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OBJECTIVE: Perfluorocarbon nanodroplets (NDs) have been widely investigated as both diagnostic and therapeutic agents. There remains, however, a challenge in generating NDs that do not vaporize spontaneously but can be activated at ultrasound pressures that do not produce unwanted bioeffects. In previous work, it has been shown that phospholipid-coated perfluorobutane (PFB) NDs can potentially overcome this challenge. The aim of this study was to investigate whether these NDs can promote drug delivery. METHODS: A combination of high-speed optical imaging and passive cavitation detection was used to study the acoustic properties of the PFB-NDs in a tissue mimicking phantom. PFB-NDs were exposed to ultrasound at frequencies from 0.5 to 1.5 MHz and peak negative pressures from 0.5 to 3.5 MPa. In addition, the penetration depth of two model drugs (Nile Red and 200 nm diameter fluorescent polymer spheres) into the phantom was measured. RESULTS: PFB NDs were found to be stable in aqueous suspension at both 4°C and 37°C; their size remaining unchanged at 215 ± 11 nm over 24 h. Penetration of both model drugs in the phantom was found to increase with increasing ultrasound peak negative pressure and decreasing frequency and was found to be positively correlated with the energy of acoustic emissions. Extravasation depths >1 mm were observed at 0.5 MHz with pressures <1 MPa. CONCLUSION: The results of the study thus suggest that PFB NDs can be used both as drug carriers and as nuclei for cavitation to enhance drug delivery without the need for high intensity ultrasound.

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Microbubble contrast agents in ultrasound/echocardiography are used to increase the echogenicity of the target tissues, thereby raising the contrast resolution of the resultant image. Recently, the trend has shifted toward the development of phase-convertible nanodroplets as ultrasound contrast agents due to their promising theragnostic potential by switching capability at the active site. Herein, we fabricated pre-PGS- perfluoropentane phase convertible nanodroplets and checked their in vitro and in vivo enhancement and safety profile. For this, we performed experiments on 20 male Wistar rats and 2 dogs. Biochemical assays of both rats and dogs included complete blood profiles, liver function tests, and renal function tests. For rat vitals, monitoring and histopathological analysis were also performed. Converted nanodroplets showed excellent contrast enhancement, better than Sonovue upon in vitro testing, with an enhancement time of up to 14 min. In vivo, experiments showed comparable opacification of the ventricles of both rats and dogs. All biochemical assays remained within the normal range during the study period. The histopathological analysis did not show any signs of drug-induced toxicity, showing the safety of these nanodroplets. Pre-PGS-PFP nanodroplets hold great potential for use in echocardiography and abdominal imaging in both human and veterinary applications after clinical trials.

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Targeted delivery of medication has the promise of increasing the effectiveness and safety of current systemic drug treatments. Focused ultrasound is emerging as noninvasive and practical energy for targeted drug release. However, it has yet to be determined which nanocarriers and ultrasound parameters can provide both effective and safe release. Perfluorocarbon nanodroplets have the potential to achieve these goals, but current approaches have either been effective or safe, but not both. We found that nanocarriers with highly stable perfluorocarbon cores mediate effective drug release so long as they are activated by ultrasound of sufficiently low frequency. We demonstrate a favorable safety profile of this formulation in a non-human primate. To facilitate translation of this approach into humans, we provide an optimized method for manufacturing the nanocarriers. This study provides a recipe and release parameters for effective and safe drug release from nanoparticle carriers in the body part specified by focused ultrasonic waves.

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BACKGROUND: Ultrasound and photoacoustic (US/PA) imaging is a promising tool for in vivo visualization and assessment of drug delivery. However, the acoustic properties of the skull limit the practical application of US/PA imaging in the brain. To address the challenges in targeted drug delivery to the brain and transcranial US/PA imaging, we introduce and evaluate an intracerebral delivery and imaging strategy based on the use of laser-activated perfluorocarbon nanodroplets (PFCnDs). METHODS: Two specialized PFCnDs were developed to facilitate blood‒brain barrier (BBB) opening and contrast-enhanced US/PA imaging. In mice, PFCnDs were delivered to brain tissue via PFCnD-induced BBB opening to the right side of the brain. In vivo, transcranial US/PA imaging was performed to evaluate the utility of PFCnDs for contrast-enhanced imaging through the skull. Ex vivo, volumetric US/PA imaging was used to characterize the spatial distribution of PFCnDs that entered brain tissue. Immunohistochemical analysis was performed to confirm the spatial extent of BBB opening and the accuracy of the imaging results. RESULTS: In vivo, transcranial US/PA imaging revealed localized photoacoustic (PA) contrast associated with delivered PFCnDs. In addition, contrast-enhanced ultrasound (CEUS) imaging confirmed the presence of nanodroplets within the same area. Ex vivo, volumetric US/PA imaging revealed PA contrast localized to the area of the brain where PFCnD-induced BBB opening had been performed. Immunohistochemical analysis revealed that the spatial distribution of immunoglobulin (IgG) extravasation into the brain closely matched the imaging results. CONCLUSIONS: Using our intracerebral delivery and imaging strategy, PFCnDs were successfully delivered to a targeted area of the brain, and they enabled contrast-enhanced US/PA imaging through the skull. Ex vivo imaging, and immunohistochemistry confirmed the accuracy and precision of the approach.

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Crystallization of alloys from a molten state is a fundamental process underpinning metallurgy. Here the direct imaging of an intermetallic precipitation reaction at equilibrium in a liquid-metal environment is demonstrated. It is shown that the outer layers of a solidified intermetallic are surprisingly unstable to the depths of several nanometers, fluctuating between a crystalline and a liquid state. This effect, referred to herein as crystal interface liquefaction, is observed at remarkably low temperatures and results in highly unstable crystal interfaces at temperatures exceeding 200 K below the bulk melting point of the solid. In general, any liquefaction process would occur at or close to the formal melting point of a solid, thus differentiating the observed liquefaction phenomenon from other processes such as surface pre-melting or conventional bulk melting. Crystal interface liquefaction is observed in a variety of binary alloy systems and as such, the findings may impact the understanding of crystallization and solidification processes in metallic systems and alloys more generally.

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Oral biofilm is the leading cause of dental caries, which is difficult to completely eradicate because of the complicated biofilm structure. What's more, the hypoxia environment of biofilm and low water-solubility of conventional photosensitizers severely restrict the therapeutic effect of photodynamic therapy (PDT) for biofilm. Although conventional photosensitizers could be loaded in nanocarriers, it has reduced PDT effect because of aggregation-caused quenching (ACQ) phenomenon. In this study, we fabricated an oxygen self-sufficient nanodroplet (PFC/TPA@FNDs), which was composed of fluorinated-polymer (FP), perfluorocarbons (PFC) and an aggregation-induced emission (AIE) photosensitizer (Triphenylamine, TPA), to eradicate oral bacterial biofilm and whiten tooth. Fluorinated-polymer was synthesized by polymerizing (Dimethylamino)ethyl methacrylate, fluorinated monomer and 1-nonanol monomer. The nanodroplets could be protonated and behave strong positive charge under bacterial biofilm acid environment promoting nanodroplets deeply penetrating biofilm. More importantly, the nanodroplets had extremely high PFC and oxygen loading efficacy because of the hydrophobic affinity between fluorinated-polymer and PFC to relieve the hypoxia environment and enhance PDT effect. Additionally, compared with conventional ACQ photosensitizers loaded system, PFC/TPA@FNDs could behave superior PDT effect to ablate oral bacterial biofilm under light irradiation due to the unique AIE effect. In vivo caries animal model proved the nanodroplets could reduce dental caries area without damaging tooth structure. Ex vivo tooth whitening assay also confirmed the nanodroplets had similar tooth whitening ability compared with commercial tooth whitener H2O2, while did not disrupt the surface microstructure of tooth. This oxygen self-sufficient nanodroplet provides an alternative visual angle for oral biofilm eradication in biomedicine.

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Radiotherapy treatment plans have become highly conformal, posing additional constraints on the accuracy of treatment delivery. Here, we explore the use of radiation-sensitive ultrasound contrast agents (superheated phase-change nanodroplets) as dosimetric radiation sensors. In a series of experiments, we irradiated perfluorobutane nanodroplets dispersed in gel phantoms at various temperatures and assessed the radiation-induced nanodroplet vaporization events using offline or online ultrasound imaging. At 25 °C and 37 °C, the nanodroplet response was only present at higher photon energies (≥10 MV) and limited to <2 vaporization events per cm2 per Gy. A strong response (~2000 vaporizations per cm2 per Gy) was observed at 65 °C, suggesting radiation-induced nucleation of the droplet core at a sufficiently high degree of superheat. These results emphasize the need for alternative nanodroplet formulations, with a more volatile perfluorocarbon core, to enable in vivo photon dosimetry. The current nanodroplet formulation carries potential as an innovative gel dosimeter if an appropriate gel matrix can be found to ensure reproducibility. Eventually, the proposed technology might unlock unprecedented temporal and spatial resolution in image-based dosimetry, thanks to the combination of high-frame-rate ultrasound imaging and the detection of individual vaporization events, thereby addressing some of the burning challenges of new radiotherapy innovations.

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HYPOTHESIS: Surface nanodroplets have important technological applications. Previous experiments and simulations have shown that their contact angle deviates from Young's equation. A modified version of Young's equation considering the three-phase line tension (τ) has been widely used in literature, and a wide range of values for τ are reported. We have recently shown that molecular branching affects the liquid-vapour surface tension γlv of liquid alkanes. Therefore, the wetting behaviour of surface nanodroplets should be affected by molecular branching. This study conducted molecular dynamics (MD) simulations to gain insight into the wetting behaviour of linear and branched alkane nanodroplets on oleophilic and oleophobic surfaces. We aim to examine the Young equation's validity and branching's effect on fundamental properties, including solid-liquid surface tension γsl and line tension τ. SIMULATIONS: The simulations were performed on a linear alkane, triacontane (C30H62), as well as four of its branched isomers: 2,6,13,17-tetrapropyloctadecane,2,6,9,10,13,17-hexaethyloctadecane, 2,5,7,8,11,12,15-heptaethylhexadecane and 2,3,6,7,10,11-hexapropyldodecane. Nanodroplets with a diameter of approximately 15 nm were released onto the surfaces, and their contact angles were measured. Additionally, using a novel approach, the solid-liquid surface tension (γsl), the validity of Young's equation and line tension for all alkane and surface combinations are determined. FINDINGS: It was discovered that the calculated γsl, deviated from the theoretical γsl,Young predicted from Young's equation for all alkanes on oleophilic surfaces. However, this deviation was minimal for branched alkanes on the oleophobic surfaces but more significant for the linear alkane. The findings indicated that γsl < 0 for oleophilic surfaces and γsl > 0 for oleophobic surfaces. Moreover, it was observed that |γsl| was lower for branched molecules and decreased as branching increased. Line tension values were then determined through a novel method, showing τ was positive for oleophilic surfaces ranging from 1.30 × 10-10 to 6.27 × 10-11N. On an oleophobic surface, linear alkane shows a negative line tension of -1.15 × 10-10N and branched alkanes up to two orders of magnitude lower values ranging from -2.09 × 10-12 to 2.43 × 10-11N. Line tension values between -1.15 × 10-10 and + 1.1 × 10-10N are calculated for various linear alkane and surface combinations. These findings show the dependence of line tension on the contact angle and branching, demonstrating that for linear alkanes, τ is significant, whereas, for branched alkanes, line tension is smaller or negligible for large contact angles.

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Lipid-coated perfluorocarbon nanodroplets (lp-NDs) hold great promise in bio-medicine as vehicles for drug delivery, molecular imaging and vaccine agents. However, their clinical utility is restricted by limited targeted accumulation, attributed to the innate immune system (IIS), which acts as the initial defense mechanism in humans. This study aimed to optimize lp-ND formulations to minimize non-specific clearance by the IIS. Ginsenosides (Gs), the principal components of Panax ginseng, possessing complement inhibition ability, structural similarity to cholesterol, and comparable fat solubility to phospholipids, were used as promising candidate IIS inhibitors. Two different types of ginsenoside-based lp-NDs (Gs lp-NDs) were created, and their efficacy in reducing IIS recognition was examined. The Gs lp-NDs were observed to inhibit the adsorption of C3 in the protein corona (PC) and the generation of SC5b-9. Adding Gs to lp-NDs reduced complement adsorption and phagocytosis, resulting in a longer blood circulation time in vivo compared to lp-NDs that did not contain Gs. These results suggest that Gs can act as anti-complement and anti-phagocytosis adjuvants, potentially reducing non-specific clearance by the IIS and improving lifespan.

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Detection of microplastics from water is crucial for various reasons, such as food safety monitoring, monitoring of the fate and transport of microplastics, and development of preventive measures for their occurrence. Currently, microplastics are detected by isolating them using filtration, separation by centrifugation, or membrane filtration, subsequently followed by analysis using well-established analytical methods, such as Raman spectroscopy. However, due to their variability in shape, color, size, and density, isolation using the conventional methods mentioned above is cumbersome and time-consuming. In this work, we show a surface-nanodroplet-decorated microfluidic device for isolation and analysis of small microplastics (diameter of 10 µm) from water. Surface nanodroplets are able to capture nearby microplastics as water flows through the microfluidic device. Using a model microplastic solution, we show that microplastics of various sizes and types can be captured and visualized by using optical and fluorescence microscopy. More importantly, as the surface nanodroplets are pinned on the microfluidic channel, the captured microplastics can also be analyzed using a Raman spectroscope, which enables both physical (i.e., size and shape) and chemical (i.e., type) characterization of microplastics at a single-particle level. The technique shown here can be used as a simple, fast, and economical detection method for small microplastics.

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Ultrasound-stimulated contrast agents have gained significant attention in the field of tumor treatment as drug delivery systems. However, their limited drug-loading efficiency and the issue of bulky, imprecise release have resulted in inadequate drug concentrations at targeted tissues. Herein, we developed a highly efficient approach for doxorubicin (DOX) precise release at tumor site and real-time feedback via an integrated strategy of "programmable ultrasonic imaging guided accurate nanodroplet destruction for drug release" (PND). We synthesized DOX-loaded nanodroplets (DOX-NDs) with improved loading efficiency (15 %) and smaller size (mean particle size: 358 nm). These DOX-NDs exhibited lower ultrasound activation thresholds (2.46 MPa). By utilizing a single diagnostic transducer for both ultrasound stimulation and imaging guidance, we successfully vaporized the DOX-NDs and released the drug at the tumor site in 4 T1 tumor-bearing mice. Remarkably, the PND group achieved similar tumor remission effects with less than half the dose of DOX required in conventional treatment. Furthermore, the ultrasound-mediated vaporization of DOX-NDs induced tumor cell apoptosis with minimal damage to surrounding normal tissues. In summary, our PND strategy offers a precise and programmable approach for drug delivery and therapy, combining ultrasound imaging guidance. This approach shows great potential in enhancing tumor treatment efficacy while minimizing harm to healthy tissues.

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Ultrasound-responsive agents have shown great potential as targeted drug delivery agents, effectively augmenting cell permeability and facilitating drug absorption. This review focuses on two specific agents, microbubbles and nanodroplets, and provides a sequential overview of their drug delivery process. Particular emphasis is given to the mechanical response of the agents under ultrasound, and the subsequent physical and biological effects on the cells. Finally, the state-of-the-art in their pre-clinical and clinical implementation are discussed. Throughout the review, major challenges that need to be overcome in order to accelerate their clinical translation are highlighted.

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Research into and applications of phthalocyanines (Pc) are mostly connected to their intriguing electronic properties. Here, messenger-type UV-vis spectroscopy of two metal-free ions from the phthalocyanine family, cationic H2Pc+ and H2PcD+, along with their hydrates is performed. They show that the electronic properties of both ions can be traced to those in the conjugate base, Pc2-, however, they are affected by state splitting due to the reduced symmetry; in the H2Pc+ radical cation, a new band appears due to excitations into the singly-occupied molecular orbital. Quantum chemical spectra modeling reproduces all important features of the measured spectra and provides insight into the nature of electronic transitions. Hydration of the ions has only a mild effect on the electronic spectra, showing the stability of the electronic structure with respect to solvation effects.

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Despite the real-time, nonionizing, and cost-effective nature of ultrasound imaging, there is a dearth of methods to visualize two or more populations of contrast agents simultaneously─a technique known as multiplex imaging. Here, we present a new approach to multiplex ultrasound imaging using perfluorocarbon (PFC) nanodroplets. The nanodroplets, which undergo a liquid-to-gas phase transition in response to an acoustic trigger, act as activatable contrast agents. This work characterized the dynamic responses of two PFC nanodroplets with boiling points of 28 and 56 °C. These characteristic responses were then used to demonstrate that the relative concentrations of the two populations of PFC nanodroplets could be accurately measured in the same imaging volume within an average error of 1.1%. Overall, the findings indicate the potential of this approach for multiplex ultrasound imaging, allowing for the simultaneous visualization of multiple molecular targets simultaneously.

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Focused ultrasound-stimulated microbubbles can induce blood flow shutdown and ischemic necrosis at higher pressures in an approach termed antivascular ultrasound. Combined with conventional therapies of chemotherapy, immunotherapy, and radiation therapy, this approach has demonstrated tumor growth inhibition and profound synergistic antitumor effects. However, the lower cavitation threshold of microbubbles can potentially yield off-target damage that the polydispersity of clinical agent may further exacerbate. Here we investigate the use of a monodisperse nanodroplet formulation for achieving antivascular effects in tumors. We first develop stable low boiling point monodisperse lipid nanodroplets and examine them as an alternative agent to mediate antivascular ultrasound. With synchronous intravital imaging and ultrasound monitoring of focused ultrasound-stimulated nanodroplets in tumor microvasculature, we show that nanodroplets can trigger blood flow shutdown and do so with a sharper pressure threshold and with fewer additional events than conventionally used microbubbles. We further leverage the smaller size and prolonged pharmacokinetic profile of nanodroplets to allow for potential passive accumulation in tumor tissue prior to antivascular ultrasound, which may be a means by which to promote selective tumor targeting. We find that vascular shutdown is accompanied by inertial cavitation and complex-order sub- and ultraharmonic acoustic signatures, presenting an opportunity for effective feedback control of antivascular ultrasound.

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Non-invasive ultrasound neuromodulation (USNM) is a powerful tool to explore neural circuits and treat neurological disorders. Due to the heterogeneity of the skull and regional variations in modulation and treatment objectives, it is necessary to develop an efficient and spatially controllable neuromodulation approach. Recently, transcranial focused ultrasound (tFUS) combined with external biomicro/nanomaterials for brain stimulation has garnered significant attention. This study focused on tFUS combined with perfluoropentane (PFP) nanodroplets (NDs) to improve the efficacy and spatial controllability of USNM. The developed two-stage variable pulse tFUS sequence that include the acoustic droplet vaporization (ADV) pulse for vaporizing PFP NDs into microbubbles (MBs) and the USNM sequence for inducing mechanical oscillations of the formed MBs to enhance neuronal activity. Further, adjusting the acoustic pressure of the ADV pulse generated the controllable vaporization regions, thereby achieving spatially controllable neuromodulation. The results showed that the mean densities of c-fos+ cells expression in the group of PFP NDs with ADV (109 ± 19 cells/mm2) were significantly higher compared to the group without ADV (37.34 ± 8.24 cells/mm2). The acoustic pressure of the ADV pulse with 1.98 MPa and 2.81 MPa in vitro generated the vaporization regions of 0.146 ± 0.032 cm2 and 0.349 ± 0.056 cm2, respectively. Under the same stimulation conditions, a larger vaporization region was also obtained with higher acoustic pressure in vivo, inducing a broader region of neuronal activation. Therefore, this study will serve as a valuable reference for developing the efficient and spatially controllable tFUS neuromodulation strategy.

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Valacyclovir (VACV) was developed as a prodrug of the most common anti-herpetic drug Acyclovir (ACV), aiming to enhance its bioavailability. Nevertheless, prolonged VACV oral treatment may lead to the development of important side effects. Nanotechnology-based formulations for vaginal administration represent a promising approach to increase the concentration of the drug at the site of infection, limiting systemic drug exposure and reducing systemic toxicity. In this study, VACV-loaded nanodroplet (ND) formulations, optimized for vaginal delivery, were designed. Cell-based assays were then carried out to evaluate the antiviral activity of VACV loaded in the ND system. The chitosan-shelled ND exhibited an average diameter of about 400 nm and a VACV encapsulation efficiency of approximately 91% and was characterized by a prolonged and sustained release of VACV. Moreover, a modification of chitosan shell with an anionic cyclodextrin, sulfobutyl ether ß-cyclodextrin (SBEßCD), as a physical cross-linker, increased the stability and mucoadhesion capability of the nanosystem. Biological experiments showed that SBEßCD-chitosan NDs enhanced VACV antiviral activity against the herpes simplex viruses type 1 and 2, most likely due to the long-term controlled release of VACV loaded in the ND and an improved delivery of the drug in sub-cellular compartments.

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Drug-loaded perfluorocarbon nanodroplets (NDs) can be activated non-invasively by focused ultrasound (FUS) and allow for precise drug-delivery. Anesthetic-loaded NDs and transcranial FUS have previously achieved targeted neuromodulation. To assess the clinical potential of anesthetic-loaded NDs, in depth physical characterization and investigation of storage strategies and triggered-activation is necessary. Pentobarbital-loaded decafluorobutane nanodroplets (PBNDs) with a Definity-derived lipid shell (237 nm; 4.08 × 109 particles/mL) were fabricated and assessed. Change in droplet stability, concentration, and drug-release efficacy were tested for PBNDs frozen at -80 °C over 4 weeks. PBND diameter and the polydispersity index of thawed droplets remained consistent up to 14 days frozen. Cryo-TEM images revealed NDs begin to lose circularity at 7 days, and by 14 days, perfluorocarbon dissolution and lipid fragmentation occurred. The level of acoustic response and drug release decreases through prolonged storage. PBNDs showed no hemolytic activity at clinically relevant concentrations and conditions. At increasing sonication pressures, liquid PBNDs vaporized into gas microbubbles, and acoustic activity at the second harmonic frequency (2 f0) peaked at lower pressures than the subharmonic frequency (1/2 f0). Definity-based PBNDs have been thoroughly characterized, cryo-TEM has been shown to be suitable to image the internal structure of volatile NDs, and PBNDs can be reliably stored at -80 °C for future use up to 7 days without significant degradation, loss of acoustic response, or reduction in ultrasound-triggered drug release.

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Activating patients' immune cells, either by reengineering them or treating them with bioactive molecules, has been a breakthrough in the field of immunotherapy and has revolutionized treatment, especially against cancer. As immune cells naturally home to tumors or injured tissues, labeling such cells holds promise for non-invasive tracking and biologic manipulation. Our study demonstrates that macrophages loaded with extremely low boiling point perfluorocarbon nanodroplets not only survive ultrasound-induced phase change but also maintain their phagocytic function. Unlike observations made when using higher boiling point perfluorocarbon nanodroplets, our results show that phase change occurs intracellularly at a low mechanical index using a clinical scanner operating within the energy limit set by the Food and Drug Administration (FDA). After nanodroplet-loaded macrophages were given intravenously to nude rats, they were invisible in the liver when imaged at a very low mechanical index using a clinical ultrasound scanner. They became visible when power was increased but still within the FDA limits up to 8 h after administration. The acoustic labeling and in vivo detection of macrophages using a clinical ultrasound scanner represent a paradigm shift in the field of cell tracking and pave the way for potential therapeutic strategies in the clinical setting.

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Perfluorocarbon nanodroplets (PFCnDs) are sub-micrometer emulsions composed of a surfactant-encased perfluorocarbon (PFC) liquid and can be formulated to transiently vaporize through optical stimulation. However, the factors governing repeated optical droplet vaporization (ODV) have not been investigated. In this study, we employ high-frame-rate ultrasound (US) to characterize the ODV thresholds of various formulations and imaging parameters and identify those that exhibit low vaporization thresholds and repeatable vaporization. We observe a phenomenon termed "preconditioning", where initial laser pulses generate reduced US contrast that appears linked with an increase in nanodroplet size. Variation in laser pulse repetition frequency is found not to change the vaporization threshold, suggesting that "preconditioning" is not related to residual heat. Surfactants (bovine serum albumin, lipids, and zonyl) impact the vaporization threshold and imaging lifetime, with lipid shells demonstrating the best performance with relatively low thresholds (21.6 ± 3.7 mJ/cm2) and long lifetimes (t1/2 = 104 ± 21.5 pulses at 75 mJ/cm2). Physiological stiffness does not affect the ODV threshold and may enhance nanodroplet stability. Furthermore, PFC critical temperatures are found to correlate with vaporization thresholds. These observations enhance our understanding of ODV behavior and pave the way for improved nanodroplet performance in biomedical applications.