Local and Systemic Delivery of the BimS Gene Nano-Complex for Efficient Oral Squamous Cell Carcinoma Therapy.
Local and Systemic Delivery of the BimS Gene Nano-Complex for Efficient Oral Squamous Cell Carcinoma Therapy.
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DOI：
10.2147/ijn.s357702
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发表时间：
2022
影响因子：
8
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口腔鳞状细胞癌（OSCC）是最常见的口腔癌类型，每年新发病例超过30万例。尽管现有的治疗方法取得了进展，包括手术、放疗、化疗和免疫治疗，但总体生存率和预后仍然很差。而基于非病毒载体的基因治疗为口腔鳞癌的治疗提供了新的思路。在这里，我们的目的是制备和描述DOTAP-mPEG-PCL（PEG）的合成，生物安全性和临床前疗效在口腔鳞癌基因治疗。我们制备了一种纳米级的杂化阳离子胶束。通过阳离子脂质DOTAP和mPEG-PCL聚合物的自组装制备了胶束。我们在体外评价了这种阳离子胶束的特性。结合编码诱导肿瘤细胞凋亡的BimS基因，构建了rhBimS/phBimS复合物，并对其体外抗肿瘤作用进行了评价。我们还建立了小鼠舌异种移植物模型，以通过局部和全身给药前瞻性地评估p53/phBimS复合物在体内的抗肿瘤作用。胶束为球形，平均粒径为28.32 ± 3.56 nm，平均zeta电位为43.43 ± 0.82 mV。通过激活脂筏介导的胞吞作用，脂质体介导的胞吞作用可有效地将质粒导入SCC 15细胞（效率为52.07% ± 1.63%），具有较好的生物安全性。在体外，当负载BimS基因后，该复合物可通过凋亡途径抑制SCC 15的增殖（33.9% ± 2.62%）。局部给药后，该复合物对裸鼠舌移植瘤的平均抑瘤率为65.66%。系统给药后，复合物对口腔鳞癌生长有明显的抑制作用，平均抑制率为45.63%（复合物/phBimS），并具有良好的生物相容性。phBimS复合物是口腔鳞癌自杀基因治疗的有效选择。
Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, with more than 300,000 new cases annually. Despite advances in existing treatments, including surgery, radiation, chemotherapy, and immunotherapy, the overall survival and prognosis have remained poor. However, gene therapy based on non-viral vectors provides new ideas for the treatment of OSCC. Here, we aimed to prepare and describe the synthesis, biosafety, and preclinical efficacy of DOTAP-mPEG-PCL (DMP) in OSCC gene therapy. We prepared a nano-sized hybrid cationic micelle DMP. DMP micelles were prepared by self-assembling cationic lipid DOTAP and mPEG-PCL polymer. We evaluated the characteristics of this cationic micelle in vitro. Combined with encoding the apoptosis-inducing BimS gene, we established the DMP/phBimS complex and evaluated its anti-tumor effect in vitro. We also established a mouse tongue xenograft model to evaluate the antitumor effect of the DMP/phBimS complex in vivo through local and systemic administration prospectively. The DMP cationic micelle is spherical in shape, with an average diameter of 28.32 ± 3.56 nm and an average zeta potential of 43.43 ± 0.82 mV. By activation of lipid raft-mediated endocytosis caveolin-mediated endocytosis, DMP could efficiently deliver plasmid into SCC15 cells (efficiency: 52.07% ± 1.63%), with an ideal biosecurity. When loaded by plasmid encoding the apoptosis-inducing BimS gene, the DMP/phBimS complex exhibited an obvious anti-proliferation effect of SCC15 in vitro through the apoptosis pathway (33.9% ± 2.62% apoptosis rate). By local administration, the DMP/phBimS complex showed ideal anti-tumor properties in the nude mouse tongue xenograft model, with an average tumor inhibition rate of 65.66%. Furthermore, through systematic administration, the DMP/phBimS complex obviously inhibited OSCC growth, with an average inhibition rate of 45.63% (DMP/phBimS) and an appropriate biocompatibility. The DMP/phBimS complex is an optional effective option for suicide gene therapy for OSCC.