Direct 99mTc labeling of pegylated liposomal doxorubicin (Doxil) for pharmacokinetic and non-invasive imaging studies

Pharmacokinetic and organ distribution studies of liposomal drugs in humans are a challenge. A direct labeling method using Tc-99m-N,N-bis(2-mercaptoethyl)-N',N'-diethyl-ethylenediamine (BMEDA) complex to label the commercially available pegylated liposomal doxorubicin, Doxil, has been introduced. Biodistributions of Tc-99m-Doxil in normal rats were performed to evaluate the feasibility of using it for monitoring the pharmacokinetics of liposomes encapsulating drugs. Labeling efficiency of Tc-99m-Doxil was 70.6+/-0.8% (n=3). In vitro incubation of Tc-99m-Doxil in 50% fetal bovine serum or 50% human serum at 37degreesC showed good labeling stability with 72.3+/-3.6% or 78.6+/-1.8% of activity associated with Doxil at 24 h, respectively (n=3). There was a two-phase blood clearance with half-clearance times of 2.2 and 26.2 h after bolus intravenous injection in normal rats. Distribution of Tc-99m-Doxil at 44 h after injection had 19.8+/-1.3% of injected dose in blood, 14.1+/-1.7% in liver, 2.6+/-0.3% in spleen, 9.0+/-0.8% in bone with marrow, 6.0+/-0.5% in skin, and 15.3+/-4.3% in bowel (n=5). Unencapsulated Tc-99m-BMEDA had a very rapid blood clearance with a half-clearance time of only 0.12 h (n=4). By using this Tc-99m labeling method, biodistribution and pharmacokinetics of ammonium gradient liposomes encapsulating drugs can be determined by noninvasive scintigraphic imaging. This labeling method may be extended to Re-186 and Re-188 labeling to combine chemotherapy and radionuclide therapy for tumor treatment.