Extracorporeal Removal of Thermosensitive Liposomal Doxorubicin from Systemic Circulation after Tumor Delivery to Reduce Toxicities

• Published in: Cancers 2022-03, Vol.14 (5), p.1322
• Main Authors: Motamarry, Anjan, Wolfe, A Marissa, Ramajayam, Krishna K, Pattanaik, Sanket, Benton, Thomas, Peterson, Yuri, Faridi, Pegah, Prakash, Punit, Twombley, Katherine, Haemmerich, Dieter
• Format: Article
• Language: English
• Subjects: Activated carbon; Blood; Blood levels; Cancer; Cardiotoxicity; Carotid artery; Chemotherapy; Clinical trials; Computer applications; Doxorubicin; Drug delivery; Drug delivery systems; Drug dosages; Fever; Heart; Hyperthermia; Intravenous administration; Jugular vein; Nanoparticles; Pharmacokinetics; Plasma; Toxicity; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14051322

Thermosensitive liposomal doxorubicin (TSL-Dox) combined with localized hyperthermia enables targeted drug delivery. Tumor drug uptake occurs only during hyperthermia. We developed a novel method for removal of systemic TSL-Dox remaining after hyperthermia-triggered delivery to reduce toxicities. The carotid artery and jugular vein of Norway brown rats carrying two subcutaneous BN-175 tumors were catheterized. After allowing the animals to recover, TSL-Dox was infused at 7 mg/kg dose. Drug delivery to one of the tumors was performed by inducing 15 min microwave hyperthermia (43 °C). At the end of hyperthermia, an extracorporeal circuit (ECC) comprising a heating module to release drug from TSL-Dox followed by an activated carbon filter to remove free drug was established for 1 h ( = 3). A computational model simulated TSL-Dox pharmacokinetics, including ECC filtration, and predicted cardiac Dox uptake. In animals receiving ECC, we were able to remove 576 ± 65 mg of Dox (29.7 ± 3.7% of the infused dose) within 1 h, with a 2.9-fold reduction of plasma AUC. Fluorescent monitoring enabled real-time quantification of blood concentration and removed drug. Computational modeling predicted that up to 59% of drug could be removed with an ideal filter, and that cardiac uptake can be reduced up to 7×. We demonstrated removal of drug remaining after tumor delivery, reduced plasma AUC, and reduced cardiac uptake, suggesting reduced toxicity.