Closed-loop trans-skull ultrasound hyperthermia leads to improved drug delivery from thermosensitive drugs and promotes changes in vascular transport dynamics in brain tumors

Abstract

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 (K trans 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-F...

Triggered Release from Thermosensitive Liposomes Improves Tumor Targeting of Vinorelbine

“…Particularly, when comparing different drug delivery approaches with such different pharmacokinetics and drug release mechanisms as free drug, traditional liposomes, or intravascular releasing thermosensitive liposomes. Most commonly, tumor drug accumulation following thermosensitive liposome administration is assessed immediately post heating [27,36,59,60]. Here, immediately post heating, VRL concentrations in the tumor are significantly higher when administered as ThermoVRL compared to the administration as free drug as well as a nonthermosensitive liposome formulation.…”

Ultrasound‐mediated nano‐sized drug delivery systems for cancer treatment: Multi‐scale and multi‐physics computational modeling

“…(d) Thermal field induced by a flat LIPUS transducer (T. Hornsby, Jakhmola, et al, 2021). (e) The temperature rise in ROI caused by FUS considering a simple binary (on–off) controller for different perfusion parameters incorporated into the BHTE (Kim et al, 2021).…”

“…In addition, researchers have not adequately evaluated the dependence of parameters of tumor tissue, NPs, and chemotherapeutic agents on both thermal and nonthermal effects induced by US. A few studies have recently attempted to address some of these issues limited to US thermal effects in specific drug delivery applications (Gasselhuber et al, 2012; Kim et al, 2021; Rezaeian et al, 2019; Zhan et al, 2019). However, there is still a long way to achieve a comprehensive theoretical model that integrates the applicable physics at all relevant scales.…”

Focused ultrasound for treatment of peripheral brain tumors

“…While the use of carrier vehicles including MBs, liposomes, and nanoparticles to deliver chemotherapeutics offers protection from systemic side effects, it limits release of the agent at the target site (particularly in CNS tumors) and may result in subtherapeutic local drug levels [ 110 ]. Preclinical studies have demonstrated the ability of MRgFUS to increase the targeted release of therapeutic agents from drug delivery vehicles through hyperthermia, stable cavitation, and radiation forces [ 111 – 113 ].…”

“…Preclinical studies have demonstrated the ability of MRgFUS to increase the targeted release of therapeutic agents from drug delivery vehicles through hyperthermia, stable cavitation, and radiation forces [ 111 – 113 ]. In addition to improving delivery of carrier vehicles through the BBB in rodents, MRgFUS has been successfully applied in a trans-skull model to generate controlled hyperthermia and effectively release thermosensitive drugs in glioma [ 110 , 114 ]. Other studies have examined the frequency and duration of FUS for this purpose, with some results suggesting high intensity bursts may be optimal [ 115 – 117 ].…”