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

ABSTRACT: 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 (R2?=?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.

SUBMITTER: Motamarry A

PROVIDER: S-EPMC6715149 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Motamarry Anjan A Negussie Ayele H AH Rossmann Christian C Small James J Wolfe A Marissa AM Wood Bradford J BJ Haemmerich Dieter D

International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 20190101 1

<b>Objective:</b> 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. <b>Methods:</b> Nude mice carrying subcutaneous t ...[more]

PMID: 31451077

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Project description:The future of nanomedicines in oncology requires leveraging more than just the passive drug accumulation in tumors through the enhanced permeability and retention effect. Promising results combining mild hyperthermia (HT) with lyso-thermosensitive liposomal doxorubicin (LTSL-DOX) has led to improved drug delivery and potent antitumor effects in pre-clinical studies. The ultimate patient benefit from these treatments can only be realized when robust methods of HT can be achieved clinically. One of the most promising methods of non-invasive HT is the use of focused ultrasound (FUS) with MRI thermometry for anatomical targeting and feedback. MRI-guided focused ultrasound (MRgFUS) is limited by respiratory motion and large blood vessel cooling. In order to translate exciting pre-clinical results to the clinic, novel heating approaches capable of overcoming the limitations on clinical MRgFUS+HT must be tested and evaluated on their ability to locally release drug from LTSL-DOX. Methods: In this work, a new system is described to integrate focused ultrasound (FUS) into a two-photon microscopy (2PM) setting to image the release of drug from LTSL-DOX in real-time during FUS+HT in vivo. A candidate scheme for overcoming the limitations of respiratory motion and large blood vessel cooling during MRgFUS+HT involves applying FUS+HT to 42°C in short ~30s bursts. The spatiotemporal drug release pattern from LTSL-DOX as a result is quantified using 2PM and compared against continuous (3.5min and 20min at 42°C) FUS+HT schemes and unheated controls. Results: It was observed for the first time in vivo that these short duration temperature elevations could produce substantial drug release from LTSL-DOX. Ten 30s bursts of FUS+HT was able to achieve almost half of the interstitial drug concentration as 20min of continuous FUS+HT. There was no significant difference between the intravascular area under the concentration-time curve for ten 30s bursts of FUS+HT and 3.5min of continuous FUS+HT. Conclusion: We have successfully combined 2PM with FUS+HT for imaging the release of DOX from LTSL-DOX in vivo in real-time, which will permit the investigation of FUS+HT heating schemes to improve drug delivery from LTSL-DOX. We have evaluated the ability to release DOX in short 30s FUS+HT bursts to 42°C as a method to overcome limitations on clinical MRgFUS+HT and have found that such exposures are capable of releasing measurable amounts of drug. Such an exposure has the potential to overcome limitations that hamper conventional MRgFUS+HT treatments in targets that are associated with substantial tissue motion.

Dataset Information

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

Publications

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

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