Real-time fluorescence imaging for visualization and drug uptake prediction during drug delivery by thermosensitive liposomes

• Published in: International journal of hyperthermia Vol. 36; no. 1; pp. 816 - 825
• Main Authors: Motamarry, Anjan, Negussie, Ayele H., Rossmann, Christian, Small, James, Wolfe, A. Marissa, Wood, Bradford J., Haemmerich, Dieter
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.01.2019; Taylor & Francis Group
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - blood; Antibiotics, Antineoplastic - pharmacokinetics; cancer; Carcinoma, Lewis Lung - diagnostic imaging; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - therapy; chemotherapy; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Doxorubicin - blood; Doxorubicin - pharmacokinetics; Drug Delivery Systems; Female; Hyperthermia; Hyperthermia, Induced; liposomes; Mice, Inbred BALB C; Mice, Nude; Optical Imaging; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - pharmacokinetics; Temperature; thermosensitive liposomes; drug delivery systems; cancer; liposomes; Hyperthermia; chemotherapy; thermosensitive liposomes
• ISSN: 0265-6736; 1464-5157
• DOI: 10.1080/02656736.2019.1642521

Objective: Thermosensitive liposomal doxorubicin (TSL-Dox) is a promising stimuli-responsive nanoparticle drug delivery system that rapidly releases the contained drug in response to hyperthermia (HT) (>40 °C). Combined with localized heating, TSL-Dox allows highly localized delivery. The goals of this study were to demonstrate that real-time fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake. Methods: Nude mice carrying subcutaneous tumors (Lewis lung carcinoma) were anesthetized and injected with TSL-Dox (5 mg/kg dose). Localized HT was induced by heating tumors for 15, 30 or 60 min via a custom-designed HT probe placed superficially at the tumor location. In vivo fluorescence imaging (excitation 523 nm, emission 610 nm) was performed before, during, and for 5 min following HT. After imaging, tumors were extracted, drug uptake was quantified by high-performance liquid chromatography, and correlated with in vivo fluorescence. Plasma samples were obtained before and after HT to measure TSL-Dox pharmacokinetics. Results: Local drug uptake could be visualized in real-time during HT. Compared to unheated control tumors, fluorescence of heated tumors increased by 4.6-fold (15 min HT), 9.3-fold (30 min HT), and 13.2-fold (60 min HT). HT duration predicted tumor drug uptake (p = .02), with tumor drug concentrations of 4.2 ± 1.3 µg/g (no HT), 7.1 ± 5.9 µg/g (15 min HT), 14.1 ± 6.7 µg/g (30 min HT) and 21.4 ± 12.6 µg/g (60 min HT). There was good correlation (R 2  = 0.67) between fluorescence of the tumor region and tumor drug uptake. Conclusions: Real-time in vivo fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake.