TY - JOUR
T1 - Development and evaluation of an isolated limb infusion model for investigation of drug delivery kinetics to solid tumors by thermosensitive liposomes and hyperthermia
AU - Lokerse, Wouter J.M.
AU - Eggermont, Alexander M.M.
AU - Grüll, Holger
AU - Koning, Gerben A.
N1 - Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2018/1/28
Y1 - 2018/1/28
N2 - The combined administration of thermosensitive liposomes (TSLs) and hyperthermia (HT) has been increasingly shown to be a powerful tool for the treatment of solid tumors. At present, it is hypothesized that the circulation of TSLs through the vasculature of a heated tumor results in the rapid release of the entrapped drug, followed by its uptake and distribution within the tumor microenvironment. However, simple questions on the transport kinetics of TSLs through the heated tumor and how much drug is retained upon passage of TSLs through the tumor microcirculation have not been investigated in an experimental setting to-date. The present work describes a novel methodology for investigating these parameters by isolated limb infusion (ILI), developed in a rat model of sarcoma. This approach was used to assess the efficacy of Doxorubicin (Dox) delivery by TSL in a heated (42 °C) tumor following a single passage of TSL through the tumor vasculature. Analysis of the effluent post-ILI, whole-tumor histological sections, and tissue homogenates revealed that upon a single passage, Dox delivery by TSL at 42 °C did not exceed delivery under conventional (i.e. free Dox) or physiological (i.e. TSL at 37 °C, or normothermia; NT) conditions. In fact, mathematical modeling demonstrated that at least thirteen passages are required to obtain the intratumoral Dox levels typically achieved using TSL (i.e. ~ 5%ID/g). Overall, this work investigates TSL-based determinants for achieving efficacious drug delivery using a model of ILI in tumor-bearing rats and the results bear important implications for TSL disposition in vivo.
AB - The combined administration of thermosensitive liposomes (TSLs) and hyperthermia (HT) has been increasingly shown to be a powerful tool for the treatment of solid tumors. At present, it is hypothesized that the circulation of TSLs through the vasculature of a heated tumor results in the rapid release of the entrapped drug, followed by its uptake and distribution within the tumor microenvironment. However, simple questions on the transport kinetics of TSLs through the heated tumor and how much drug is retained upon passage of TSLs through the tumor microcirculation have not been investigated in an experimental setting to-date. The present work describes a novel methodology for investigating these parameters by isolated limb infusion (ILI), developed in a rat model of sarcoma. This approach was used to assess the efficacy of Doxorubicin (Dox) delivery by TSL in a heated (42 °C) tumor following a single passage of TSL through the tumor vasculature. Analysis of the effluent post-ILI, whole-tumor histological sections, and tissue homogenates revealed that upon a single passage, Dox delivery by TSL at 42 °C did not exceed delivery under conventional (i.e. free Dox) or physiological (i.e. TSL at 37 °C, or normothermia; NT) conditions. In fact, mathematical modeling demonstrated that at least thirteen passages are required to obtain the intratumoral Dox levels typically achieved using TSL (i.e. ~ 5%ID/g). Overall, this work investigates TSL-based determinants for achieving efficacious drug delivery using a model of ILI in tumor-bearing rats and the results bear important implications for TSL disposition in vivo.
KW - Delivery kinetics
KW - Hyperthermia
KW - Isolated limb infusion
KW - Thermosensitive liposome
UR - http://www.scopus.com/inward/record.url?scp=85038864480&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2017.12.012
DO - 10.1016/j.jconrel.2017.12.012
M3 - Article
C2 - 29269141
AN - SCOPUS:85038864480
SN - 0168-3659
VL - 270
SP - 282
EP - 289
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -