Molecular Targeting of Drug Delivery System to Cancer

肺癌是美国癌症死亡的主要原因。小细胞肺癌最具侵袭性 肺癌是肺癌的一种类型，是导致高死亡率的原因。由于小肺癌的大小和分布， 细胞减灭术对这种疾病不是非常有效，因此化疗和/或放疗是治疗的主要手段。 选择治疗。然而，肺癌的快速发展限制了化疗的疗效 治疗过程中的细胞阻力。抗药性的产生需要大幅度增加有毒物质的剂量 抗癌药物，从而对健康器官产生不利的副作用。两个主要机制负责 观察到的阻力：泵和非泵阻力。泵阻力是由膜外排泵引起的， 降低细胞内的抗癌药物浓度。负责泵阻力的主要运输者 在肺癌细胞中，最常见的是所谓的“多药耐药相关蛋白”（MRP）。p-gp糖 外排泵在肺癌耐药中不起重要作用。非泵耐药主要归因于 BCL 2蛋白在抗凋亡细胞防御中起关键作用。 拟议研究的主要目标是通过开发， 制备、表征以及体外和体内评价一种新的药物递送系统，其包含四种 主要成分：（1）脂质体作为载体;（2）抗癌药物（阿霉素）;（3）泵耐药抑制剂 （4）非泵细胞的抑制因子， 抗性（靶向BCL 2蛋白的反义寡核苷酸或siRNA）。除了同时 泵和非泵细胞阻力的抑制使用所提出的脂质体药物递送系统允许 将活性成分直接吸入局部递送至肺部，使不良副作用最小化。我们假设 同时抑制泵细胞和非泵细胞阻力将显著增加 耐药肺癌的化疗。 所提出的药物递送系统利用了一种新的双管齐下的分子靶向策略（同时靶向 在细胞泵和非泵阻力中起关键作用的蛋白质）。这将使我们能够提高 通过同时抑制泵和非泵抵抗的癌症化疗。

Lung cancer is the leading cause of cancer death in the United States. Small cell lung carcinoma is the most aggressive type of lung cancer and is responsible for the high mortality. Because of the size and distribution of small lung cancer, cytoreductive surgery is not very effective for this disease and therefore chemotherapy and/or radiation are the treatment of choice. However, the efficacy of chemotherapy in lung cancer is limited by the fast development of cancer cell resistance during the treatment. Development of resistance demands significant increases in the doses of the toxic anticancer drug, thus producing adverse side effects upon healthy organs. Two main mechanisms are responsible for the observed resistance: pump and nonpump resistance. Pump resistance is caused by membrane efflux pumps that decrease the anticancer drug concentration inside the cells. The main transporters responsible for the pump resistance in lung cancer cells are the members of the so-called "multidrug resistance associated proteins" (MRP). P-glycoprotein efflux pump does not play an important role in lung cancer resistance. Nonpump drug resistance is primarily attributed to the activation of antiapoptotic cellular defense and BCL2 protein is a key player in this defense. The main objective of the proposed research is to mitigate the above described resistance through the development, manufacture, characterization and in vitro and in vivo evaluation of a novel drug delivery system which contains four main components: (1) liposomes as a carrier; (2) anticancer drug (doxorubicin); (3) suppressor of pump drug resistance (antisense oligonucleotides or siRNA targeted to MRP1 and MRP2 proteins); (4) suppressor of nonpump cellular resistance (antisense oligonucleotides or siRNA targeted to the BCL2 protein). In addition to the simultaneous suppression of pump and nonpump cellular resistance the use of proposed liposomal drug delivery system allows for inhalatory local delivery of active components directly to the lungs minimizing adverse side effects. We hypothesize that simultaneous suppression of pump and nonpump cellular resistance will significantly increase the efficacyof chemotherapy of resistant lung cancer. The proposed drug delivery system utilizes a novel two-pronged molecular targeting strategy (simultaneous targeting of proteins that are key players in cellular pump and nonpump resistance). This will permit us to increase the efficacyof cancer chemotherapy by simultaneous suppression of pump and nonpump resistance.