DRUG DELIVERY-SUBPRO:INHALATION DELIVERY FOR THE TREATMENT OF LUNG CANCER

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。塞来昔布（Cel）是一种有效的选择性环氧化酶-2 （Cox-2）抑制剂，在临床前研究中已显示出口服给药时与抗癌药物具有抗肿瘤和协同抗肿瘤作用。然而，到目前为止，还没有关于Cel吸入给药的研究。我们的假设是：a)吸入给药细胞将与静脉给药多西紫杉醇在肺癌治疗中提供协同抗肿瘤作用；b)吸入细胞联合静脉注射多西紫杉醇的抗肿瘤效果将大于口服细胞或联合静脉注射多西紫杉醇。适用于检验这些假设的实验设计是：a)使用氢氟烷烃（HFA） 134a和227将Cel配制成计量吸入器（mdI）；B)评估其气动特性的公式；c)评估雾化细胞单独和与无毒浓度的多西紫杉醇联合使用对肺癌细胞系A549和NCI H460的体外细胞毒性；d)研究雾化细胞在BALB/c小鼠肺药代动力学和吸入毒性；e)评价雾化细胞增强静脉给药多西紫杉醇对肺肿瘤SCID小鼠抗肿瘤作用的潜力。我们的结果表明，Cel可以配制成MDI，提供230 ？G /次，50.7%的剂量是可呼吸的，由8级级冲击器确定。此外，该制剂的两次注射被发现显著增强了A549细胞在第5和第6期的多西他赛活性。我们的研究证明了雾化细胞增强多西紫杉醇细胞毒性的潜力，目前正在进行仅鼻腔雾化室的研究，以确定肺药代动力学。此外，将在荷瘤小鼠中进行研究，以研究雾化细胞对多西紫杉醇体内细胞毒性增强的有效性。

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.