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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。塞来昔布(Celecoxib，CEL)是一种高效、选择性的环氧合酶-2(COX-2)抑制剂，临床前研究表明，口服给药具有抗肿瘤及与抗癌药物协同抗肿瘤作用。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)CEL吸入给药与静脉注射多西紫杉醇在肺癌治疗中具有协同抗肿瘤作用；b)吸入CEL与静脉注射多西紫杉醇的抗肿瘤作用将大于口服CEL或其与静脉注射多西紫杉醇的联合作用。适合验证这些假设的实验设计为：a)使用氢氟烷烃(HFA)134a和227将CEL配制成计量吸入器(MDI)；b)评估各制剂的空气动力学特性；c)评估雾化CEL单独以及与无毒浓度的多西紫杉醇联合使用对肺癌A549和NCI H460细胞的体外细胞毒性；d)研究CEL雾化吸入对BALB/c小鼠的肺部药代动力学和吸入毒性；e)评价雾化CEL增强多西紫杉醇静脉滴注抗肺癌作用的潜力。我们的结果表明，CEL可以配制成MDI，其剂量为230g/次，其中50.7%的剂量是可呼吸的，由八级级联撞击器测定。此外，该配方的两针被发现显著增强了活着冲击器第五和第六阶段A549细胞中的多西紫杉醇活性。我们的研究证实了雾化CEL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小室的研究，以确定肺部的药代动力学。此外，还将在荷瘤小鼠中进行研究，以探讨雾化CEL在增强多西紫杉醇体内细胞毒性方面的有效性。

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.