Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
Lonza-Bend Research Institute, Bend, OR, USA.
Drug Deliv. 2021 Dec;28(1):767-775. doi: 10.1080/10717544.2021.1912209.
Topotecan is potent anti-cancer drug approved for various malignancies but hematopoietic toxicities undermine its wider application and use of its most effective dose. This study aims to improve these limitations through inhalation-delivery. The pharmacokinetics, efficacy, and toxicity of 2-5 times lower inhalation doses of topotecan dry-powder were compared with the standard intravenous (IV) delivery once/twice-a-week. Human-derived EGFR-mutant (H1975), KRAS-mutant (A549), and EGFR/KRAS wild-type (H358) orthotopic and distant lung tumors were evaluated in murine models. Inhalation of 1 mg/kg topotecan significantly improved the half-life and drug exposure (area under the curve, AUC) compared to 5 mg/kg via IV-delivery. AUCs (h*ng/mL) for inhaled/IV topotecan in plasma, lung, liver, and brain were, 831/888, 60,000/1080, 8380/4000, and 297/15, respectively; while the half-life was also greatly increased in these tissues. The average lung tumor burden of H358-derived tumors was reduced from 15.0 g to 8.4 g (44%) in rats treated once-a-week with 2 mg/kg IV and 1.8 g (88%) with 1 mg/kg inhaled topotecan, corroborating previous findings using A549- and H1975-derived orthotopic lung tumors. Importantly, inhaled topotecan showed superior efficacy in suppressing lung tumors at distant sites. The growth of H1975- and H358-derived subcutaneous xenografts were completely arrested and A549-derived tumors were significantly reduced in mice treated twice-a-week with 1 mg/kg inhaled topotecan compared to a minor (H1975 and H358) or no reduction (A549) with twice-a-week 5 mg/kg IV topotecan.
拓扑替康是一种有效的抗癌药物，已批准用于多种恶性肿瘤，但血液系统毒性限制了其更广泛的应用和最有效剂量的使用。本研究旨在通过吸入给药来改善这些局限性。本研究比较了 2-5 倍低剂量的拓扑替康干粉吸入剂与标准的每周一次/两次静脉（IV）给药的药代动力学、疗效和毒性。在人类 EGFR 突变（H1975）、KRAS 突变（A549）和 EGFR/KRAS 野生型（H358）原位和远处肺肿瘤的小鼠模型中评估了吸入 1mg/kg 拓扑替康与 5mg/kg 静脉给药的疗效。与静脉 5mg/kg 相比，吸入 1mg/kg 拓扑替康可显著延长半衰期和药物暴露（AUC）。血浆、肺、肝和脑的吸入/静脉拓扑替康 AUC（h*ng/mL）分别为 831/888、60000/1080、8380/4000 和 297/15，同时这些组织中的半衰期也大大延长。每周一次静脉注射 2mg/kg 和每周一次吸入 1mg/kg 治疗大鼠的 H358 衍生肿瘤的平均肺肿瘤负荷从 15.0g 降低至 8.4g（44%），与先前使用 A549 和 H1975 衍生的原位肺肿瘤的研究结果一致。重要的是，吸入拓扑替康在抑制远处肺肿瘤方面显示出更好的疗效。与每周两次静脉注射 5mg/kg 相比，每周两次吸入 1mg/kg 治疗的 H1975 和 H358 衍生的皮下异种移植物的生长完全被抑制，A549 衍生的肿瘤明显减少。
