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 (99m)Tc-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 (99m)Tc-Doxil in normal rats were performed to evaluate the feasibility of using it for monitoring the pharmacokinetics of liposomes encapsulating drugs. Labeling efficiency of (99m)Tc-Doxil was 70.6 +/- 0.8% (n = 3). In vitro incubation of (99m)Tc-Doxil in 50% fetal bovine serum or 50% human serum at 37 degrees C 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 (99m)Tc-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 (99m)Tc-BMEDA had a very rapid blood clearance with a half-clearance time of only 0.12 h (n = 4). By using this (99m)Tc 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 (186)Re and (188)Re labeling to combine chemotherapy and radionuclide therapy for tumor treatment.