Inhalation delivery of topotecan is superior to intravenous exposure for suppressing lung cancer in a preclinical model

Intravenous (IV) topotecan is approved for the treatment of various malignancies including lung cancer but its clinical use is greatly undermined by severe hematopoietic toxicity. We hypothesized that inhalation delivery of topotecan would increase local exposure and efficacy against lung cancer while reducing systemic exposure and toxicity. These hypotheses were tested in a preclinical setting using a novel inhalable formulation of topotecan against the standard IV dose. Respirable dry-powder of topotecan was manufactured through spray-drying technology and the pharmacokinetics of 0.14 and 0.79 mg/kg inhalation doses were compared with 0.7 mg/kg IV dose. The efficacy of four weekly treatments with 1 mg/kg inhaled vs. 2 mg/kg IV topotecan were compared to untreated control using an established orthotopic lung cancer model for a fast (H1975) and moderately growing (A549) human lung tumors in the nude rat. Inhalation delivery increased topotecan exposure of lung tissue by approximately 30-fold, lung and plasma half-life by 5- and 4-folds, respectively, and reduced the maximum plasma concentration by 2-fold than the comparable IV dose. Inhaled topotecan improved the survival of rats with the fast-growing lung tumors from 7 to 80% and reduced the tumor burden of the moderately-growing lung tumors over 5- and 10-folds, respectively, than the 2-times higher IV topotecan and untreated control (p

静脉注射（Intravenous, IV）拓扑替康已获批用于治疗包括肺癌在内的多种恶性肿瘤，但其严重的造血系统毒性极大限制了临床应用。本研究提出如下假说：采用吸入递送（inhalation delivery）拓扑替康，可提升其肺部局部暴露量与抗肺癌疗效，同时降低全身暴露与毒性。该假说通过临床前实验得以验证：我们采用一种新型可吸入拓扑替康制剂，与标准静脉注射剂量开展对照研究。通过喷雾干燥（spray-drying）技术制备了可吸入干粉（respirable dry-powder）拓扑替康，并比较了0.14、0.79 mg/kg吸入给药剂量与0.7 mg/kg静脉注射剂量的药代动力学（pharmacokinetics）特征。我们采用已建立的原位肺癌模型（orthotopic lung cancer model），以裸鼠为实验对象，分别针对增殖快速的H1975细胞与增殖中等的A549细胞来源的人源肺癌移植瘤，对比了每周给药1次、共4次的1 mg/kg吸入给药组与2 mg/kg静脉给药组的疗效，并以未给药对照组作为参照。与相当剂量的静脉给药组相比，吸入给药使肺部组织中拓扑替康的暴露量提升约30倍，肺组织与血浆中的半衰期分别延长5倍与4倍，同时使血浆最大药物浓度降低2倍。相较于给药剂量为其2倍的静脉给药组与未给药对照组，吸入拓扑替康可将增殖快速型肺癌模型大鼠的生存率从7%提升至80%，并分别使增殖中等型肺癌模型的肿瘤负荷降低5倍与10倍以上(p