Hyperthermia-Targeted Rectal Delivery of Thermosensitive Liposomal Doxorubicin via Intra-Arterial and Intravenous Administration

Andrew S Mikhail^1*Ivane Bakhutashvili¹William F Pritchard¹Dieter Haemmerich²Rochel Hecht¹Reza Seifabadi¹Mattew F Starost³Rachel Ashe⁴Keith Schmidt⁴William D Figg⁴Bradford J Wood¹John W Karanian¹Michal Mauda-Havakuk^1,5

• ¹Center for Interventional Oncology, Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health (NIH), Bethesda, United States
• ²Department of Pediatrics, Medical University of South Carolina, Charleston, United States
• ³Division of Veterinary Resources, National Institutes of Health (NIH), Bethesda, United States
• ⁴Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health (NIH), Bethesda, United States
• ⁵Interventional Radiology, Interventional Oncology Laboratory, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel

Introduction: Lyso-thermosensitive liposomal doxorubicin (LTLD) is a thermosensitive nanomedicine designed to release doxorubicin rapidly at mild hyperthermic temperatures (around 41-43°C). Unlike systemic doxorubicin, which is limited by cardiotoxicity and poor tumor penetration, LTLD enables targeted drug delivery enhanced by localized hyperthermia through heat-triggered release. While LTLD has demonstrated improved drug delivery with tumor-localized hyperthermia, comparative analyses of intravenous (IV) versus intra-arterial (IA) delivery routes for rectal targeting remain unexplored. This study evaluates doxorubicin pharmacokinetics, rectal tissue accumulation, and tolerability following LTLD administration via IV or IA routes, with or without localized rectal hyperthermia in swine, to identify the optimal delivery strategy for maximizing rectal drug concentrations while minimizing systemic exposure. Methods: Eight healthy swine were assigned to four groups: IV LTLD with or without rectal hyperthermia, IA free doxorubicin with hyperthermia, or IA LTLD with hyperthermia. Animals received 30-minute drug infusions (0.7 mg/kg) via the jugular vein or by bilateral selective catheterization of the internal iliac arteries. Serial blood samples were collected for one hour, followed by post-mortem tissue collection from the rectal wall, heart, and perirectal fat. A custom rectal heating device produced homogeneous localized hyperthermia. Results: IV and IA LTLD combined with localized hyperthermia markedly increased doxorubicin accumulation (µg/g) in rectal tissue (7.45 ± 6.18, 8.41 ± 5.15, respectively) compared with normothermic IV LTLD (0.49 ± 0.16) or hyperthermic IA free-drug controls (0.67 ± 0.46). Plasma AUC0-1h (µg/mL*min) was lowest with IA administration of free drug (12.7 ± 8.36) compared to IV LTLD with and without hyperthermia (424 ± 85.6, 544 ± 148, respectively) and IA LTLD with hyperthermia (305 ± 221). Doxorubicin concentrations in the heart did not differ among treatment groups. Fluorescence microscopy confirmed enhanced doxorubicin distribution within the rectal wall when LTLD was delivered via either route and combined with rectal hyperthermia. Conclusions: Intravenous and intra-arterial LTLD combined with localized rectal hyperthermia produced similar increases in rectal doxorubicin concentrations in a swine model. These findings support the feasibility of integrating thermosensitive liposomal drug delivery with localized rectal hyperthermia and intra-arterial catheter-based delivery.