Strategy to enhance lung cancer treatment by five essential elements: inhalation delivery, nanotechnology, tumor-receptor targeting, chemo- and gene therapy
Strategy to enhance lung cancer treatment by five essential elements: inhalation delivery, nanotechnology, tumor-receptor targeting, chemo- and gene therapy
复制标题
DOI：
10.7150/thno.39816
复制
发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Minko, Tamara
中科院分区：
文献类型：
--
作者：
Garbuzenko, Olga B.;Kuzmov, Andriy;Minko, Tamara
非小细胞肺癌（NSCLC）是最常见的肺癌类型（占所有病例的80%以上）。作用于表皮生长因子受体（EGFR）的小分子酪氨酸激酶（TK）抑制剂是携带EGFR-TK受体致敏突变的NSCLC患者的标准治疗。然而，只有不到10%的NSCLC患者从这种治疗中获益。此外，即使是最新一代的EGFR抑制剂也可能导致严重的全身毒性，并且在预防非典型EGFR信号传导方面无效。为了最小化甚至克服这些限制，我们提出了一种新的多层生物技术治疗方法，包括：（1）通过一组小干扰RNA（siRNA）抑制所有四种类型的EGFR-TK;（2）通过抗癌药物诱导细胞死亡，（3）通过将治疗剂直接局部吸入递送至肺来提高治疗效率（被动靶向），（4）主动受体介导的治疗特异性靶向癌细胞，这反过来应使治疗的不良副作用最小化，和（5）通过使用肿瘤靶向纳米结构脂质载体（NLC）增加siRNA和药物的稳定性、溶解度和细胞渗透。通过合成的促黄体激素释放激素（LHRH）十肽靶向NSCLC细胞的NLC用于同时递送紫杉醇（TAX）和靶向EGFR-TK的四种主要形式的siRNA库。LHRH-NLC-siRNAs-TAX纳米粒的合成、表征和体外测试使用对吉非替尼具有不同敏感性的人肺癌细胞（EGFR的抑制剂）和在原位NSCLC小鼠模型上的体内研究。提出的含有抗癌药物的基于纳米颗粒的复合物，靶向肿瘤特异性受体的不同类型EGFR-TK和肽的抑制剂当与通过单一药物、一种EGFR-TK的抑制剂和非靶向治疗的治疗相比时，LHRH-NLC-siRNA-TAX显示有利的器官分布和上级抗癌效果。多功能NLC递送系统的使用大大提高了NSCLC治疗的效率，并可能限制治疗的不良副作用。所获得的结果有可能显著影响药物递送领域，并提高肺癌和其他类型癌症的治疗效率。
Non-Small Cell Lung Carcinoma (NSCLC), is the most common type of lung cancer (more than 80% of all cases). Small molecule Tyrosine Kinase (TK) Inhibitors acting on the Epidermal Growth Factor Receptors (EGFRs) are standard therapies for patients with NSCLC harboring EGFR-TK inhibitor-sensitizing mutations. However, fewer than 10 % of patients with NSCLC benefit from this therapy. Moreover, even the latest generation of EGFR inhibitors can cause severe systemic toxicities and are ineffective in preventing non-canonical EGFR signaling. In order to minimize and even overcome these limitations, we are proposing a novel multi-tier biotechnology treatment approach that includes: (1) suppression of all four types of EGFR-TKs by a pool of small interfering RNAs (siRNAs); (2) induction of cell death by an anticancer drug, (3) enhancing the efficiency of the treatment by the local inhalation delivery of therapeutic agents directly to the lungs (passive targeting), (4) active receptor-mediated targeting of the therapy specifically to cancer cells that in turn should minimize adverse side effects of treatment and (5) increasing the stability, solubility, and cellular penetration of siRNA and drug by using tumor targeted Nanostructured Lipid Carriers (NLC).Methods: NLCs targeted to NSCLC cells by a synthetic Luteinizing Hormone-Releasing Hormone (LHRH) decapeptide was used for the simultaneous delivery of paclitaxel (TAX) and a pool of siRNAs targeted to the four major forms of EGFR-TKs. LHRH-NLC-siRNAs-TAX nanoparticles were synthesized, characterized and tested in vitro using human lung cancer cells with different sensitivities to gefitinib (inhibitor of EGFR) and in vivo on an orthotopic NSCLC mouse model.Results: Proposed nanoparticle-based complex containing an anticancer drug, inhibitors of different types of EGFR-TKs and peptide targeted to the tumor-specific receptors (LHRH-NLC-siRNAs-TAX) demonstrated a favorable organ distribution and superior anticancer effect when compared with treatment by a single drug, inhibitor of one EGFR-TK and non-targeted therapy.Conclusions: The use of a multifunctional NLC-based delivery system substantially enhanced the efficiency of therapy for NSCLC and possibly will limit adverse side effects of the treatments. The results obtained have the potential to significantly impact the field of drug delivery and to improve the efficiency of therapy of lung and other types of cancer.