Ultrasound Irradiation Research Articles

One Stone, Three Birds: Design and Synthesis of “All-in-One” Nanoscale Mn-Porphyrin Coordination Polymers for Magnetic Resonance Imaging-Guided Synergistic Photodynamic-Sonodynamic Therapy

Multifunctional nanomaterials with potential applications in both bioimaging and photodynamic-sonodynamic therapy have great advantages in cancer theranostic, but the design and preparation of “all-in-one” type of multifunctional nanomaterials with single component remains challenging. Herein the “all-in-one” type of Mn-PpIX (Protoporphyrin IX) coordination polymers (MnPPs) was reported as efficient nano-photo/sonosensitizers. The MnPPs had an average size of ∼ 110 nm. Upon light/US (ultrasound) irradiation for 5 min, 61.8 % (light) and 32.4 % (US) of DPBF (1.3-diphenyl isobenzofuran) was found to be oxidized by MnPPs, which showed effective ROS (reactive oxygen species) generation for photodynamic/sonodynamic therapy (PDT/SDT). In addition, MnPPs revealed excellent biosafety and could be engulfed by cells to produce intracellular ROS under light/US excitation for efficient killing tumor cells. When MnPPs was injected into mice, the tumor could be monitored via MRI (magnetic resonance imaging). In addition, tumor growth could be significantly inhibited by the synergistic PDT-SDT. Therefore, the present study not only represents MnPPs as an “all-in-one” type of multifunctional nanomaterials for MRI-guided PDT-SDT therapy, but also provides some insights for designing other PpIX-related molecules with the similar structure for bioapplication.

Design, synthesis, anti-mycobacterial activity, molecular docking and ADME analysis of spiroquinoxaline-1,2,4-oxadiazoles via [3 + 2] cycloaddition reaction under ultrasound irradiation.

The development of anti-tuberculosis (anti-TB) drugs has become a challenging task in medicinal chemistry. This is because Mycobacterium tuberculosis (TB), the pathogen that causes tuberculosis, has an increasing number of drug-resistant strains, and existing medication therapies are not very effective. This resistance significantly demands new anti-TB drug profiles. Here, we present the design and synthesis of a number of hybrid compounds with previously known anti-mycobacterial moieties attached to quinoxaline, quinoline, tetrazole, and 1,2,4-oxadiazole scaffolds. A convenient ultrasound methodology was employed to attain spiroquinoxaline-1,2,4-oxadiazoles via [3 + 2] cycloaddition of quinoxaline Schiff bases and aryl nitrile oxides at room temperature. This approach avoids standard heating and column chromatography while producing high yields and shorter reaction times. The target compounds 3a-p were well-characterized, and their in vitro anti-mycobacterial activity (anti-TB) was evaluated. Among the screened compounds, 3i displayed promising activity against the Mycobacterium tuberculosis cell line H37Rv, with an MIC99 value of 0.78µg/mL. However, three compounds (3f, 3h, and 3o) exhibited potent activity with MIC99 values of 6.25µg/mL. To further understand the binding interactions, the synthesized compounds were docked against the tuberculosis protein 5OEQ using in silico molecular docking. Moreover, the most active compounds were additionally tested for their cytotoxicity against the RAW 264.7 cell line, and the cytotoxicity of compounds 3f, 3h, 3i, and 3o was 27.3, 28.9, 26.4, and 30.2µg/mL, respectively. These results revealed that the compounds 3f, 3h, 3i, and 3o were less harmful to humans. Furthermore, the synthesized compounds were tested for ADME qualities, and the results suggest that this series is useful for producing innovative and potent anti-tubercular medicines in the future.

Facile Synthesis of Pyrazolopyranopyrimidines by Synergism of Ultrasound Irradiation and Biocompatible Inulin Biopolymer as Catalyst

AbstractInulin, a natural polysaccharide has been utilized as a novel biodegradable, efficient, and environmentally benign catalyst for the ultrasound‐assisted one‐pot, single‐step multicomponent formation of a library of pyrazolopyrano[2,3‐d]pyrimidine‐diones 5(a‐k) from the reaction of ethyl acetoacetate, hydrazine hydrate, aromatic aldehydes, and barbituric/ thiobarbituric acid in aqueous ethanol (1 : 1) at 50 °C. This facile methodology offers a metal‐free, sustainable, selective synthesis of pyrazolopyrano[2,3‐d]pyrimidine‐diones with no by‐product having excellent product yield (≥90 %) in a shorter reaction time. Additionally, the biocompatible inulin is recyclable for up to five consecutive runs without much decrease in its catalytic potential. Inulin has been characterized by spectral techniques such as XRD, FTIR, Raman, and SEM. It shows remarkable stability in the reaction medium as evident from the zeta potential value of −21.39 mV and hydrodynamic diameter of 459.5 nm. Novel pyrazolopyrano[2,3‐d]pyrimidine‐diones (5g, 5h, 5j, and 5k) were also synthesized using this protocol and the synthesized compounds were examined for their antimicrobial activity.

MX@MIL-125(Ti)-mediated sonocatalytic degradation for the dyes and microplastics

Organic pollution has attracted global attention for the threat to the biota. In this study, the catalyst-mediated sono-degradation was purposefully employed to remove the organic pollutants including dyes and microplastics (MPs) because it could provide a green and sustainable strategy in industrial production. Herein, the Ti-based MOFs (Ti-MOFs) was successfully prepared on the Ti3C2 MXene by the hydrothermal method, forming new plicated MX@MIL-125(Ti). The as-prepared composite had lower specific surface area than the MIL-125(Ti), but it remained porous structure, and the presence of O-Ti-O species and graphitic carbon could help to enhance the photosensitive and catalytic activity. Significantly, the MX@MIL-125(Ti) showed good catalytic removal performances under ultrasound irradiation, and could clear away over 90 % Rhodamine B (RhB) within 60 min or over 75.0 % micro-polyethylene (micro-PE) within 4 h, where the removal process obeyed the pseudo first-order kinetic reaction model and the sonocatalytic degradation was superior to the adsorption. Moreover, a degradation-dominant mechanism was proposed to administrate the MX@MIL-125(Ti)/ultrasound treatment of organic molecules. Thus, the sonocatalysis of Ti-MOFs will be attractive to apply in the degradation of organic contaminants.

An Oral Nanomedicine Elicits In Situ Vaccination Effect against Colorectal Cancer.

Oral administration is the most preferred approach for treating colon diseases, and in situ vaccination has emerged as a promising cancer therapeutic strategy. However, the lack of effective drug delivery platforms hampered the application of in situ vaccination strategy in oral treatment of colorectal cancer (CRC). Here, we construct an oral core-shell nanomedicine by preparing a silk fibroin-based dual sonosensitizer (chlorin e6, Ce6)- and immunoadjuvant (imiquimod, R837)-loaded nanoparticle as the core, with its surface coated with plant-extracted lipids and pluronic F127 (p127). The resultant nanomedicines (Ce6/R837@Lp127NPs) maintain stability during their passage through the gastrointestinal tract and exert improved locomotor activities under ultrasound irradiation, achieving efficient colonic mucus infiltration and specific tumor penetration. Thereafter, Ce6/R837@Lp127NPs induce immunogenic death of colorectal tumor cells by sonodynamic treatment, and the generated neoantigens in the presence of R837 serve as a potent in situ vaccine. By integrating with immune checkpoint blockades, the combined treatment modality inhibits orthotopic tumors, eradicates distant tumors, and modulates intestinal microbiota. As the first oral in situ vaccination, this work spotlights a robust oral nanoplatform for producing a personalized vaccine against CRC.

An Intelligent and Soluble Microneedle Composed of Bi/BiVO4 Schottky Heterojunction for Tumor Ct Imaging and Starvation/Gas Therapy-Promoted Synergistic Cancer Treatment.

Phototherapy and sonodynamic therapy (SDT) are widely used for the synergistic treatment of tumors and have received considerable attention. However, an inappropriate tumor microenvironment, including pH, H2O2, oxygen, and glutathione levels, can reduce the therapeutic effects of synergistic phototherapy and SDT. Here, a novel Bi-based soluble microneedle (MN) is designed for the CT imaging of breast tumors and starvation therapy/gas therapy-enhanced phototherapy/SDT. The optimized Bi/BiVO4 Schottky heterojunction serves as the tip of the MN, which not only has excellent photothermal conversion ability and CT contrast properties, but its heterojunction can also avoid the rapid combination of electrons and hole pairs, thereby enhancing the photodynamic/sonodynamic effects. A degradable MN with excellent mechanical properties is fabricated by optimizing the ratios of poly(vinyl alcohol), poly(vinyl pyrrolidone), and sodium hyaluronate. Glucose oxidase (GOx) and diallyl trisulfide are loaded into the MN to achieve tumor starvation and gas therapy, respectively; And the controlled release of GOx and H2S can be achieved under ultrasound or near-infrared laser irradiation. The in vitro and in vivo results demonstrate that this multifunctional MN can achieve high therapeutic efficacy through starvation therapy/gas therapy-enhanced phototherapy/SDT. The designed multifunctional MN provides a prospective approach for synergistic phototherapy and SDT.

A tumor‐targeting nano‐adjuvant for in situ vaccine based on ultrasound therapy

AbstractUltrasound‐generated antigens combined with TLR7/8 agonists as adjuvants have demonstrated significant anti‐tumor efficacy as an in‐situ vaccine. However, the use of TLR7/8 agonists can cause severe inflammatory responses. In this study, we present a novel tumor‐targeting nano‐adjuvant termed aPDL1‐PLG/R848 NPs, which are composed of aPDL1 antibody, Fc‐III‐4C peptide linker (Fc‐linker) and poly(L‐glutamic acid)‐grafted‐R848. Under ultrasound irradiation, antigen‐presenting cells activate immune mechanisms in vivo under dual stimulation of in situ antigens and immune adjuvants. The strategy inhibits primary tumor growth and induces a strong antigen‐specific immune memory effect to prevent tumor recurrence in vivo. This work offers a safe and potent platform for an in situ cancer vaccine based on ultrasound therapy.

An Ultrasound-Triggered STING Pathway Nanoagonist for Enhanced Chemotherapy-Induced Immunogenic Cell Death.

Although chemotherapy has the potential to induce tumor immunotherapy via immunogenic cell death (ICD) effects, how to control the intensity of the immune responses still deserves further exploration. Herein, a controllable ultrasound (US)-triggered chemo-immunotherapy nanoagonist is successfully synthesized by utilizing the pH and reactive oxygen species (ROS) dual-responsive PEG-polyphenol to assemble sonosensitizer zinc oxide (ZnO) and doxorubicin (DOX). The PZnO@DOX nanoparticles have an intelligent disassembly to release DOX and zinc ions in acidic pH conditions. Notably, US irradiation generates ROS by sonodynamic therapy and accelerates the drug release process. Interestingly, after the PZnO@DOX+US treatment, the injured cells release double-stranded DNA (dsDNA) from the nucleus and mitochondria into the cytosol. Subsequently, both the dsDNA and zinc ions bind with cyclic GMP-AMP synthase and activate the stimulator of interferon genes (STING)pathway, resulting in the dendritic cell maturation, ultimately promoting DOX-induced ICD effects and antigen-specific T cell immunity. Therefore, chemotherapy-induced immune responses can be modulated by non-invasive control of US.

Oxygen‐Supplying Piezocatalytic Therapy of Hypoxic Tumors by Intratumoral Delivery of pH‐Responsive Multicompartmental Carriers with Sequential Drug Release Capability

AbstractPiezocatalytic cancer therapy, in which piezoelectric nanomaterials generate reactive oxygen species (ROS) via piezocatalytic redox reactions under mechanical stress, has emerged as an effective strategy for cancer treatment. However, the inherent hypoxia in tumor microenvironments enormously restricts its efficacy. To address this issue, acid‐degradable Janus‐type multicompartmental carriers able to separately encapsulate piezocatalytic gold nanoparticle‐coated poly(ethylene glycol)‐modified zinc oxide nanorods (Au@P‐ZnO NRs) and O2‐generating catalase (CAT) are fabricated in this study using stop‐flow lithography (SFL). The CAT and Au@P‐ZnO NRs are sequentially released by modulating the composition ratios of acid‐cleavable monomers in the precursor solution during the SFL. The sequential release by the Janus carriers significantly increased the intracellular ROS levels under hypoxia conditions upon ultrasound irradiation owing to the O2 supplied by the CAT. An in vivo study showed that a single intratumoral injection of Janus particles encapsulating the CAT and Au@P‐ZnO NRs efficiently alleviated tumor hypoxia and substantially suppressed tumor growth. This study demonstrates that pH‐responsive, O2‐generating, and piezocatalytic Janus carriers have high potential for piezocatalytic therapy of hypoxic tumors and offers insights into using pH‐responsive Janus carriers for efficient hypoxia‐relieving piezocatalytic cancer therapy via the cascade of oxygenation and ROS generation.

Novel green protocols for the synthesis of tetrahydropyrazolopyrazolones

1,3 – Dipolar cycloadditions represent an important method for obtaining novel bicyclic heterocycles which is of great importance due to their medicinal application and diverse bioactivity such as antitumor, antibacterial and etc. The most suitable way for the synthesis of bicyclic heterocycles such as pyrazolopyrazolones is based on dipolar cycloaddition of azomethine imines and enones. This reaction was explored to develop more sustainable protocols by using less toxic chemicals and different sources of energy. Herein novel green protocols for the synthesis of tetrahydropyrazolopyrazolones are presented. These green protocols avoid hazardous AlCl3 and CH2Cl2 which were used until now, and implement green sources of irradiation. In this research, acetic acid has proved itself as a great catalyst for this type of reaction. Different azomethine imines and enones were submitted to the reaction in the presence of acetic acid for 12 h. A series of ten tetrahydropyrazolopyrazolones is successfully synthesized. The impact of ultrasound and microwave irradiation was also investigated. Three novel protocols for the synthesis of tetrahydropyrazolopyrazolones were established. The best results with significant improvement in yield, reaction time, and cleaner reaction conditions were observed when acetic acid and microwave irradiation were used. These novel protocols for the synthesis of pyrazolopyrazolones based on the usage of acetic acid as a catalyst and ultrasound and microwave irradiation represent a noteworthy advancement in research of sustainable methods for obtaining heterocycles.

A Review of the Synthesis of Oxazoline Derivatives.

Oxazolines are important heterocyclic systems due to their biological activities, such as antibacterial, antimalarial, anticancer, antiviral, anti-inflammatory, antifungal, antipyretic, and antileishmanial. They have been widely applied as chiral auxiliaries, polymers, catalysts, protecting groups, building blocks, and ligands in asymmetric synthesis. Due to their importance, many synthetic routes to prepare oxazoline moieties have been investigated and developed by researchers around the world. In this review, we summarized several synthetic methodologies published in the literature. The main substrates are nitriles, carboxylic acids, and acid derivatives, which react with a variety of reactants under conventional heating, microwave irradiation or ultrasound irradiation conditions. Syntheses via intramolecular cyclisation from amides have also been reported. Many publications have highlighted procedures based on solvent-free conditions using eco-friendly, reusable, and easy-availability catalysts.

Harnessing HfO2 Nanoparticles for Wearable Tumor Monitoring and Sonodynamic Therapy in Advancing Cancer Care.

Addressing the critical requirement for real-time monitoring of tumor progression in cancer care, this study introduces an innovative wearable platform. This platform employs a thermoplastic polyurethane (TPU) film embedded with hafnium oxide nanoparticles (HfO2 NPs) to facilitate dynamic tracking of tumor growth and regression in real time. Significantly, the synthesized HfO2 NPs exhibit promising characteristics as effective sonosensitizers, holding the potential to efficiently eliminate cancer cells through ultrasound irradiation. The TPU-HfO2 film, acting as a dielectric elastomer (DE) strain sensor, undergoes proportional deformation in response to changes in the tumor volume, thereby influencing its electrical impedance. This distinctive behavior empowers the DE strain sensor to continuously and accurately monitor alterations in tumor volume, determining the optimal timing for initiating HfO2 NP treatment, optimizing dosages, and assessing treatment effectiveness. Seamless integration with a wireless system allows instant transmission of detected electrical impedances to a smartphone for real-time data processing and visualization, enabling immediate patient monitoring and timely intervention by remote medical staff. By combining the dynamic tumor monitoring capabilities of the TPU-HfO2 film with the sonosensitizer potential of HfO2 NPs, this approach propels cancer care into the realm of telemedicine, representing a significant advancement in patient treatment.

Bionanoengineered 2D monoelemental selenene for piezothrombolysis

Thrombosis-related diseases represent the leading causes of disability or death worldwide. However, conventional thrombolytic therapies are subjected to narrow therapeutic window, short circulation half-life and bleeding. Herein, we rationally design and develop a safe and efficient nonpharmaceutical thrombolysis strategy based on a specific piezocatalytic effect arising from platelet membrane (PM)-conjugated two-dimensional (2D) piezoelectric selenene, Se-PM nanosheets (NSs). The 2D selenene is fabricated from nonlayered bulk selenium powder by a facile liquid-phase exfoliation method, and the PM conjugation confers selenene with the distinct thrombus-homing feature. Under ultrasonic activation, the piezoelectric characteristic of selenene triggers electrons and holes separation, resulting in generation of reactive oxygen species (ROS) by reacting with surrounding H2O and O2 in the thrombosis microenvironment for thrombolysis. Both systematic in vitro and in vivo assessments demonstrate that the biocompatible Se-PM NSs efficiently degrade erythrocytes, fibrin and artificial blood clots under ultrasound irradiation. Compared to the clinical thrombolytic drug urokinase plasminogen activator, the engineered Se-PM NSs possess excellent thrombolytic efficacy by single treatment in the tail thrombosis animal model without bleeding risk. The engineered Se-PM nanoplatform marks an exciting jumping-off point for research into the application of piezocatalysis in clinical treatment of thrombosis.

Stomata damage, photosynthesis, and transpiration evaluation of aquatic lirium after ultrasound irradiation

Purpose Evaluate the structural damage and the changes in the photosynthesis and transpiration rates of aquatic lirium leaves caused by ultrasound (US) irradiation in search of environmentally friendly methodologies for the control of this weed. Materials and methods Aquatic lirium plants were extracted from Xochimilco water canals in Mexico City. A part of the group of plants was selected for irradiation, and the rest formed the control group. The irradiation plants group was exposed to US irradiation of 17 kHz frequency and 30 W × 4 output power for 2 h, at noon and 25 °C room temperature. The structural analysis was done with a MOTICAM 1 digital camera, 800 × 600 pixels, incorporated into the MOTIC PSM-1000 optical microscope and edited with Motic Images Plus 2.0 ML software. The total stomata density and the damaged stomata density were determined by dividing the numbers of total and damaged stomata by the visual field area (67,917 mm2), respectively. The leaves’ photosynthesis and transpiration rates were measured using an LI-6400XT Portable Photosynthesis System. Results Significant damage was observed in the stomata and epidermal cells, finding that the average ratio between the damaged and total stomata densities as a function of time (days) showed an exponential increase described by a Box–Lucas equation with a saturation value near unity and a maximum rate of change of the density of damaged stomata on zero-day (immediately after irradiation), decreasing as the days go by. The transpiration rate showed a sudden increase during the first hour after irradiation, reaching a maximum of 36% of its value before irradiation. It then quickly fell during the next 6 days and more slowly until the 21st day, decreasing 79.9% of its value before irradiation. The photosynthetic rate showed similar behavior with a 37.7% maximum increment and a 73.6% minimum decrease of its value before irradiation. Conclusions The results of structural stomata damage on the ultrasound-irradiated aquatic lirium leaves are consistent with an excessive ultrasound stimulation on stomata’s mechanical operation by guard cells that produce the measured significant increase of the photosynthetic and transpiration rates during the first hour after irradiation. The initial high evaporation could alter the water potential gradient, with a possible generation of tensions in the xylem that could cause embolism in their conduits. The loss of xylem conductivity or hydraulic failure would be consistent with the observed significant fall in the photosynthesis and transpiration rates of the aquatic lirium leaves after its sudden rise in the first hour after irradiation.

Ultrasound-activated prodrug-loaded liposome for efficient cancer targeting therapy without chemotherapy-induced side effects.

Off-targeted distribution of chemotherapeutic drugs causes severe side effects, further leading to poor prognosis and patient compliance. Ligand/receptor-mediated targeted drug delivery can improve drug accumulation in the tumor but it always attenuated by protein corona barriers. To address these problems, a radically different strategy is proposed that can leave the off-targeted drugs inactive but activate the tumor-distributed drugs for cancer-targeting therapy in a tumor microenvironment-independent manner. The feasibility and effectiveness of this strategy is demonstrated by developing an ultrasound (US)-activated prodrug-loaded liposome (CPBSN38L) comprising the sonosensitizer chlorin e6 (Ce6)-modified lipids and the prodrug of pinacol boronic ester-conjugated SN38 (PBSN38). Once CPBSN38L is accumulated in the tumor and internalized into the cancer cells, under US irradiation, the sonosensitizer Ce6 rapidly induces extensive production of intracellular reactive oxygen species (ROS), thereby initiating a cascade amplified ROS-responsive activation of PBSN38 to release the active SN38 for inducing cell apoptosis. If some of the injected CPBSN38L is distributed into normal tissues, the inactive PBSN38 exerts no pharmacological activity on normal cells. CPBSN38L exhibited strong anticancer activity in multiple murine tumor models of colon adenocarcinoma and hepatocellular carcinoma with no chemotherapy-induced side effects, compared with the standard first-line anticancer drugs irinotecan and topotecan. This study established a side-effect-evitable, universal, and feasible strategy for cancer-targeting therapy.

Metal-amplified sonodynamic therapy of Ti-based chitosan-polyvinyl alcohol hybrid hydrogel dressing against subcutaneous Staphylococcus aureus infection

Ultrasound (US)-mediated sonodynamic therapy (SDT) has received extensive attention in pathogen elimination for non-invasiveness and high spatial and temporal accuracy. Considering that hydrogel can provide a healing-friendly environment for wounds, in this work, hybrid hydrogels are constructed by embedding Ag doped TiO2 nanoparticles in chitosan-polyvinyl alcohol hydrogels for enhanced sonodynamic antibacterial therapy. With metal silver doped, TiO2 nanoparticles sonosensitivity is improved to generate more reactive oxygen species (ROS), which endows hybrid hydrogels with high-efficient antibacterial properties. In vivo results show that hybrid hydrogel dressing can prevent infection and promote wound closure within 2 days. The healing ratio excess 95 % with no pus produced at the end of treatment. The therapeutic mechanism was identified that heterojunction formed in Ag doped TiO2 facilitates the separation of charge carriers under US irradiation, leading to elevating ROS generation. The generated ROS promote hybrid hydrogels sonodynamic antibacterial therapeutic efficacy to thoroughly eliminate pathogen via disrupting bacterial cell membrane integrity, decreasing membrane fluidity and increasing membrane permeability. Besides, biofilm formation could be effectively inhibited. This work developed a hybrid hydrogel with amplified SDT effect for wound healing, which is expected to provide inspiration of hybrid hydrogels design and Ti-based nanomaterials sonosensitivity enhancement.

Influence of thermophysical and acoustic properties on temperature elevation at muscle/bone interface induced by ultrasound hyperthermia

Therapeutic ultrasound heating is a very common technique in the treatment of muscular and joints injuries. However, insufficient or excessive heating delivered to living tissues can be either innocuous or hazardous to the patient. The present work deals with the heat transfer process in living tissues, with particular concern on the behavior at the muscle-bone interface, when ultrasound irradiation is applied. Based on the Generalized Integral Transform Technique (GITT), a hybrid numerical-analytical solution of the Pennes’ equation using the open-source UNIT code (“UNified Integral Transforms”) is proposed, considering different boundary conditions. The influence of physical properties and parameters, such as beam incidence angle, acoustic attenuation coefficients for refracted longitudinal and shear waves in the bone, and blood perfusion in the muscle, were more closely analyzed. Numerical results of temperature profiles showing variations of up to 2 °C for different situations are presented, illustrating a marked dependence of heating patterns on the perfusion rates as well as on the effect of shear waves. The conclusions are that such type of more detailed analysis is essential for the accurate identification of physical properties in living tissues and phantoms and can contribute to the treatment planning for therapeutic ultrasound.

Ionized water-soluble organic nanosheets with light/ultrasound dual excitation channels for efficient killing of multidrug-resistant bacteria.

A novel ionized heavy-atom-free two-dimensional organic nanosheet was prepared and exhibited highly selective generation of singlet oxygen under both light and ultrasound excitation. These ionized nanosheets displayed excellent dispersibility in water and enhanced singlet oxygen production efficiency compared to their non-assembled monomers. Antimicrobial experiments have revealed their potent bactericidal effects on drug-resistant E. coli and S. aureus under both visible light and ultrasound irradiation.

MnO2/Ce6 microbubble-mediated hypoxia modulation for enhancing sono-photodynamic therapy against triple negative breast cancer.

Sono-photodynamic therapy (SPDT) has emerged as a promising treatment modality for triple negative breast cancer (TNBC). However, the hypoxic tumor microenvironment hinders the application of SPDT. Herein, in this study, a multifunctional platform (MnO2/Ce6@MBs) was designed to address this issue. A sono-photosensitizer (Ce6) and a hypoxia modulator (MnO2) were loaded into microbubbles and precisely released within tumor tissues under ultrasound irradiation. MnO2in situ reacted with the excess H2O2 and H+ and produced O2 within the TNBC tumor, which alleviated hypoxia and augmented SPDT by increasing ROS generation. Meanwhile, the reaction product Mn2+ was able to achieve T1-weighted MRI for enhanced tumor imaging. Additionally, Ce6 and microbubbles served as a fluorescence imaging contrast agent and a contrast-enhanced ultrasound imaging agent, respectively. In in vivo anti-tumor studies, under the FL/US/MR imaging guidance, MnO2/Ce6@MBs combined with SPDT significantly reversed tumor hypoxia and inhibited tumor growth in 4T1-tumor bearing mice. This work presents a theragnostic system for reversing tumor hypoxia and enhancing TNBC treatment.

Integrin αvβ3-targeted self-assembled polypeptide nanomicelles for efficacious sonodynamic therapy against breast cancer.

Sonodynamic therapy (SDT) is an advanced non-invasive cancer treatment strategy with moderate tissue penetration, less invasiveness and a reliable curative effect. However, due to the low stability, potential bio-toxicity and lack of tumor targeting capability of most sonosensitizers, the vast clinical application of SDT has been challenging and limited. Therefore, it is desirable to develop a novel approach to implement sonosensitizers to SDT for cancer treatments. In this study, an amphiphilic polypeptide was designed to effectively encapsulate rose bengal (RB) as a model sonosensitizer to form peptido-nanomicelles (REPNs). The as-fabricated REPNs demonstrated satisfactory tumor targeting and fluorescence performances, which made them superb imaging tracers in vivo. In the meantime, they generated considerable amounts of reactive oxygen species (ROS) to promote tumor cell apoptosis under ultrasound irradiation and showed excellent anti-tumor performance without obvious side effects. These engineered nanomicelles in combination with medical ultrasound may be used to achieve integrin αvβ3-targeted sonodynamic therapy against breast cancer, and it is also a promising non-invasive cancer treatment strategy for clinical translations.