This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Celecoxib (Cel) is a potent and selective cyclooxygnease-2 (Cox-2) inhibitor that has been shown to exert antitumor and synergistic antitumor effect with anticancer drugs in preclincal studies, when administered by oral route. However, no study has been done for the inhalation delivery of Cel so far. Our hypotheses are: a) inhalation delivery of Cel will provide a synergistic antitumor effect with intravenous administration of docetaxel in the treatment of lung cancer; and b) the antitumor effect of the inhaled Cel along with intravenous docetaxel will be greater than either oral Cel or its combination with intravenous docetaxel. The experimental design adapted to test these hypotheses are: a) to formulate Cel into metered dose inhaler (mdI) using hydrofluoralkane (HFA) 134a and 227; b) to evaluate the formulations for their aerodynamic characteristics; c) to assess the in-vitro cytotoxicity of aerosolized Cel alone and in combination with a non-toxic concentration of docetaxel against lung cancer cell lines A549 and NCI H460; d) to study the pulmonary pharmacokinetics and inhalation toxicity of aerosolized Cel in BALB/c mice and e) to evaluate the potential of aerosolized Cel to enhance the antitumor effect of intravenously administered docetaxel in SCID mice with lung tumors. Our results indicate that Cel could be formulated into MDI delivering 230 ?g/shot with 50.7% of dose being respirable as determined by an eight-stage cascade impactor. Further, two shots of this formulation was found to significantly enhance the docetaxel activity in A549 cells on fifth and sixth stages of the viable impactor. Our studies demonstrate the potential of aerosolized Cel for enhancing the docetaxel cytotoxicity and currently studies are in progress with the nose-only aerosol chamber to determine the pulmonary pharmacokinetics. Further, studies will be conducted in tumor bearing mice to investigate the usefulness of aerosolized Cel for in-vivo cytotoxicity enhancement of docetaxel.
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