[186Re]Liposomal doxorubicin (Doxil): in vitro stability, pharmacokinetics, imaging and biodistribution in a head and neck squamous cell carcinoma xenograft model

Abstract

The purpose of this study was to determine the feasibility of radiolabeling liposomal doxorubicin (Doxil) for cancer chemoradionuclide therapy by directly loading the therapeutic radionuclide rhenium-186 ((186)Re) into the liposome interior. The pharmacokinetics, imaging and biodistribution of [(186)Re]Doxil (555 MBq/kg) and control [(186)Re]polyethylene glycol (PEG) liposomes (555 MBq/kg) were determined after intravenous administration in a head and neck cancer xenograft model in nude rats. [(186)Re]Doxil and [(186)Re]PEG liposomes were radiolabeled using [(186)Re]N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine. (186)Re labeling efficiency was 76.1+/-8.3% with Doxil. The in vitro serum stability of [(186)Re]Doxil at 37 degrees C was 38.06+/-12.13% at 24 h. Pharmacokinetic studies revealed that [(186)Re]Doxil had a two-phase blood clearance with half clearance times of 0.8 and 28.2 h. Images acquired over 120 h showed that [(186)Re]Doxil had slow blood clearance, low liver accumulation and increasing spleen accumulation. The biodistribution study at 120 h indicated that the percentage of injected dose (%ID) in the blood and tumor for [(186)Re]Doxil was 20-fold higher than that of [(186)Re]PEG liposomes. The %ID values in the kidney and liver were not significantly different between [(186)Re]Doxil and [(186)Re]PEG liposomes. These results suggest that the long circulation and prolonged bioavailability of [(186)Re]Doxil could potentially deliver high concentrations of both doxorubicin and (186)Re to tumor when encapsulated in the same liposome vehicle.

Chemoradionuclide Therapy with186Re-Labeled Liposomal Doxorubicin: Toxicity, Dosimetry, and Therapeutic Response

“…33,34 The labeling efficiency, in vitro stability, pharmacokinetics, and biodistribution of 186 Re-Doxil and 186 Re-PEG-liposomes have been previously evaluated. 35 Control PEG-liposomes were prepared with similar lipid composition, ammonium sulfate gradient, and diameter as Doxil. The results of the study revealed that 186 Re-Doxil and 186 Re-PEG-liposomes had similar in vitro stability but 186 Re-Doxil had a circulation time of 28.2 hours and 186 Re-PEG-liposomes were rapidly cleared from circulation by liver and spleen.…”

Milk derived colloid as a novel drug delivery carrier for breast cancer

“…In previous studies, it was found that particles in the range of 60-400 nm extravasate and accumulate in tumors via a passive mechanism, called 'enhanced permeability and retention (EPR)' effect. 22 Accordingly, the size of MDC (60-70 nm) or Doxil (80-90 nm) 7 are in the suitable range for inducing the EPR effect. However, only particles in the range of 30 nm in diameter could penetrate into poorly permeable pancreatic tumors.…”

“…7 Doxil is a drug of doxorubicin (Dox) confined in liposomes that is sterically stabilized by grafting polyethylene glycol onto the surface [pegylated liposomal doxorubicine (PLD)]. PLD has a circulation half-life of 73.9 hours, whereas Dox has a short half-life of less than 10 min.…”

Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications

“…Similarly, Figure 2Q-R show that also for radiolabeled Doxil, (i.e. PEGylated liposomal doxorubicin), EPR-mediated passive drug targeting to tumors can be visualized and quantified, both in nude rats bearing head-and-neck cancer xenografts ( Figure 2Q), and in patients suffering from different types of sarcomas ( Figure 2R) [51,52].…”

“…from different types of sarcomas (R), thereby enabling patient preselection and (more) personalized nano-chemotherapeutic treatments. Images are adapted, with permission, from [30,[32][33][34][38][39][40][41][42][50][51][52]. Rationale for image-guided and personalized nanomedicine.…”