Molecular Targeting of Drug Delivery System to Cancer

描述（由申请人提供）：肺癌是美国癌症死亡的主要原因。小细胞肺癌是最具侵袭性的肺癌类型，死亡率高。由于小肺癌的大小和分布，细胞减少手术对这种疾病不是很有效，因此化疗和/或放疗是治疗的选择。然而，化疗对肺癌的疗效受到治疗过程中癌细胞耐药性快速发展的限制。耐药性的发展需要显著增加有毒抗癌药物的剂量，从而对健康器官产生不利的副作用。观察到的阻力有两种主要机制：泵阻力和非泵阻力。泵阻力是由降低细胞内抗癌药物浓度的膜外排泵引起的。导致肺癌细胞泵耐药的主要转运体是所谓的“多药耐药相关蛋白”（MRP）的成员。p -糖蛋白外排泵在肺癌耐药中不起重要作用。非泵耐药主要归因于抗凋亡细胞防御的激活，而BCL2蛋白在这种防御中起关键作用。拟议研究的主要目的是通过开发，制造，表征和体外和体内评估一种新型药物输送系统来减轻上述耐药性，该系统包含四个主要成分：(1)脂质体作为载体；(2)抗癌药（阿霉素）；(3)泵耐药抑制因子（针对MRP1和MRP2蛋白的反义寡核苷酸或siRNA）；(4)抑制非泵细胞抗性（针对BCL2蛋白的反义寡核苷酸或siRNA）。除了同时抑制泵和非泵细胞耐药外，所提出的脂质体给药系统的使用允许将活性成分直接吸入局部递送到肺部，最大限度地减少不良副作用。我们假设同时抑制泵和非泵细胞耐药将显著提高耐药肺癌化疗的疗效。所提出的药物递送系统采用了一种新的双管齐下的分子靶向策略（同时靶向细胞泵和非泵耐药的关键蛋白）。这将使我们能够通过同时抑制泵和非泵耐药来提高癌症化疗的疗效。

DESCRIPTION (provided by applicant): 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 efficacy of 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 efficacy of cancer chemotherapy by simultaneous suppression of pump and nonpump resistance.