Photoacoustic Cavitation Research Articles

Totally Caged Type I Pro-Photosensitizer for Oxygen-Independent Synergistic Phototherapy of Hypoxic Tumors.

Activatable type I photosensitizers are an effective way to overcome the insufficiency and imprecision of photodynamic therapy in the treatment of hypoxic tumors, however, the incompletely inhibited photoactivity of pro-photosensitizer and the limited oxidative phototoxicity of post-photosensitizer are major limitations. It is still a great challenge to address these issues using a single and facile design. Herein, a series of totally caged type I pro-photosensitizers (Pro-I-PSs) are rationally developed that are only activated in tumor hypoxic environment and combine two oxygen-independent therapeutic mechanisms under single-pulse laser irradiation to enhance the phototherapeutic efficacy. Specifically, five benzophenothiazine-based dyes modified with different nitroaromatic groups, BPN 1-5, are designed and explored as latent hypoxia-activatable Pro-I-PSs. By comparing their optical responses to nitroreductase (NTR), it is identified that the 2-methoxy-4-nitrophenyl decorated dye (BPN 2) is the optimal Pro-I-PSs, which can achieve NTR-activated background-free fluorescence/photoacoustic dual-modality tumor imaging. Furthermore, upon activation, BPN 2 can simultaneously produce an oxygen-independent photoacoustic cavitation effect and a photodynamic type I process at single-pulse laser irradiation. Detailed studies in vitro and in vivo indicated that BPN 2 can effectively induce cancer cell apoptosis through synergistic effects. This study provides promising potential for overcoming the pitfalls of hypoxic-tumor photodynamic therapy.

Biofilm removal from Difficult-to-Reach places via secondary cavitation within a constrained geometry mimicking a Periodontal/Peri-Implant pocket

Biofilm removal from the apical region of the periodontal or peri-implant pocket, which is very difficult to achieve with mechanical instruments, is a major unresolved issue in dentistry. Here, we propose the use of photoacoustically induced streaming and secondary cavitation to achieve superior cleaning efficacy in the apical region of the periodontal and peri-implant pocket. We have used a prefabricated narrow wedge system that mimics the consistency of periodontal and peri-implant pockets of both healthy and severely inflamed tissue. We studied the effect of single-pulse modality Er:YAG on Pseudomonas aeruginosa biofilm removal. We used different laser energies, fiber-tip positions, and laser treatment durations. The cleaning process was monitored in real-time with a high-speed camera after each individual laser pulse application. The obtained results suggest that biofilm cleaning efficacy in a difficult-to-reach place in healthy model tissue is directly related to the onset of secondary cavitation bubble formation, which correlates with a significant improvement of biofilm removal from the apical region of the periodontal or peri-implant pocket. In comparison to the healthy tissue model, the laser energy in inflamed tissue model had to be increased to obtain comparable biofilm cleaning efficacy. The advantage of photoacoustic cavitation compared to other methods is that laser-induced cavitation can trigger secondary cavitation at large distances from the point of laser application, which in principle allows biofilm removal at distant locations not reachable with a laser fiber tip or other mechanical instruments.

Imaging-Guided Photoacoustic Immunotherapy Based on the Polydopamine-Functionalized Black Phosphorus Nanocomposites.

Phototherapy has great application prospects in superficial tumors, such as melanoma, esophageal cancer, and breast carcinoma, owing to the advantages of noninvasiveness, high spatiotemporal selectivity, and less side effects. However, classical phototherapies including photodynamic and photothermal therapy still need to settle the bottleneck problems of poor efficacy, inevitable thermal damage, and a high rate of postoperative recurrence. In this study, we developed a nanocomposite with excellent optical properties and immune-stimulating properties, termed PBP@CpG, which was obtained by functionalizing black phosphorus (BP) with polydopamine and further adsorbing CpG. Benefiting from the protection of polydopamine against BP, ideal light absorption, and photoacoustic conversion properties, PBP@CpG not only enables precisely delineation of the tumor region with photoacoustic imaging but also powerfully disrupts the plasma membrane and cytoskeleton of tumor cells with a photoacoustic cavitation effect. In addition, we found that the photoacoustic cavitation effect was also capable of inducing immunogenic cell death and remarkably strengthening the antitumor immune response upon cooperating with immune adjuvant CpG. Therefore, PBP@CpG was expected to provide a promising nanoplatform for optical theranostics and herald a new strategy of photoimmunotherapy based on the photoacoustic cavitation effects and immunostimulatory effect.

Ultrafast photoacoustic cavitation pumped by picosecond laser for high-efficient and long-term shockwave theranostics

Photoacoustic (PA) theranostics is a new emerging field that uniquely combines diagnosis and treatment in one modality. However, its current status is compromised by the indispensable dependence on nonreversible phase-change nanoprobes that provides one-time-only action. Here, we demonstrate a picosecond-laser-pumped ultrafast PA cavitation technique for highly efficient shockwave theranostics, guaranteeing sustained PA cavitation by using non-phase-change nanoprobes. Theoretical simulations validate that, when compressing the excitation laser pulse width to hundred-picosecond, the thermal confinement effects of a conventional nanoprobe will induce transient heating of the extremely thin surrounding liquid layer of the nanoprobes beyond its cavitation point in a localized area at nanoscale, resulting in intense cavitation and PA shockwaves by the environment rather than the nanoprobes. Both cellular and mouse model experiments have demonstrated the highly effective anti-tumor effects. This method provides a sustainable, reproducible, and highly effective strategy for PA theranostics, prefiguring great potential for the clinical applications.

Passing of Nanocarriers across the Histohematic Barriers: Current Approaches for Tumor Theranostics.

Over the past several decades, nanocarriers have demonstrated diagnostic and therapeutic (i.e., theranostic) potencies in translational oncology, and some agents have been further translated into clinical trials. However, the practical application of nanoparticle-based medicine in living organisms is limited by physiological barriers (blood-tissue barriers), which significantly hampers the transport of nanoparticles from the blood into the tumor tissue. This review focuses on several approaches that facilitate the translocation of nanoparticles across blood-tissue barriers (BTBs) to efficiently accumulate in the tumor. To overcome the challenge of BTBs, several methods have been proposed, including the functionalization of particle surfaces with cell-penetrating peptides (e.g., TAT, SynB1, penetratin, R8, RGD, angiopep-2), which increases the passing of particles across tissue barriers. Another promising strategy could be based either on the application of various chemical agents (e.g., efflux pump inhibitors, disruptors of tight junctions, etc.) or physical methods (e.g., magnetic field, electroporation, photoacoustic cavitation, etc.), which have been shown to further increase the permeability of barriers.

NIR-II femtosecond laser ignites MXene as photoacoustic bomb for continuous high-precision tumor blasting.

Recently, photoacoustic (PA) cavitation-mediated therapy has become the focus of research owing to its advantage of inhibiting drug or radiation resistance; however, its application is limited because it relies on nanodroplets with one-time action. Herein, we demonstrate a femtosecond-laser-pumped ultrafast PA cavitation technique for highly efficient shockwave theranostics using niobium carbide (Nb2C) coated with polyvinylpyrrolidone-40000 (PVP), producing sustainable PA cavitation with non-phase-change nanoprobes, which effectively gets rid of the dependence on nanodroplets, guaranteeing multiple treatments. Under femtosecond (fs) laser irradiation, given that the thermal confinement regime could be well satisfied, the Nb2C-PVP nanosheets (NSs) were quickly heated, forming localized overheated nanospots with the temperature exceeding the phase-transition threshold of the surroundings, leading to precise cavitation and explosion at the tumor sites. The experiments at the cellular level showed the significant anti-tumor effects of this method. Notably, the mouse model experiments showed a relative tumor volume inhibition rate of more than 90%, demonstrating the high precision and good efficacy of the proposed anti-tumor method. This method provides a sustainable and highly effective strategy for PA theranostics, indicating its great potential for clinical applications.

Metal-Organic Framework-Derived Carbon as a Photoacoustic Modulator of Alzheimer's β-Amyloid Aggregate Structure.

Photoacoustic materials emit acoustic waves into the surrounding by absorbing photon energy. In an aqueous environment, light-induced acoustic waves form cavitation bubbles by altering the localized pressure to trigger the phase transition of liquid water into vapor. In this study, we report photoacoustic dissociation of beta-amyloid (Aβ) aggregates, a hallmark of Alzheimer's disease, by metal-organic framework-derived carbon (MOFC). MOFC exhibits a near-infrared (NIR) light-responsive photoacoustic characteristic that possesses defect-rich and entangled graphitic layers that generate intense cavitation bubbles by absorbing tissue-penetrable NIR light. According to our video analysis, the photoacoustic cavitation by MOFC occurs within milliseconds in the water, which was controllable by NIR light dose. The photoacoustic cavitation successfully transforms robust, β-sheet-dominant neurotoxic Aβ aggregates into nontoxic debris by changing the asymmetric distribution of water molecules around the Aβ's amino acid residues. This work unveils the therapeutic potential of NIR-triggered photoacoustic cavitation as a modulator of the Aβ aggregate structure.

Photoacoustic Cavitation-Ignited Reactive Oxygen Species to Amplify Peroxynitrite Burst by Photosensitization-Free Polymeric Nanocapsules.

Photoacoustic (PA) technology can transform light energy into acoustic wave, which can be used for either imaging or therapy that depends on the power density of pulsed laser. Here, we report photosensitizer-free polymeric nanocapsules loaded with nitric oxide (NO) donors, namely NO-NCPs, formulated from NIR light-absorbable amphiphilic polymers and a NO-releasing donor, DETA NONOate. Controlled NO release and nanocapsule dissociation are achieved in acidic lysosomes of cancer cells. More importantly, upon pulsed laser irradiation, the PA cavitation can excite water to generate significant reactive oxygen species (ROS) such as superoxide radical (O2.- ), which further spontaneously reacts with the in situ released NO to burst highly cytotoxic peroxynitrite (ONOO- ) in cancer cells. The resultant ONOO- generation greatly promotes mitochondrial damage and DNA fragmentation to initiate programmed cancer cell death. Apart from PA imaging, PA cavitation can intrinsically amplify reactive species via photosensitization-free materials for promising disease theranostics.

Photoacoustic-immune therapy with a multi-purpose black phosphorus-based nanoparticle.

Effective therapeutic strategies to precisely eradicate primary tumors with minimal side effects on normal tissue, inhibit metastases, and prevent tumor relapses, are the ultimate goals in the battle against cancer. We report a novel therapeutic strategy that combines adjuvant black phosphorus nanoparticle-based photoacoustic (PA) therapy with checkpoint-blockade immunotherapy. With the mitochondria targeting nanoparticle, PA therapy can achieve localized mechanical damage of mitochondria via PA cavitation and thus achieve precise eradication of the primary tumor. More importantly, PA therapy can generate tumor-associated antigens via the presence of the R848-containing nanoparticles as an adjuvant to promote strong antitumor immune responses. When combined with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4, the generated immunological responses will further promote the infiltrating CD8 and CD4 T-cells to increase the CD8/Foxp3 T-cell ratio to inhibit the growth of distant tumors beyond the direct impact range of the PA therapy. Furthermore, the number of memory T cells detected in the spleen is increased, and these cells inhibit tumor recurrence. This proposed strategy offers precise eradication of the primary tumor and can induce long-term tumor-specific immunity.Electronic Supplementary MaterialSupplementary material is available for this article at 10.1007/s12274-020-3028-x and is accessible for authorized users.

Specific photoacoustic cavitation through nucleus targeted nanoparticles for high-efficiency tumor therapy

As a new type of cancer treatment, photoacoustic (PA) therapy is based on PA shockwave for rapid, selective and effective killing of cancer cells. The nucleus has been widely used as a target for tumor therapy, which has obtained a very considerable therapeutic effect. In situ destruction of tumor cell nucleus by photoacoustic therapy has not been studied. In this paper, a highly efficient nucleus-targeted photoacoustic theranostic polymer was developed for fluorescence and photoacoustic dual-mode imaging-guided PA therapy. The prepared polymer consists of nucleus targeting TAT peptide (TAT: YGRKKRRQRRR), hydrophilic chain poly (N,N-dimethylacrylamide) (PDMA), and near-infrared (NIR) light absorbing agent (hCyR), which can self-assemble to form nanoparticles of approximately 28 nm (denoted as TAT-PDMA-hCyR NPs). The designed nanoparticles show excellent nucleus targeting and tumor cell death (up to 80%) caused by DNA damage under pulsed laser irradiation compared to non-nucleus target counterpart PDMA-hCyR NPs without TAT peptide in vitro. As expected, the fluorescence and PA dual-mode imaging observed that TAT-PDMA-hCyR NPs were able to passively target and enrich in tumors, providing an experimental basis for in vivo treatment and thus ensuring a significant tumor inhibition rate (about 92%). In conclusion, this study provides a new and practicable method for the development of nucleus-targeting nanoparticles as potential theranostic agent for in vivo cancer imaging and therapy.

Photoacoustic Therapy for Precise Eradication of Glioblastoma with a Tumor Site Blood–Brain Barrier Permeability Upregulating Nanoparticle

AbstractGlioblastoma is an extremely difficult clinical indication with very few therapeutic choices. In this study, a nanoparticle is constructed featuring high red absorbance and selective penetration of the blood–brain barrier (BBB) at the tumor site. This nanoparticle can provide timely activation of the adenosine receptor on the BBB to allow self‐passage and accumulation in the tumor. The nanoparticle converts pulsed laser energy into a shockwave via photoacoustic (PA) cavitation to achieve localized mechanical damage and thus yields a precision antitumor effect. In addition to its therapeutic function, the nanoparticle‐mediated PA process can also generate images that provide valuable information regarding tumor depth, size, and vascular morphology to inform treatment planning and monitoring. The results show that the nanoparticles can be efficiently delivered into the glioblastoma via intravenous infusion and this PA shockwave therapy can selectively destroy glioblastoma tumors with no observable side effects on normal tissue.

Bubble growth in cylindrically-shaped optical absorbers during photo-mediated ultrasound therapy

Photo-mediated ultrasound therapy (PUT) is a non-invasive, agent-free technique to shut down microvessels with high precision by promoting cavitation activity precisely in the targeted microvessels. PUT is based on the photoacoustic (PA) cavitation generated through concurrently applied nanosecond laser pulses and ultrasound bursts. In this study, a PA cavitation model is employed to understand the enhanced cavitation activity during PUT, with full consideration of the optical absorption of blood vessels. Bubble size evolution in cylindrically-shaped optical absorbers (vessels) due to rectified diffusion is simulated. Results show that the ultrasound pressure required for bubble growth decreases dramatically with the increased laser fluence. At a relatively low ultrasound driving pressure, bubble equilibrium radius increases rapidly due to concurrently applied nanosecond laser pulses and ultrasound bursts, resulting in a transition from inertial cavitation to stable cavitation. This inertial to stable transition is verified by the experimentally measured results on 0.76 mm silicone tubes filled with human whole blood with 0.5 MHz ultrasound at 0.243 MPa. This study demonstrated the potential to induce stable bubbles in blood vessels by PUT non-invasively.

PHOTOACOUSTIC CAVITATION OF NANODROPLETS: HIGH SPEED OBSERVATION AND ACOUSTIC SIGNAL ANALYSIS

Perfluorocarbon (PFC) nanodroplet has a longer lifespan and small volume to circulate freely in blood microcirculation. Its phase transition has great potential in localized therapy. Photoacoustic cavitation, a new approach involving synergetic laser and ultrasound to achieve the phase transition of PFC nanodroplets, could improve the spatial and temporal resolution and reduce the energy threshold compared to individual use of either modalities. In this study, we present a confocal microscopic system to induce photoacoustic cavitation of nanodroplets and study its characteristics by high speed observation and acoustic detection. Upon excitation by laser and ultrasound pulses, the liquid–gas phase transition of PFC nanodroplets and subsequent bubble dynamics were demonstrated. Two distinct bubble formation patterns were observed. It is associated with the size distribution of the droplets within the confocal volume of laser and ultrasound. Moreover, the detected acoustic signals suggested the presence of stable cavitation. Due to the reduced energy threshold of phase transition, the proposed method enables the theranostic applications of PFC nanodroplets at lower and safer laser/ultrasound energies in tissues or cells. Detection of high amplitude signals also revealed the potential of this method to generate strong photoacoustic signals for the photoacoustic imaging.

Photoacoustic cavitation for theranostics: mechanism, current progress and applications

As an emerging cavitation technology, photoacoustic cavitation (PAC) means the formation of bubbles in liquids using focused laser and pre-established ultrasound synchronously. Its significant advantages include the decreased threshold of each modality and the precise location of cavitation determined by the focused laser. In this paper, a brief review of PAC is presented, including the physical mechanism description, the classic experimental technology, the representative results in variety of media, and its applications in biomedical imaging and therapy. Moreover, some preliminary results of PAC in perfluoropentane (PFP) liquid and PFP droplets investigated by passive cavitation detection (PCD) in our group are also presented.

Modeling photoacoustic cavitation nucleation and bubble dynamics with modified classical nucleation theory.

Photoacoustic cavitation (PAC) is the formation of bubbles in liquids using a focused laser and a pre-established ultrasound synchronously. The decreased threshold of each modality and the precise location of cavitation determined by the focused laser are both significant in the targeted theranostics. In this study, PAC nucleation was described using the modified classical nucleation theory by Kashchiev's scaling function. A two-stage model of the PAC bubble dynamics was presented based on the two different bubble behaviors. It was clarified that both negative acoustic pressure and laser-induced temperature rise, resulting in the decrease in critical radius and the increase in nucleation rate, and thereby contribute to the increase in nucleation probability in the confocal region. Ultrasound determined the whole PAC bubble dynamics with temperature-dependent parameters, while the laser mainly contributed to its initial conditions. Moreover, the effects of certain parameters on PAC were further discussed, including the relative acoustic phase when a laser is introduced (φ), laser pulse duration (τ(L)), laser focus radius (R(f)), and ultrasound amplitude (P(A)). The model would be helpful in understanding the PAC process and further in introducing PAC to potential targeted theranostics.

Gold nanoparticle targeted photoacoustic cavitation for potential deep tissue imaging and therapy

The laser generation of vapor bubbles around plasmonic nanoparticles can be enhanced through the application of an ultrasound field; a technique referred to as photoacoustic cavitation. The combination of light and ultrasound allows for bubble formation at lower laser fluence and peak negative ultrasound pressure than can be achieved using either modality alone. The growth and collapse of these bubbles leads to local mechanical disruption and acoustic emission, and can potentially be used to induce and monitor tissue therapy. Photoacoustic cavitation is investigated for a broad range of ultrasound pressures and nanoparticle concentrations for gold nanorods and nanospheres. The cavitation threshold fluences for both nanoparticle types are found to drastically reduce in the presence of an ultrasound field. The results indicate that photoacoustic cavitation can potentially be produced at depth in biological tissue without exceeding the safety limits for ultrasound or laser radiation at the tissue surface.

Nanoparticle-targeted photoacoustic cavitation for deep tissue optical imaging.

Photoacoustic tomography is a non-invasive imaging technique based on broadband acoustic emissions from light absorption in tissue. Light-absorbing gold nanoparticles can be introduced and targeted to specific cell populations, thereby promoting both contrast and the ability to delineate tissue types. For sufficiently high laser fluence, a transient vapor cavity is formed and undergoes inertial collapse, generating enhanced emission and additional contrast. However, the fluence required to achieve this effect usually exceeds the maximum permissible exposure for tissue. By combining ultrasonic and optical pulses, the light and sound thresholds required to repeatedly generate inertial cavitation were reduced to 5 mJ/cm2 and 1 MPa, respectively. Experiments employed a transparent arylimide gel possessing a small (<600 μm) region doped with 80nm diameter gold nanoparticles and simultaneously exposed to pulsed laser light (532 nm) and pulsed ultrasound (1.1 MHz). The amplitude of broadband emissions induced by both light and sound exceeded that produced by light alone by almost two orders of magnitude, thereby facilitating imaging a deeper depth within tissue. Two-dimensional images of doped regions generated from conventional photoacoustic and ultrasound-enhanced emissions are presented and compared. Implications for imaging and HIFU therapy are discussed. [Work is supported by a Boston University Dean’s Catalyst Award.]

Photoacoustic cavitation and heat transfer effects in the laser-induced temperature jump in water

The finite element method is employed to analyze photoacoustic cavitation and heat transfer occurring when modest temperature jumps (T-jumps) are induced by a laser in D2O solution, which may contain a small concentration of a protein or peptide sample. Cavitation can be initiated through a photoacoustic mechanism at intensities well below optical breakdown thresholds. Cavitation probability is related to test medium properties, initial temperature, T-jump magnitude and test region geometry. Parameters affecting thermal conduction losses are also examined because such losses limit the useful duration of the T-jump induced in protein folding experiments. From this study, guidelines are offered for reducing the occurrence of cavitation and extending the useful duration of the T-jump.

Photoacoustic cavitation in spherical and cylindrical absorbers

Photomechanical damage in absorbing regions or particles surrounded by a non-absorbing medium is investigated experimentally and theoretically. The damage mechanism is based on the generation of thermoelastic pressure by absorption of pulsed laser radiation under conditions of stress confinement. Principles of photoacoustic sound generation predict that the acoustic wave generated in a finite-size absorbing region must contain both compressive and tensile stresses. Time-resolved imaging experiments were performed to examine whether the tensile stress causes cavitation in absorbers of spherical or cylindrical shape. The samples were absorbing water droplets and gelatin cylinders suspended in oil. They were irradiated with 6-ns-long pulses from an optical parametric oscillator. Photoacoustic cavitation was observed near the center of the absorbers, even if the estimated temperature caused by absorption of the laser pulse did not exceed the boiling point. The experimental findings are supported by theoretical simulations that reveal strong tensile stress in the interior of the absorbers, near the center of symmetry. Tensile stress amplitudes depend on the shape of the absorber, the laser pulse duration, and the ratio of absorber size to optical absorption length. The photoacoustic damage mechanism has implications for the interaction of ns and sub-nslaser pulses with pigmented structures in biological tissue.