title: Nebulized interleukin 2 liposomes: aerosol characteristics and biodistribution.
abstract: Although interleukin 2 (IL-2) has been associated with modest anti-tumour responses in man, treatment-related toxicity has limited its widespread use. The local delivery of liposomal formulations of interleukin 2 to the lung as aerosols has been demonstrated to be non-toxic, biologically active, and associated with regression of spontaneous pulmonary metastases in dogs. This study was undertaken to evaluate the physical and biological characteristics of nebulized interleukin 2 liposomes. The aerosol droplet size distribution and the physical stability of interleukin 2 liposomes were examined in-vitro using an Andersen cascade impactor and studies of liposome entrapment of interleukin 2 before and after nebulization. The biological stability of interleukin 2 liposomes after nebulization was demonstrated using the CTLL-2 bioassay for interleukin 2. In-vivo studies of pulmonary biodistribution and clearance of inhaled technetium (99mTc)-labelled interleukin 2 liposomes were undertaken in a normal dog. Aerosols of free interleukin 2 and of interleukin 2 liposomes were compared in both in-vitro and in-vivo experiments. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of interleukin 2 liposomes were 1.98 microns and 2.02, respectively. Independent analysis of aerosol particle-size distribution using the constitutive components of the interleukin 2 liposomes (interleukin 2: lipid:HSA) demonstrated a close correlation of size distributions (r = 0.9445; P < 0.001). The entrapment of interleukin 2 in liposomes was 93 +/- 4.3% before nebulization and 90 +/- 8.9% after. After delivery to an anaesthetized dog, interleukin 2 liposome aerosols were deposited evenly throughout the lung (mean +/- s.d. central lung-to-peripheral lung deposition was 1.12 +/- 0.03). After approximately 24 h inhalation, interleukin 2 liposomes were retained within the lung and were taken up in part by the spleen. The results of this study are indicative of the stability of this interleukin 2 liposome formulation to nebulization. Such nebulization might be an attractive immunotherapeutic strategy for treatment of pulmonary metastases and primary lung cancers.
authors.affiliation: Department of Small Animal Clinical Sciences, University of Minnesota, St. Paul, USA.
authors.forename: C
authors.initials: C
authors.lastname: Khanna
authors.forename: J C
authors.initials: JC
authors.lastname: Waldrep
authors.forename: P M
authors.initials: PM
authors.lastname: Anderson
authors.forename: R W
authors.initials: RW
authors.lastname: Weischelbaum
authors.forename: D E
authors.initials: DE
authors.lastname: Hasz
authors.forename: E
authors.initials: E
authors.lastname: Katsanis
authors.forename: J S
authors.initials: JS
authors.lastname: Klausner
mesh_terms: D000336:Aerosols; D000818:Animals; D004285:Dogs; D004337:Drug Carriers; D004355:Drug Stability; D005260:Female; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D008081:Liposomes; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D010316:Particle Size; D011877:Radionuclide Imaging; D017556:Technetium Compounds / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D000336:Aerosols; D004337:Drug Carriers; D007376:Interleukin-2; D008081:Liposomes; D017556:Technetium Compounds