Innovative Strategy for Treatment of Lung Cancer: Inhalatory Codelivery of Anticancer Drugs and siRNA for Suppression of Cellular Resistance

摘要

One of the main reasons for the poor survival rates among patients with lung cancer is the limited efficiency of traditional chemotherapy. The conventional treatments use high doses of toxic anticancer drugs which often produce severe adverse side effects on healthy organs 1. Hence, an ideal anticancer therapy would involve the local administration of high drug concentration directly to the target tissue for the maximum treatment effect, limitation of drug degradation in the systemic circulation and low adverse side effects 2. For lung diseases, aerosol technology had been developed to achieve this objective. However, the efficient aerosolized drug transfer is possible only for a limited number of drugs. In addition, the efficacy of chemotherapy is also limited by the rapid development of tumor resistance. The mechanisms of this resistance are common to most cancers and include pump and nonpump resistance 2. Therefore, only simultaneous suppression of both pump and nonpump resistances is capable of substantial increasing in the efficacy of anticancer drugs. Consequently, the main objective of the proposed research is to mitigate resistance of lung cancer to chemotherapy through the development, characterization and in vivo evaluation of a novel drug delivery system (DDS) for inhalation therapy which contains five main components: (1) nanocarrier; (2) anticancer drugs; (3) suppressor of pump drug resistance; (4) suppressor of nonpump cellular resistance and (5) targeting moiety to the lung cancer cells. The nanomedicine platform based on Mesoporous Silica Nanoparticles (MSNs) has been developed for inhalation local delivery of anticancer drugs such as Doxorubicin (DOX) and Cisplatin (CIS) in combination with MRP1 and BCL2 targeted siRNAs as suppressors of cellular resistance, respectively. Thiol- functionalized MSNs were synthesized by using a surfactant-templated, base- catalyzed condensation method by following post-modification of particle surface.