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

SIMPLE SUMMARY: Thermosensitive liposomes (TSL) are lipid-based nanoparticles that release the encapsulated drug in response to heat. TSL are administered systemically, e.g., by intravenous infusion, and circulate within the bloodstream for an extended duration. When combined with localized heating of cancerous tumors to fever-range temperatures, TSL enable targeted delivery of chemotherapy agents, such as doxorubicin as used in this study. Following heat-activated tumor drug delivery, the majority of administered drug remains encapsulated in TSL in the bloodstream and causes undesired toxicities. We developed a method to remove this remaining drug based on an extracorporeal circuit, where first blood is heated to release drug from TSL, followed by removal of the released drug by a filter. We demonstrate removal of ~30% of the administered dose, as well as reduced drug uptake by heart tissue. The results suggest that the method can reduce toxicities that would result from remaining drug after tumor delivery. ABSTRACT: 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 (n = 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.