Inhalation delivery dramatically improves the efficacy of topotecan for the treatment of local and distant lung cancer

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.

Keywords: EGFR mutant; KRAS; Topoisomerase inhibitor; aerosol; chemotherapy; dry powder; inhalation therapy; non-small cell lung cancer.

MeSH terms

  • Administration, Inhalation
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical
  • Genes, erbB-1 / genetics
  • Half-Life
  • Humans
  • Lung Neoplasms / drug therapy*
  • Metabolic Clearance Rate
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Topoisomerase I Inhibitors / administration & dosage
  • Topoisomerase I Inhibitors / pharmacokinetics
  • Topoisomerase I Inhibitors / pharmacology*
  • Topotecan / administration & dosage
  • Topotecan / pharmacokinetics
  • Topotecan / pharmacology*
  • Tumor Burden
  • Xenograft Model Antitumor Assays


  • KRAS protein, human
  • Topoisomerase I Inhibitors
  • Topotecan
  • Proto-Oncogene Proteins p21(ras)