach for NSCLC by targeting resistance to apoptosis. Loss of function mutations of caspase 8 (CASP8) and downregulation of microRNAs (miRs) 29A-B1 and 34A were identified as key contributors to resistance to apoptosis in NSCLC. A biodegradable polymeric nano-gene delivery system composed of chitosan-poly-lactic-co-glycolic acid was formulated to deliver initiator CASP8 and miRs 29A-B1 and 34A. The nano-formulation efficiently encapsulated the therapeutic genes effectively internalized into NSCLC cells and induced significant apoptosis. Evaluation of the nano-formulation in A549 tumor spheroids showed a significant increase in apoptosis within the core of the spheroids, suggesting effective penetration into the spheroid structures. We provide a novel nano-formulation that demonstrate therapeutic potential for suicidal gene therapy in NSCLC.
非小细胞肺癌（NSCLC）是全球癌症相关死亡的主要原因，对细胞凋亡的抗性是治疗抗性和侵袭性表型的主要驱动因素。本研究旨在通过靶向细胞凋亡抗性来开发一种用于NSCLC的新型基因治疗方法。半胱天冬酶8（CASP8）的功能丧失突变以及微小RNA（miR）29A-B1和34A的下调被确定为NSCLC中细胞凋亡抗性的关键因素。制备了一种由壳聚糖-聚乳酸-乙醇酸组成的可生物降解聚合物纳米基因递送系统，以递送起始因子CASP8以及miR 29A-B1和34A。该纳米制剂有效地包裹了治疗基因，有效地内化到NSCLC细胞中并诱导了显著的细胞凋亡。在A549肿瘤球体中对该纳米制剂的评估显示，球体核心内的细胞凋亡显著增加，表明其有效地渗透到球体结构中。我们提供了一种新型纳米制剂，证明了其在NSCLC自杀基因治疗中的治疗潜力。
