The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, MD 21287, USA.
Mol Cancer Ther. 2013 Apr;12(4):405-15. doi: 10.1158/1535-7163.MCT-12-0956. Epub 2013 Jan 30.
Small cell lung cancer (SCLC) is an aggressive disease with one of the highest case-fatality rates among cancer. The recommended therapy for SCLCs has not changed significantly over the past 30 years; new therapeutic approaches are a critical need. TP53 is mutated in the majority of SCLC cases and its loss is required in transgenic mouse models of the disease. We synthesized an array of biodegradable poly(β-amino ester) (PBAE) polymers that self-assemble with DNA and assayed for transfection efficiency in the p53-mutant H446 SCLC cell line using high-throughput methodologies. Two of the top candidates were selected for further characterization and TP53 delivery in vitro and in vivo. Nanoparticle delivery of TP53 resulted in expression of exogenous p53, induction of p21, induction of apoptosis, and accumulation of cells in sub-G1 consistent with functional p53 activity. Intratumoral injection of subcutaneous H446 xenografts with polymers carrying TP53 caused marked tumor growth inhibition. This is the first demonstration of TP53 gene therapy in SCLC using nonviral polymeric nanoparticles. This technology may have general applicability as a novel anticancer strategy based on restoration of tumor suppressor gene function.
小细胞肺癌（SCLC）是一种侵袭性疾病，其病死率在所有癌症中位居前列。过去 30 年来，SCLC 的推荐疗法并未发生显著变化，因此急需新的治疗方法。大多数 SCLC 病例都存在 TP53 突变，而且在疾病的转基因小鼠模型中需要丢失该基因。我们合成了一系列可生物降解的聚（β-氨基酸酯）（PBAE）聚合物，这些聚合物可与 DNA 自组装，并使用高通量方法在 p53 突变的 H446 SCLC 细胞系中检测转染效率。选择了两种最优秀的候选物进行进一步的特性分析和体外及体内的 TP53 传递。TP53 的纳米颗粒传递导致外源性 p53 的表达、p21 的诱导、细胞凋亡的诱导以及与功能性 p53 活性一致的亚 G1 期细胞的积累。携带 TP53 的聚合物对皮下 H446 异种移植物的瘤内注射导致明显的肿瘤生长抑制。这是首次使用非病毒聚合物纳米颗粒在 SCLC 中进行 TP53 基因治疗的证明。该技术可能具有广泛的适用性，可作为一种基于恢复肿瘤抑制基因功能的新型抗癌策略。
