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Focused Ultrasound Hyperthermia Mediated Drug Delivery Using Thermosensitive Liposomes and Visualized With in vivo Two-Photon Microscopy.

ABSTRACT: 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.

SUBMITTER: Santos MA

PROVIDER: S-EPMC5558564 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:Effective drug delivery in brain tumors remains a major challenge in oncology. Although local hyperthermia and stimuli-responsive delivery systems, such as thermosensitive liposomes, represent promising strategies to locally enhance drug delivery in solid tumors and improve outcomes, their application in intracranial malignancies remains unexplored. We hypothesized that the combined abilities of closed-loop trans-skull Magnetic Resonance Imaging guided Focused Ultrasound (MRgFUS) hyperthermia with those of thermosensitive drugs can alleviate challenges in drug delivery and improve survival in gliomas. Methods: To conduct our investigations, we first designed a closed loop MR-guided Focused Ultrasound (MRgFUS) system for localized trans-skull hyperthermia (ΔT < 0.5 °C) in rodents and established safety thresholds in healthy mice. To assess the abilities of the developed system and proposed therapeutic strategy for FUS-triggered chemotherapy release we employed thermosensitive liposomal Dox (TSL-Dox) and tested it in two different glioma tumor models (F98 in rats and GL261 in mice). To quantify Dox delivery and changes in the transvascular transport dynamics in the tumor microenvironment we combined fluorescent microscopy, dynamic contrast enhanced MRI (DCE-MRI), and physiologically based pharmacokinetic (PBPK) modeling. Lastly, to assess the therapeutic efficacy of the system and of the proposed therapeutic strategy we performed a survival study in the GL261 glioma bearing mice. Results: The developed closed-loop trans-skull MRgFUS-hyperthermia system that operated at 1.7 MHz, a frequency that maximized the brain (FUS-focus) to skull temperature ratio in mice, was able to attain and maintain the desired focal temperature within a narrow range. Histological evidence (H&E and Nissl) suggests that focal temperature at 41.5 ± 0.5 °C for 10 min is below the threshold for tissue damage. Quantitative analysis of doxorubicin delivery from TSLs with MRgFUS-hyperthermia demonstrated 3.5-fold improvement in cellular uptake in GL261 glioma mouse tumors (p < 0.001) and 5-fold increase in delivery in F98 glioma rat tumors (p < 0.05), as compared to controls (TSL-Dox-only). Moreover, PBPK modeling of drug transport that was calibrated using the experimental data indicated that thermal stress could lead to significant improvement in the transvascular transport (2.3-fold increase in the vessel diffusion coefficient; P < 0.001), in addition to promoting targeted Dox release. Prospective experimental investigations with DCE-MRI during FUS-hyperthermia, supported these findings and provided evidence that moderate thermal stress (≈41 °C for up to 10 min) can promote acute changes in the vascular transport dynamics in the brain tumor microenvironment (Ktrans value for control vs. FUS was 0.0097 and 0.0148 min-1, respectively; p = 0.026). Crucially, survival analysis demonstrated significant improvement in the survival in the TSL-Dox-FUS group as compared to TSL-Dox-only group (p < 0.05), providing supporting evidence on the therapeutic potential of the proposed strategy. Conclusions: Our investigations demonstrated that spatially controlled thermal stress can be attained and sustained in the mouse brain, using a trans-skull closed-loop MRgFUS system, and used to promote the effective delivery of chemotherapy in gliomas from thermosensitive drugs. This system also allowed us to conduct mechanistic investigations that resulted in the refinement of our understanding on the role of thermal stress in augmenting mass and drug transport in brain tumors. Overall, our study established a new paradigm for effective drug delivery in brain tumors based on closed-loop ultrasound-mediated thermal stress and thermosensitive drugs.

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Focused Ultrasound Hyperthermia Mediated Drug Delivery Using Thermosensitive Liposomes and Visualized With in vivo Two-Photon Microscopy.

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