Title: Biodistribution and renal clearance of biocompatible lung targeted poly(ethylene glycol) (PEG) nanogel aggregates.

Authors: Deshmukh, Manjeet; Kutscher, Hilliard L; Gao, Dayuan; Sunil, Vasanthi R; Malaviya, Rama; Vayas, Kinal; Stein, Stanley; Laskin, Jeffrey D; Laskin, Debra L; Sinko, Patrick J

Published In J Control Release, (2012 Nov 28)

Abstract: A novel stabilized aggregated nanogel particle (SANP) drug delivery system was prepared for injectable passive lung targeting. Gel nanoparticles (GNPs) were synthesized by irreversibly cross-linking 8 Arm PEG thiol with 1,6-hexane-bis-vinylsulfone (HBVS) in phosphate buffer (PB, pH 7.4) containing 0.1% v/v Tween™ 80. Aggregated nanogel particles (ANPs) were generated by aggregating GNPs to micron-size, which were then stabilized (i.e., SANPs) using a PEG thiol polymer to prevent further growth-aggregation. The size of SANPs, ANPs and GNPs was analyzed using a Coulter counter and transmission electron microscopy (TEM). Stability studies of SANPs were performed at 37°C in rat plasma, phosphate buffered saline (PBS, pH 7.4) and PB (pH 7.4). SANPs were stable in rat plasma, PBS and PB over 7 days. SANPs were covalently labeled with HiLyte Fluor™ 750 (DYE-SANPs) to facilitate ex vivo imaging. Biodistribution of intravenous DYE-SANPs (30 μm, 4 mg in 500 μL PBS) in male Sprague-Dawley rats was compared to free HiLyte Fluor™ 750 DYE alone (1mg in 500 μL PBS) and determined using a Xenogen IVIS® 100 Imaging System. Biodistribution studies demonstrated that free DYE was rapidly eliminated from the body by renal filtration, whereas DYE-SANPs accumulated in the lung within 30 min and persisted for 48 h. DYE-SANPs were enzymatically degraded to their original principle components (i.e., DYE-PEG-thiol and PEG-VS polymer) and were then eliminated from the body by renal filtration. Histological evaluation using H & E staining and broncho alveolar lavage (BAL) confirmed that these flexible SANPs were not toxic. This suggests that because of their flexible and non-toxic nature, SANPs may be a useful alternative for treating pulmonary diseases such as asthma, pneumonia, tuberculosis and disseminated lung cancer.

PubMed ID: 23041417

MeSH Terms: Animals; Biocompatible Materials/chemistry; Biocompatible Materials/pharmacokinetics*; Drug Carriers/chemistry; Drug Carriers/pharmacokinetics*; Drug Compounding; Drug Delivery Systems; Drug Stability; Injections, Intravenous; Kidney/metabolism*; Lung/drug effects*; Lung/metabolism; Male; Metabolic Clearance Rate; Microscopy, Electron, Transmission; Nanogels; Particle Size; Polyethylene Glycols/chemistry; Polyethylene Glycols/pharmacokinetics*; Polyethyleneimine/chemistry; Polyethyleneimine/pharmacokinetics*; Rats; Rats, Sprague-Dawley; Surface Properties; Tissue Distribution