Distribution of camptothecin after delivery as a liposome aerosol or following intramuscular injection in mice.
OBJECTIVE
The plant alkaloid camptothecin (CPT) has shown significant antitumor activity against a wide variety of human tumors xenografted in nude mice. In previous studies we have found that administration of dilauroylphosphatidylcholine (DLPC) liposome aerosols containing 9-nitrocamptothecin (9-NC) inhibits the growth of human breast, colon and lung cancer xenografts. The purpose of this study was to analyze the pharmacokinetics and tissue distribution of inhaled CPT formulated in DLPC liposomes.


METHODS
C57BL/6 mice with subcutaneous Lewis lung carcinoma, Swiss nu/nu mice with human lung carcinoma xenografts and BALB/c mice without tumors were used for pharmacokinetic studies of CPT administered as a liposome aerosol and BALB/c mice were given CPT intramuscularly.


RESULTS
After 30 min inhalation of CPT liposome aerosol, drug was deposited in the lungs (310 ng/g) and was followed promptly by the appearance of high concentrations in the liver (192 ng/g) and with lesser amounts appearing in other organs. Drug concentration in the brain was 61 ng/g. After intramuscular injection of CPT dissolved in DMSO, drug was released from the site of injection very slowly and accumulated mainly in the liver (136 ng/g). Only trace amounts appeared in the lungs (2-4 ng/g). These results demonstrate a prompt pulmonary and later systemic distribution of CPT following liposome aerosol administration.


CONCLUSIONS
The substantial concentrations of CPT in lungs and other organs following inhalation of liposome aerosol suggest the possible benefit of it and of its more active derivative, 9-NC, in the treatment of lung, liver, kidney and brain cancer in humans.
Koshkina
N V
NV
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Gilbert
B E
BE
Waldrep
J C
JC
Seryshev
A
A
Knight
V
V
D000336:Aerosols; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004337:Drug Carriers; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010713:Phosphatidylcholines
D000336:Aerosols; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008081:Liposomes; D010713:Phosphatidylcholines; C015153:1,2-dilauroylphosphatidylcholine; D002166:Camptothecin