9-Nitrocamptothecin liposome aerosol treatment of human cancer subcutaneous xenografts and pulmonary cancer metastases in mice.
The purpose of this study was to test the anticancer properties of the water-insoluble derivative of camptothecin, 9-nitrocamptothecin (9NC), administered in a liposome formulation (L-9NC) in aerosol to mice with subcutaneous xenografts of three human cancers and in mice with murine melanoma and human osteosarcoma pulmonary metastases. The drug was formulated with dilauroylphosphatidylcholine and nebulized in particle sizes of 1.2-1.6 microns mass median aerodynamic diameter and a geometric standard deviation of 2.0. The aerosol was generated with the nebulizer flowing at 10 l/min and delivered to mice in sealed plastic cages or in a nose-only exposure chamber. Aerosol was administered for 15 min to 2 hr daily, delivering deposited doses in the respiratory tract of 8.1-306.7 micrograms of 9NC/kg. With subcutaneous tumors, growth was greatly inhibited or tumors were undetectable after several weeks of treatment. We also showed that oral dosage with L-9NC had no detectable effect on cancer growth, and thus the benefit from aerosol treatment was due to pulmonary deposition and not the larger fraction of drug deposited in the nose of mice during aerosol treatment which is promptly swallowed. Intramuscular L-9NC in slightly larger doses than given in the aerosol had detectable anticancer activity, but it was significantly less than in mice receiving the drug by aerosol. With metastatic pulmonary cancers, treated animals showed highly significantly less cancer growth than control animals. L-9NC aerosol showed a major therapeutic benefit in the treatment of subcutaneous human cancer xenografts in nude mice, suggesting that cancers at systemic sites might be responsive to this treatment. In addition, the strong anticancer effect of L-9NC aerosol on pulmonary metastases offers a therapeutic approach for treatment of pulmonary cancers. Thus, L-9NC aerosol may have applicability in the treatment of cancers throughout the body.
Knight
V
V
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Kleinerman
E S
ES
Waldrep
J C
JC
Giovanella
B C
BC
Gilbert
B E
BE
Koshkina
N V
NV
D000336:Aerosols; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000737:chemistry; D003110:Colonic Neoplasms / Q000188:drug therapy; D004337:Drug Carriers; D005260:Female; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008854:Microscopy, Electron; D012516:Osteosarcoma / Q000188:drug therapy / Q000556:secondary; D010316:Particle Size; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
D000336:Aerosols; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D010713:Phosphatidylcholines; C015153:1,2-dilauroylphosphatidylcholine; C079905:rubitecan; D002166:Camptothecin