Effects of sub-atmospheric pressure and dissolved oxygen concentration on lesions generated in ex vivo tissues by high intensity focused ultrasound.

BACKGROUND: Acoustic cavitation plays an important role in the medical treatment using high-intensity focused ultrasound (HIFU), but unnecessarily strong cavitation also could deform the morphology and enlarge the size of lesions. It is known that the increase of ambient hydrostatic pressure (Pstat) can control the acoustic cavitation. But the question of how the decrease of Pstat and dissolved oxygen concentration (DOC) influence the strength of cavitation has not been thoroughly answered. In this study, we aimed to investigate the relationship among the Pstat, DOC and the strength of cavitation. METHODS: Ex vivo bovine liver tissues were immersed in degassed water with different DOC of 1.0 mg/L, 1.5 mg/L and 2.0 mg/L. Ultrasound (US) of 1 MHz and the spatial and temporal average intensity (Isata) of 6500 W/cm2 was used to expose two groups of in vitro bovine livers for 2 s; one group was under atmospheric pressure (Pstat = 1 bar) and the other was under sub-atmospheric pressure (Pstat = 0.1 bar). Acoustic cavitation was detected by a passive cavitation detector (PCD) during the exposure process. Echo signals at the focal zone of HIFU were monitored by B-mode ultrasound imaging before and after exposure. The difference between two pressure groups was tested using paired sample t-test. The difference among different DOC groups was evaluated by one-way analysis of variance (ANOVA). RESULTS: The results demonstrated a significant difference of broadband acoustic emissions from the cavitation bubbles, echo signals on B-mode image, morphology of lesions under various conditions of ambient pressure and DOC. The lesion volume in tissue was increased with the increase of ambient pressure and DOC. CONCLUSION: Cavitation could be suppressed through sub-atmospheric pressure and low DOC level in liver tissue, which could provide a method of controlling cavitation in HIFU treatment to avoid unpredictable lesions.

A redox-sensitive core-crosslinked nanosystem combined with ultrasound for enhanced deep penetration of nanodiamonds into tumors.

Nanodiamonds (NDs) as drug delivery vehicles are of great significance in anticancer therapy through enhancing drug retention. However, the major barrier to clinical application of NDs is insufficient tumor penetration owing to their strong aggregation and low passive penetration efficiency. Herein, the core-crosslinked pullulan carrier, assembled using the visible light-induced diselenide (Se-Se) bond crosslinking method for encapsulating nanodiamonds-doxorubicin (NDX), is proposed to improve monodispersity. Furthermore, the core-crosslinked diselenide bond provides the nanosystem with redox-responsive capability and improved structural stability in a physiological environment, which prevents premature drug leakage and achieves tumor site-specific controlled release. What's more, ultrasound (US) is utilized to promote nanosystem intratumoral penetration via enlarged tumor vascular endothelium cell gaps. As expected, the nanosystem combined with ultrasound can enhance anti-tumor efficacy with deep penetration and excellent retention performance in a HepG2 xenograft mouse model. This study highlights the ability of the integrated therapeutic paradigm to overcome the limitation of nanodiamonds and the potential for further application in cancer therapy.

Enzyme-Catalytic Self-Triggered Release of Drugs from a Nanosystem for Efficient Delivery to Nuclei of Tumor Cells.

Stimulus-responsive drug delivery nanosystems (DDSs) are of great significance in improving cancer therapy for intelligent control over drug release. However, among them, many DDSs are unable to realize rapid and sufficient drug release because most internal stimulants might be consumed during the release process. To address the plight, an abundant supply of stimulants is highly desirable. Herein, a core crosslinked pullulan-di-(4,1-hydroxybenzylene)diselenide nanosystem, which could generate abundant exogenous-stimulant reactive oxygen species (ROS) via tumor-specific NAD(P)H:quinone oxidoreductase-1 (NQO1) catalysis, was constructed by the encapsulation of ß-lapachone. The enzyme-catalytic-generated ROS induced self-triggered cascade amplification release of loaded doxorubicin (DOX) in the tumor cells, thus achieving efficient delivery of DOX to the nuclei of tumor cells by breaking the diselenide bond of the nanosystem. As a result, the antitumor effect of this nanosystem was significantly improved in the HepG2 xenograft model. In general, this study offers a new paradigm for utilizing the interaction between the loaded agent and carrier in the tumor cells to obtain self-triggered drug release in the design of DDSs for enhanced cancer therapy.

Ultrasound-Enhanced Delivery of Doxorubicin-Loaded Nanodiamonds from Pullulan-all-trans-Retinal Nanoparticles for Effective Cancer Therapy.

Nanodiamond as a drug carrier is of great significance in improving cancer therapy by overcoming chemoresistance. However, its clinical application is severely limited because of insufficient tumor vascular penetration. To address this limitation, pullulan-all-trans-retinal (pullulan-ATR) self-assembled nanoparticles were prepared as nanocarriers, which encapsulated doxorubicin-loaded nanodiamonds, to construct a core-shell structured coloading nanosystem. The obtained composite nanoparticles show a homogeneous size distribution with good dispersity and pH sensitivity. Furthermore, ultrasound was utilized to promote the intratumoral penetration of these nanoparticles. As a result, the intracellular retention of DOX was efficiently enhanced, and DOX in the tumor tissue reached 17.3% of the injected dosage. The antitumor effect of this combined strategy was remarkably improved in both the DOX-sensitive HepG2 and DOX-resistant HepG2/ADR tumor models in vivo. This new strategy might serve as a powerful method to address the limitation of nanodiamonds and provide innovative ideas for the application of nanoparticles in clinical cancer therapy.

Self-Assembled Chiral Nanoparticle Superstructures and Identification of Their Collective Optical Activity from Ligand Asymmetry.

The spontaneous self-assembly of chiral nanoparticles (NPs) into stationary fabrication has garnered great interest in technique investigation and science advancement due to its expected apparent properties via orderly collective behaviors. However, this kind of characterization of assembled nanoparticles superstructure (NPS) is rarely reported and is distinguished with monodispersed chiral NPs. In this work, we used l-cysteine (Cys) as the chiral molecule in the form of functional surfactant, which had capped CdS/CdTe NPs and was treated as a linkage bridge for constructing orderly assembled NPS. Among the circular dichrosim (CD) phenomenon, Cys ligands exhibit related changes in CD absorption, while whole-molecule solution was used for treatment in different pH-controlling procedures. Synthesized chiral NPs are organized into ordered rod-shaped NPS during the spontaneous self-assembly process, and the CD response of NPS is monitored in different cultivating times; it showed a persuasive response appears in sum frequency generation (SFG) spectroscopy. Both experimental works and theory calculation convey that the ordered stacking of chiral stabilizer and the chirality of NPS, which are identified from chiral molecular status and their collective optical activity, originated from ligand asymmetry.

pH-sensitive pullulan-doxorubicin nanoparticles loaded with 1,1,2-trichlorotrifluoroethane as a novel synergist for high intensity focused ultrasound mediated tumor ablation.

Nanoemulsions as synergists of high intensity focused ultrasound (HIFU) have been widely investigated, since they possess huge potential for improving the efficiency to ablate tumor. However, their clinical applications are limited due to the unsatisfactory phase-transition effect of nanoemulsions during the process of generating nanobubbles. Herein, a novel synergist for HIFU therapy was designed by encapsulating 1,1,2-trichlorotrifluoroethane (CFC) into pH-sensitive pullulan-doxorubicin (Pu-DOX/CFC) nanoparticles. These Pu-DOX/CFC nanoemulsions, with moderate vaporization temperature threshold of 47 °C, could provide favorable phase-transition effect, thus facilitating HIFU energy deposition. Meanwhile, Pu-DOX/CFC nanoemulsions could effectively deliver DOX/CFC to the tumor site and carry out combined therapy. The in vitro and in vivo results confirmed that Pu-DOX/CFC nanoemulsions notably enhanced both ablation and therapeutic efficiency comparing with other synergists. In conclusion, Pu-DOX/CFC nanoemulsions might serve as a novel synergist for HIFU therapy, and possess great potential in clinical implication.

Ultrasound-enhanced delivery of doxorubicin/all-trans retinoic acid-loaded nanodiamonds into tumors.

AIM: To build up a combined therapy strategy to address limitations of the enhanced permeability and retention (EPR) effect and improve the efficiency of tumor therapy. MATERIALS & METHODS: A pH-sensitive nanocomplex for co-delivery of doxorubicin (DOX) and all-trans retinoic acid (ATRA) was developed based on nanodiamonds (DOX/ATRA-NDs) to enhance intracellular retention of drugs. Meanwhile, ultrasound was employed to enhance tumor vascular penetration of DOX-ATRA-NDs. RESULTS: The distribution of DOX/ATRA-NDs in the tumor tissues increased threefold when ultrasound was applied at 1 MHz and 0.6 W/cm2. Comparing with unmodified chemotherapeutics, the combined therapy induced more tumor cells apoptosis and greater tumor growth inhibition in both liver and breast tumor models. CONCLUSION: DOX-ATRA-NDs demonstrate great potential in clinical applications.

A rapid and non-invasive method for measuring the peak positive pressure of HIFU fields by a laser beam.

Based on the acousto-optic interaction, we propose a laser deflection method for rapidly, non-invasively and quantitatively measuring the peak positive pressure of HIFU fields. In the characterization of HIFU fields, the effect of nonlinear propagation is considered. The relation between the laser deflection length and the peak positive pressure is derived. Then the laser deflection method is assessed by comparing it with the hydrophone method. The experimental results show that the peak positive pressure measured by laser deflection method is little higher than that obtained by the hydrophone, confirming that they are in reasonable agreement. Considering that the peak pressure measured by hydrophones is always underestimated, the laser deflection method is assumed to be more accurate than the hydrophone method due to the absence of the errors in hydrophone spatial-averaging measurement and the influence of waveform distortion on hydrophone corrections. Moreover, noting that the Lorentz formula still remains applicable to high-pressure environments, the laser deflection method exhibits a great potential for measuring HIFU field under high-pressure amplitude. Additionally, the laser deflection method provides a rapid way for measuring the peak positive pressure, without the scan time, which is required by the hydrophones.

[Realization of Heart Sound Envelope Extraction Implemented on LabVIEW Based on Hilbert-Huang Transform].

We proposed a research of a heart sound envelope extraction system in this paper. The system was implemented on LabVIEW based on the Hilbert-Huang transform (HHT). We firstly used the sound card to collect the heart sound, and then implemented the complete system program of signal acquisition, pretreatment and envelope extraction on LabVIEW based on the theory of HHT. Finally, we used a case to prove that the system could collect heart sound, preprocess and extract the envelope easily. The system was better to retain and show the characteristics of heart sound envelope, and its program and methods were important to other researches, such as those on the vibration and voice, etc.

[Research on visualization of ultrasonic rhinitis therapeutic apparatus based on V4L2].

This paper reports the study and design of a visualization system of the ultrasonic rhinitis therapeutic apparatus with the function of endoscopic sinus. On Linux operating platform, we captured the video data of a video capture card that connected the endoscopic sinus using Video4Linux (V4L2) that was provided by the operating system. The video images were displayed by Qt. The visualization system solved the problem that the current ultrasonic rhinitis therapeutic apparatus had to rely on the large and expensive endoscopy equipment. And this simplified the doctors' operation, met the need of monitoring nasal cavity in the process of operating, greatly reduced the costs of treatment and would contribute to the promotion of the instrument. As a result, it has been tested that the nasal endoscopic image achieved by the system is clear and smooth, and fully meet the clinical needs of ultrasonic treatment of rhinitis.

An intelligent nanotheranostic agent for targeting, redox-responsive ultrasound imaging, and imaging-guided high-intensity focused ultrasound synergistic therapy.

A novel multifunctional nanotheranostic agent with targeting, redox-responsive ultrasound imaging and ultrasound imaging-guided high-intensity focused ultrasound (HIFU) therapy (MSNC-PEG-HA(SS)-PFH, abbreviated as MPH(SS)-PFH) capabilities is developed. The redox-responsive guest molecule release and ultrasound imaging functions can be both integrated in such a "smart" theranostic agent, which is accomplished by the redox-triggered transition from the crosslinking state to retrocrosslinking state of the grafted polyethylene glycol-disulfide hyaluronic acid molecules on the particle surface when reaching a reducing environment in vitro. More importantly, under the tailored ultrasound imaging guiding, in vivo Hela tumor-bearing nude mice can be thoroughly and spatial-accurately ablated during HIFU therapy, due to the targeted accumulation, responsive ultrasound imaging guidance and the synergistic ablation functions of nanotheranostic agent MPH(SS)-PFH in the tumors. This novel multifunctional nano-platform can serve as a promising candidate for further studies on oncology therapy, due to its high stability, responsive and indicative ultrasound imaging of tumors, and enhanced HIFU therapeutic efficiency and spatial accuracy under ultrasound-guidance.

Au-nanoparticle coated mesoporous silica nanocapsule-based multifunctional platform for ultrasound mediated imaging, cytoclasis and tumor ablation.

Au nanoparticles-coated, perfluorohexane-encapsulated and PEGylated mesoporous silica nanocapsule-based enhancement agents (MSNC@Au-PFH-PEG, abb. as MAPP) have been synthesized, for the ultrasound-induced cytoclasis, contrast-intensified ultrasound (US) imaging and US-guided high intensity focused ultrasound (HIFU) surgical therapy. Both the US-induced thermal effect and US triggered release of loaded model drug with MAPP under US exposure indicated the excellent US sensitivity of MAPP and its applicability for the combined chemo-/thermal therapy and future potential for HIFU ablation; US imaging under different modes verify the attractive US contrast intensification by using MAPP; US-guided HIFU therapy ex vivo and in vivo with MAPP is found to be highly efficient on rabbit VX2 xenograft tumor ablation due to the high thermal energy accumulation and increased mechanical/thermal effects from US-induced PFH bubble cavitations. MAPP can be promisingly used as an inorganic theranostic platform for contrast-intensified US imaging, combined chemotherapy and efficient HIFU tumor ablation under the guidance by the intensified US.

Multifunctional mesoporous composite nanocapsules for highly efficient MRI-guided high-intensity focused ultrasound cancer surgery.

Bloodless surgical knife: Nano-biotechnology has been introduced into imaging-guided high-intensity focused ultrasound (HIFU) cancer surgery by adopting engineered multifunctional manganese-based mesoporous composite nanocapsules as the contrast agents for T(1)-weighted magnetic resonance imaging (MRI) and simultaneously as synergistic agents for MRI-guided HIFU cancer surgery.

Core/shell structured hollow mesoporous nanocapsules: a potential platform for simultaneous cell imaging and anticancer drug delivery.

A potential platform for simultaneous anticancer drug delivery and MRI cell imaging has been demonstrated by uniform hollow inorganic core/shell structured multifunctional mesoporous nanocapsules, which are composed of functional inorganic (Fe(3)O(4), Au, etc.) nanocrystals as cores, a thin mesoporous silica shell, and a huge cavity in between. The synthetic strategy for the creation of huge cavities between functional core and mesoporous silica shell is based on a structural difference based selective etching method, by which solid silica middle layer of Fe(2)O(3)@SiO(2)@mSiO(2) (or Au@SiO(2)@mSiO(2)) composite nanostructures was selectively etched away while the mesoporous silica shell could be kept relatively intact. The excellent biocompatibility of obtained multifunctional nanocapsules (Fe(3)O(4)@mSiO(2)) was demonstrated by very low cytotoxicity against various cell lines, low hemolyticity against human blood red cells and no significant coagulation effect against blood plasma. The cancer cell uptake and intracellular location of the nanocapsules were observed by confocal laser scanning microscopy and bio-TEM. Importantly, the prepared multifunctional inorganic mesoporous nanocapsules show both high loading capacity (20%) and efficiency (up to 100%) for doxorubicin simultaneously because of the formation of the cavity, enhanced surface area/pore volume and the electrostatic interaction between DOX molecules and mesoporous silica surface. Besides, the capability of Fe(3)O(4)@mSiO(2) nanocapsules as contrast agents of MRI was demonstrated both in vitro and in vivo, indicating the simultaneous imaging and therapeutic multifunctionalities of the composite nanocapsules. Moreover, the concept of multifunctional inorganic nanocapsules was extended to design and prepare Gd-Si-DTPA grafted Au@mSiO(2) nanocapsules for nanomedical applications, further demonstrating the generality of this strategy for the preparation of various multifunctional mesoporous nanocapsules.