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 (<i>p</i>

静脉注射（Intravenous, IV）拓扑替康已获批用于包括肺癌在内的多种恶性肿瘤的治疗，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：吸入式递送拓扑替康可提升其肺部局部暴露量与抗肺癌疗效，同时降低全身暴露量及毒性反应。本研究在临床前研究框架下，以标准静脉注射剂量为对照，采用一种新型吸入式拓扑替康制剂对上述假说进行验证。研究通过喷雾干燥技术制备了可吸入式拓扑替康干粉，并对比了0.14 mg/kg、0.79 mg/kg两种吸入剂量与0.7 mg/kg静脉注射剂量的药代动力学特征。本研究利用已构建的裸大鼠原位肺癌模型（分别接种增殖快速的H1975细胞与增殖中等的A549细胞来源的人源肺肿瘤），对比了每周给药1次、连续给药4次的1 mg/kg吸入式拓扑替康与2 mg/kg静脉注射拓扑替康的抗肿瘤疗效，并以未给药组作为空白对照。与等效剂量的静脉注射给药相比，吸入式递送可使肺组织中拓扑替康的暴露量提升约30倍，肺与血浆半衰期分别延长5倍与4倍，同时使血浆峰浓度降低2倍。相较于给药剂量翻倍的静脉注射拓扑替康组与未给药对照组，吸入式拓扑替康可使增殖快速型肺癌模型裸大鼠的生存率从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（<i>p</i>