Inhalation delivery has been recognized as an attractive approach for the pulmonary delivery of drugs to treat asthma, cystic fibrosis and emphysema. Inhalation approaches like metered dose inhalers (mdI) or nebulization of drug containing liposomes (NDL) can also be utilized to deliver anticancer drugs and chemopreventive agents to lungs for the treatment of lung cancer. The long-term objective of this proposal is to develop appropriate inhalation drug delivery systems for novel anticancer drugs, such that their therapeutic benefit can be significantly improved. This proposal aims to identify the most optimal inhalation delivery approach (mdI or NDL) to be adapted for the delivery of two anticancer drugs, gemcitabine and taxotere intended for the treatment of lung cancer. The experiments proposed to achieve this objective are a) to formulate gemcitabine and taxotere in mdI using hydrofluoroalkane-134a and into liposomes using various phospholipids, b) to evaluate the formulations for their aerosol properties such as medication delivery and mass median aerodynamic diameter by using an Andersen Cascade Impactor, c) to assess the in vitro cytotoxicity of aerosolized anticancer drugs against human lung cancer cell lines, A549, NCI 460 and L2987 using a six-stage viable impactor, d) to determine the pharmacokinetics of the aerosolized drug in BALB/c mice and e) to determine pulmonary toxicity and antitumor efficacy of mdI and NDL in BALB/c mice and SCID mice with lung tumor (developed by i.v. administration of human A549 tumor cells), respectively. A nose-only exposure system will be used for the aerosol exposure to mice in experiments as mentioned in d) and e). The antitumor efficacy of aerosolized drug will be determined with respect to the control (untreated) and compared with that of parenteral administration by determination of the number of visible lung tumors, microscopic lung colonies and presence of apoptotic cells. The results emanating from these studies will help us to identify the most optimal formulation (mdI or NDL) for the treatment of lung cancer.
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