Image-guided drug delivery with magnetic resonance guided high intensity focused ultrasound and temperature sensitive liposomes in a rabbit Vx2 tumor model.
Clinical-grade doxorubicin encapsulated low temperature sensitive liposomes (LTSLs) were combined with a clinical magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) platform to investigate in vivo image-guided drug delivery. Plasma pharmacokinetics were determined in 3 rabbits. Fifteen rabbits with Vx2 tumors within superficial thigh muscle were randomly assigned into three treatment groups: 1) free doxorubicin, 2) LTSL and 3) LTSL + MR-HIFU. For the LTSL + MR-HIFU group, mild hyperthermia (40-41 °C) was applied to the tumors using an MR-HIFU system. Image-guided non-invasive hyperthermia was applied for a total of 30 min, completed within 1h after LTSL infusion. High-pressure liquid chromatography (HPLC) analysis of the harvested tumor and organ/tissue homogenates was performed to determine doxorubicin concentration. Fluorescence microscopy was performed to determine doxorubicin spatial distribution in the tumors. Sonication of Vx2 tumors resulted in accurate (mean = 40.5 ± 0.1 °C) and spatially homogenous (SD = 1.0 °C) temperature control in the target region. LTSL + MR-HIFU resulted in significantly higher tumor doxorubicin concentrations (7.6- and 3.4-fold greater compared to free doxorubicin and LTSL respectively, p<0.05, Newman-Keuls). This improved tumor concentration was achieved despite heating <25% of the tumor volume. Free doxorubicin and LTSL treatments appeared to deliver more drug in the tumor periphery as compared to the tumor core. In contrast, LTSL + MR-HIFU treatment suggested an improved distribution with doxorubicin found in both the tumor periphery and core. Doxorubicin bio-distribution in non-tumor organs/tissues was fairly similar between treatment groups. This technique has potential for clinical translation as an image-guided method to deliver drug to a solid tumor.
Center for Interventional Oncology, Clinical Center and National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Ashish
A
Ranjan
Genevieve C
GC
Jacobs
David L
DL
Woods
Ayele H
AH
Negussie
Ari
A
Partanen
Pavel S
PS
Yarmolenko
Carmen E
CE
Gacchina
Karun V
KV
Sharma
Victor
V
Frenkel
Bradford J
BJ
Wood
Matthew R
MR
Dreher
D000818:Animals; D004317:Doxorubicin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005260:Female; D057086:High-Intensity Focused Ultrasound Ablation; D008081:Liposomes; D009682:Magnetic Resonance Spectroscopy; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000628:therapy; D011817:Rabbits; D013696:Temperature; D014018:Tissue Distribution; D014463:Ultrasonography
D008081:Liposomes; D004317:Doxorubicin