寡核苷酸作为细胞耐药性抑制剂的药物复杂肺部递送来抑制肺肿瘤生长。
Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance.
机构信息
Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
出版信息
Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10737-42. doi: 10.1073/pnas.1004604107. Epub 2010 May 24.
Development of cancer cell resistance, low accumulation of therapeutic drug in the lungs, and severe adverse treatment side effects represent main obstacles to efficient chemotherapy of lung cancer. To overcome these difficulties, we propose inhalation local delivery of anticancer drugs in combination with suppressors of pump and nonpump cellular resistance. To test this approach, nanoscale-based delivery systems containing doxorubicin as a cell death inducer, antisense oligonucleotides targeted to MRP1 mRNA as a suppressor of pump resistance and to BCL2 mRNA as a suppressor of nonpump resistance, were developed and examined on an orthotopic murine model of human lung carcinoma. The experimental results show high antitumor activity and low adverse side effects of proposed complex inhalatory treatment that cannot be achieved by individual components applied separately. The present work potentially contributes to the treatment of lung cancer by describing a unique combinatorial local inhalation delivery of drugs and suppressors of pump and nonpump cellular resistance.
癌细胞耐药性的发展、治疗药物在肺部的低积累以及严重的治疗副作用是肺癌化疗效果不佳的主要障碍。为了克服这些困难，我们提出将抗癌药物吸入局部给药与泵和非泵细胞耐药性抑制剂联合使用。为了验证这种方法，我们开发了基于纳米技术的载药系统，其中包含多柔比星作为细胞死亡诱导剂，针对 MRP1 mRNA 的反义寡核苷酸作为泵耐药抑制剂，以及针对 BCL2 mRNA 的非泵耐药抑制剂，并在人肺癌的原位小鼠模型上进行了检测。实验结果表明，所提出的复杂吸入治疗具有高抗肿瘤活性和低不良反应，这是单独使用各个成分无法实现的。本工作通过描述一种独特的联合局部吸入药物和泵及非泵细胞耐药抑制剂的方法，为肺癌的治疗提供了新的思路。
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