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A phantom for visualization of three-dimensional drug release by ultrasound-induced mild hyperthermia.

ABSTRACT: Ultrasound-induced mild hyperthermia has advantages for noninvasive, localized and controlled drug delivery. In this study, a tissue-mimicking agarose-based phantom with a thermally sensitive indicator was developed for studying the spatial drug delivery profile using ultrasound-induced mild hyperthermia.Agarose powder, regular evaporated milk, Dulbecco's phosphate-buffered saline (DPBS), n-propanol, and silicon carbide powder were homogeneously mixed with low temperature sensitive liposomes (LTSLs) loaded with a self-quenched near-infrared (NIR) fluorescent dye. A dual-mode linear array ultrasound transducer was used for insonation at 1.54 MHz with a total acoustic power and acoustic pressure of 2.0 W and 1.5 MPa, respectively. After insonation, the dye release pattern in the phantom was quantified based on optical images, and the three-dimensional release profile was reconstructed and analyzed. A finite-difference time-domain-based algorithm was developed to simulate both the temperature distribution and spatial dye diffusion as a function of time. Finally, the simulated dye diffusion patterns were compared to experimental measurements.Self-quenching of the fluorescent dye in DPBS was substantial at a concentration of 6.25×10(-2) mM or greater. The transition temperature of LTSLs in the phantom was 35 °C, and the release reached 90% at 37 °C. The simulated temperature for hyperthermia correlated with the thermocouple measurements with a mean error between 0.03±0.01 and 0.06±0.02 °C. The R2 value between the experimental and simulated spatial extent of the dye diffusion, defined by the half-peak level in the elevation, lateral and depth directions, was 0.99 (slope=1.08), 0.95 (slope=0.99), and 0.80 (slope=1.04), respectively, indicating the experimental and simulated dye release profiles were similar.The combination of LTSLs encapsulating a fluorescent dye and an optically transparent phantom is useful for visualizing and modeling drug release in vitro following ultrasound-induced mild hyperthermia. The coupled temperature simulation and dye-diffusion simulation tools were validated with the experimental system and can be used to optimize the thermal dose and spatial and temporal dye release pattern.

SUBMITTER: Lai CY

PROVIDER: S-EPMC3739833 | biostudies-other | 2013 Aug

REPOSITORIES: biostudies-other

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Project description:Background: Increasing evidence points to the critical role of extracellular vesicles (EVs) as molecular parcels that carry a diverse array of bioactive payloads for coordination of complex intracellular signaling. Focused ultrasound (FUS) hyperthermia is a technique for non-invasive, non-ionizing sublethal heating of cells in a near-instantaneous manner; while it has been shown to improve drug delivery and immunological recognition of tumors, its impact on EVs has not been explored to date. The goal of this study was to determine whether FUS impacts the release, proteomic profile, and immune-activating properties of tumor-derived EVs. Methods: Monolayered murine glioma cells were seeded within acoustically transparent cell culture chambers, and FUS hyperthermia was applied to achieve complete coverage of the chamber. Glioma-derived EVs (GEVs) were isolated for characterization by Nanoparticle Tracking Analysis, cryo-electron microscopy and mass spectrometry. An in vitro experimental setup was designed to further dissect the impact of GEVs on innate inflammation; immortalized murine dendritic cells (DCs) were pulsed with GEVs (either naïve or FUS hyperthermia-exposed) and assayed for production of IL-12p70, an important regulator of DC maturation and T helper cell polarization toward the interferon-γ-producing type 1 phenotype. Results: We confirmed that FUS hyperthermia significantly augments GEV release (by ~46%) as well as shifts the proteomic profile of these GEVs. Such shifts included enrichment of common EV-associated markers, downregulation of markers associated with cancer progression and resistance and modulation of inflammation-associated markers. When DCs were pulsed with GEVs, we noted that naïve GEVs suppressed IL-12p70 production by DCs in a GEV dose-dependent manner. In contrast, GEVs from cells exposed to FUS hyperthermia promoted a significant upregulation in IL-12p70 production by DCs, consistent with a pro-inflammatory stimulus. Conclusion: FUS hyperthermia triggers release of proteomically distinct GEVs that are capable of facilitating an important component of innate immune activation, lending both to a potential mechanism by which FUS interfaces with the tumor-immune landscape and to a role for GEV-associated biomarkers in monitoring response to FUS.

Project description:BackgroundPeripheral pulmonary lesion (PPL) incidence is rising because of increased chest imaging sensitivity and frequency. For PPLs suspicious for lung cancer, current clinical guidelines recommend tissue diagnosis. Radial endobronchial ultrasound (R-EBUS) is a bronchoscopic technique used for this purpose. It has been observed that diagnostic yield is impacted by the ability to accurately manipulate the radial probe. However, such skills can be acquired, in part, from simulation training. Three-dimensional (3D) printing has been used to produce training simulators for standard bronchoscopy but has not been specifically used to develop similar tools for R-EBUS.ObjectiveWe report the development of a novel ultrasound-compatible, anatomically accurate 3D-printed R-EBUS simulator and evaluation of its utility as a training tool.MethodsComputed tomography images were used to develop 3D-printed airway models with ultrasound-compatible PPLs of "low" and "high" technical difficulty. Twenty-one participants were allocated to two groups matched for prior R-EBUS experience. The intervention group received 15 minutes to pretrain R-EBUS using a 3D-printed model, whereas the nonintervention group did not. Both groups then performed R-EBUS on 3D-printed models and were evaluated using a specifically developed assessment tool.ResultsFor the "low-difficulty" model, the intervention group achieved a higher score (21.5 ± 2.02) than the nonintervention group (17.1 ± 5.7), reflecting 26% improvement in performance (P = 0.03). For the "high-difficulty" model, the intervention group scored 20.2 ± 4.21 versus 13.3 ± 7.36, corresponding to 52% improvement in performance (P = 0.02). Participants derived benefit from pretraining with the 3D-printed model, regardless of prior experience level.Conclusion3D-printing can be used to develop simulators for R-EBUS education. Training using these models significantly improves procedural performance and is effective in both novice and experienced trainees.

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A phantom for visualization of three-dimensional drug release by ultrasound-induced mild hyperthermia.

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