title: MRI monitoring of intratumoral drug delivery and prediction of the therapeutic effect with a multifunctional thermosensitive liposome.
abstract: Non-invasive in vivo imaging of drug distribution enables real-time monitoring and prediction of therapeutic responses to treatment. We have developed a thermosensitive liposomal formulation (HaT: Hyperthermia-activated-cytoToxic) consisting of DPPC and Brij78, a formulation that enhanced drug delivery compared to the lyso-lipid temperature sensitive liposomes (LTSL). Here we report the development of a multifunctional HaT liposome co-encapsulating Gd-DTPA (an MRI probe) and doxorubicin (DOX), which simultaneously releases and reports on drug delivery in a locally heated tumor. The temperature-dependent release profiles of DOX from HaT were closely related to the change in the MR T(1) relaxation time, in which DOX was 100% released at 40-42 °C in 3 min, accompanied by a 60% reduction in T(1). By T(1) relaxometry analysis, no Gd-DTPA leakage was detected in 30 min at 30-37 °C. In the in vivo study, DOX uptake in the tumor was quantitatively correlated with T(1) response (R(2) = 0.98) and the patterns of the T(1) image and the intratumoral DOX uptake were matched, in which both signals were predominantly detected in the highly perfused tumor periphery. Finally, the extent of T(1) relaxation enhancement in the heated tumor successfully predicted the antitumor efficacy in a standard pharmacological response model (R(2) = 0.98).
authors.affiliation: Drug Delivery and Formulation, Medicinal Chemistry Platform, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tagami
authors.forename: Warren D
authors.initials: WD
authors.lastname: Foltz
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ernsting
authors.forename: Carol M
authors.initials: CM
authors.lastname: Lee
authors.forename: Ian F
authors.initials: IF
authors.lastname: Tannock
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: May
authors.forename: Shyh-Dar
authors.initials: SD
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D019786:Gadolinium DTPA / Q000737:chemistry; D006979:Hyperthermia, Induced; D007700:Kinetics; D008081:Liposomes / Q000737:chemistry*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy*; D015203:Reproducibility of Results; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D004317:Doxorubicin; D019786:Gadolinium DTPA