• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Recent progress in theranostic microbubbles

    2023-10-14 02:54:54ZiyoWngZiynFengFngxueDuXiXingXinyiTngLiQiuZhiyongQin
    Chinese Chemical Letters 2023年9期

    Ziyo Wng, Ziyn Feng, Fngxue Du, Xi Xing, Xinyi Tng, Li Qiu,?,Zhiyong Qin

    a Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, China

    b State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy,Chengdu 610041, China

    Keywords:Microbubbles Nanobubbles Ultrasound Ceus Cavitation Theranostics

    ABSTRACT Ultrasonography is an important complement to clinical diagnosis, and the application of microbubbles effectively improved diagnostic accuracy in echography.In scientific research, the sizes of microbubbles range from nanometers to microns.By optimizing the fabrication process, bubble sizes and ultrasound parameters, microbubbles can also be used for drug delivery and therapeutic monitoring.In this review,we summarize the recent advances in the diagnosis and treatment of microbubbles according to their different components.Modification of microbubble shells allows for more accurate imaging and detection and the combined utilization of US-targeted MB destruction (UTMD) allows for non-invasive, precise and targeted delivery of drug molecules to pathological tissues.These features pave the way for the emerge of theranostic microbubbles by combination of functional compositions and the application of multifunctional materials.Theranostic microbubbles allow for the simultaneous process of diagnosis, visualization of drug delivery and therapeutic monitoring.Ultimately, theranostic microbubbles are promising in clinical practice and would enhance contrast-enhanced US (CEUS) to a new qualitative level.

    1.Introduction

    Ultrasound (US) imaging is an economic, min-invasive diagnostic procedure which has been widely used in clinical fields.Because of the similar water proportion of many soft tissues and tumors, the acoustic impedances between them can be indistinguishable, making the images ambiguous and the diagnosis diffi-cult.To tackle these challenges, US contrast agents (UCAs) were explored to enable US imaging effectiveness.UCAs are mainly gaseous micro-bubbles (MBs), entering the human blood circulation to achieve different goals.Generally, MBs have a more powerful acoustic impedance than that of the surrounding fluids and biological tissue.Consequently, utilizing MBs can efficiently improve the reflection of US, reaching a better image resolution for precise diagnosis [1,2].Nanosized MBs, designed on the basis of MBs, have the capability to penetrate through blood vessels for extravascular imaging and therapy.

    Fig.1.Illustration of the structure of a MB.

    2.Composition

    MBs are mostly gas spheres of several μm diameter.Usually,they are composed of three parts: the gas core, the shell enclosing the gas core, and the cargo attached to or encapsulated by the shell, as shown in Fig.1.The most significant concern in the fabrication of MBs is their stability, which will influence the effects of both imaging and therapy [3].

    Fig.2.Pictures of diagnostic MBs.(a) SEM of air MBs.(Scale bar: 5 μm).Copied with permission [9].Copyright 2022, Elsevier.(b) SEM images of C3F8 MB.Copied with permission [11].Copyright 2018, Springer Nature.(c) TEM image of Anabaena flos-aquae derived gas vesicles.Copied with permission [17].Copyright 2022, Elsevier.(d) CEUS imaging of orthotopic breast tumor and the sentinel lymph node in mice.Copied with permission [20].Copyright 2021, Springer Nature.

    2.1. Gas core

    Stability of MBs is partly determined by the gas core inside.It is reported that gas type with higher water solubility generates larger bubbles [4].Different solubilities of different gasses, besides, can influence the blood recirculation time of MBs, which is crucial for theranostic efficacy [5].On the other hand, the gas type influences the zeta potential of MBs, which subsequently has an impact on the stability.According to literature, as for negatively-charged microbubbles, OH-ions accumulate in the gas-water interfaces [6].As a result, the ability of MBs to absorb OH-ions on the shell surface partly leans on the properties of gas core.

    Conventionally, perfluoropropane (C3F8), perfluorobutane(C4F10, PFB), and sulfur hexafluoride (SF6) have been used in clinical fields, as Definity, Sonazoid, Optison and SonoVue.

    2.2. Shell

    A unique shell is utilized to support MBs since gas bubbles in aqueous environments are unsteady on their own.Maintaining an MB’s unity throughout preparation and utilization is the shell’s primary purpose.

    The shell’s formation controls its elasticity, which in turn affects MBs stability and acoustic response when exposed to a US field [7].A range of biocompatible substances has been selected as MBs’shells, producing a variety of shell qualities.Both synthetic and natural polymers, which make up the MBs shell by themselves or after adjustment, can enhance the characteristics of MBs, like interacting with particular molecules or tissues.

    2.3. Cargo delivery

    Due to their unique qualities, such as biocompatibility, nanosize, high surface area, and various compositions, MBs are being employed more and more as carriers for both drugs and contrast agents (Fig.2a) [8,9].The hydrophobic cargo can either retain covalent or non-covalent connection to the shell of MBs,viaspecific ligands [10], or they can be enclosed within the MBs (Fig.2b) [11].

    3.Fabrication

    Approaches for preparing MBs involving stochastic techniques,forced extrusion, template layer-by-layer deposition, and microfluidic techniques [12].

    Ultrasonication, excimer laser ablation, and high shear emulsification are three main categories of stochastic techniques.Numerous bubbles of a diverse scale range are produced using stochastic techniques [13].Approaches for forced extrusion comprise electrohydrodynamic atomization, inkjet printing, and membrane emulsification.This creates MBs for medium sizes [14].Layer-by-layer(LbL) assembling based on different disposable core templates is used in template layer-by-layer deposition to produce hollow microspheres with a homogenous particle size [15].To improve control of size distribution and, therefore, accuracy and homogeneity,a microfluidic technique is used.Viathe utilization of a microfluidic system, MBs are produced by transporting the components through numerous channels [16].

    Nanosized microbubbles are bubbles of nanometer-scaled and,as a result, have particular characteristics (Fig.2c) [17].The bulk of the construction processes for nanosized microbubbles were developed from MB synthesis methods.Both self-assembled nanosized microbubbles and phase-shift perfluorocarbon droplets are made using corresponding procedures.The main method of creating nanosized microbubbles involves the direct self-assembling of several phospholipids, proteins, and surfactants at the surface of an aqueous dissolving medium [18].As for nanodroplets, condensation of MBs is a common process using existing MBs [19].

    4.Diagnostic MB

    With the air-liquid interface of bubbles, microbubbles are currently the most widely used in clinical diagnosis of diseases, as shown in Fig.2d [20].

    4.1. Gas core

    According to the mechanism of contrast enhanced imaging, gas core plays a key role in diagnostic MBs.

    4.1.1.Traditional gas core

    New approaches to US imaging have been sparked by the development of MBs.MBs vibrate when exposed to pressure alterations,resulting in a nonlinear acoustic signal.By comparing different signals, MBs can be obviously separated from the surrounding media.This process suggests a number of methods for identifying MBs that take use of nonlinear acoustic signal, including pulse/phase reversal, power modulation, and contrast pulse sequencing [21].Moreover, in the aqueous medium as well as on solid support, it has been convincingly shown that diagnostic US imaging methods are capable of identifying single MB with high susceptibility,viaselective targeting [22].

    Traditional MBs typically behave hydrodynamically similarly to red blood cells (RBCs) due to the alike size distribution, in order to travel in the circulation and communicate with the endothelial cells along the vessels [23].These traits have a significant impact on the targeting property of MBs.The utilizations of classic MB are primarily focused on atherosclerosis, ischemia-reperfusion damage, inflammatory bowel disease, and angiogenesis since only intravascular targets can be addressed by MBs.Contrast-enhanced US (CEUS) with MBs can provide very precise and trustworthy identification in comparison to standard anatomical US, particularly in the early stage of these illnesses [24].

    Despite MBs’effectiveness in several intravascular imaging applications, their relatively large particle sizes continue to hinder their ability to identify cell-surface markers extravascularly.For targeting in tissues, necessary altering of MB sizes is needed to accommodate vascular fenestrations.For example, leaky tumor vasculature permit the passage of nanoparticles which are smaller than 700 nm [25], while enhanced vascular permeability in insulitis can cause nanoparticles with a size of 100-300 nm to travel into the islet microenvironment [26].As a result, nanosized MBs were proposed.

    Recent years have seen the development of nanocarriers for their therapeutic efficiency, reduced toxicity and selective accumulation [27].In comparison with MB, nanosized MBs gain higher collection in extravascular regions, improving the signal of the target areas, especially in tumors with the help of the enhanced permeability and retention (EPR) effect [28,29].Additionally, the exterior of nanosized MBs may be altered by attaching certain targeting molecules to enhance accumulation in tissues and boost imaging effectiveness.But, there still are drawbacks to employing nanosized MBs, such as weak signal intensity and low stability [30].

    4.1.2.Novel gas core

    Various methods have been tested in order to create nanosized MBs that can maintain their stability throughout circulation while achieving the best imaging efficiency: (1) nanodroplets with acoustic droplet vaporization (ADV); (2) nanoscale gas-filled protein structures produced by cells or bacteria; (3)in situproduction of gasviabio/chemical reactions.

    Phase-shift MBs, which have an extended recirculation time due to their stability, as well as comparatively easier synthesis procedures, have become popular as MB substitutes in latest days.Most of them are nanoparticles or nanodroplets filled with perfluorocarbon (PFC), which range in size from 250 nm to 500 nm [31,32].These nanodroplets have a better chance of leaving the vessels and finding the targeted locations because of their reduced sizes[33,34].The liquid core inside can be transformed into gas and used as conventional MBs at the following stage, which is known as ADV.These ADV-produced bubbles oscillate under acoustic pressure, creating signals that a receiving transducer may pick up[35,36].Based on spontaneous nucleation, a novel PFBNB nanodroplet with a reduced vaporization threshold was created by Jian Anet al.for arterial labeling US subtraction angiography (ALUSA).The outcomes show a color-coded super-resolution ALUSA picture with a resolution of 36 μm in a rabbit kidney, showing the vessels precisely [37].Similarly, it has been demonstrated that CEUS with phase-shift nanodroplets can identify insulitis before the development of diabetes [38].

    The size of the droplets should be thoroughly evaluated in order to assure the stability and phase transition behavior of these nanoagents.Smaller particles have greater surface tension at the border between the droplet and the bulk liquid, which increases the Laplace pressure within the PFC droplet, according to several researchers [39].They have a larger vaporization threshold, as a result, which might restrict their therapeutic applications [40].The rise of vaporization threshold can be avoided by employing perfluorocarbon types with lower boiling points according to current study [41].They have previously proved their effectiveness and qualities as contrast agents assessedin vivo.According to the findings, droplets can offer contrast enhancement comparable to that of traditional MBs and, if constructed appropriately, can stay in circulation for a longer period of time [42].Another method that concentrated on spontaneous nucleation employed PFCs with boiling temperatures between 37°C and 56°C.This approach, which involves saturating a cosolvent with PFC before adding a subpar solvent to lower solvent quality, making droplets to naturally nucleate, is frequently called ouzo method [43].

    Aquatic bacteria and archaea produce special gas-filled protein structures called gas vesicles (GVs) that are 200 nm in size, have a 2-nm shell around the air core [44].GVs serve as floating devices that let aquatic microorganisms live in a habitat at the right water depth for adequate photosynthetic illumination [45].GVs are structurally stable with nanoscale size because their special shells are permeable to gas but exclude water.GVs provide great US imaging capability and are biocompatible [46].GVs have been proven to produce stable US contrast that is readily detectedin vitroandin vivo[47].In vitroandin vivoassessments of GVs have been demonstrated.These vesicles’scale makes it possible to mark targets outside the circulation.Gas vesicles may also be produced for bacterial or cell monitoring due to their intracellular detectability, like the activity of enzymes.

    However, similar to other common nanoparticles, most of the GVs are often absorbed in non-targeted organs following intravenous injection, such as the liver, spleen, and lungs [48].GVs were given surface alterations to enhance their pharmacokinetics and address the systemic clearance problem.According to several studies, coating GVs with polyethylene glycol (PEG) or hyaluronic acid(HA) can specifically boost the concentration of GVs at the tumor site [49,50].By combining PEG and HA in GV shells, PEGylated HAGVs (pH-GVs) for in-tumor molecular US imaging were designed[17].This allowed them to bypass clearance from the reticular system (RES) and utilize EPR effects.

    Without enclosing any gas precursor, such gas-generating nanoparticles may outperform conventional gas-filled MBs, since they may travel steadily in the circulation and can efficiently concentrate in tumor tissues through EPR effect [51].For illustration,gas-generating polymeric nanoparticles (GGPNPs) were developed,with the creation of carbon dioxide (CO2) nanobubbles on their surface caused by the hydrolysis reactions.Nanobubbles significantly grow or combine to form MBs, which show resonance [52].

    This is the basis for considering the specific microenvironmentin situwhich may drive gas creation.For example, at the acidic pH of tumor tissues, calcium carbonate (CaCO3) nanocomposites can break down and produce echogenic CO2bubbles [53].After mixing it with additional elements, its imaging potential has been investigated in various researches [54,55].

    4.2. Shell

    4.2.1.Basic composition

    Shell flexibility and stiffness are controlled by shell constitution,which affects MB stability and acoustic response when exposed to ultrasonic pressure [56,57].MBs have been designed using various typically biocompatible substances, including lipids, inorganic nanoscale polymers, and proteins.Due to the flexible and elastic nature of lipid MB shells, it is simple to produce echoes even in low-acoustic pressure evaluations [1,58].MB shells made of both polymers and proteins are more robust to contraction and expansion.These kind of MBs have the potential of using in high frequency US imaging [59].

    Shells can be established to perform certain tasks based on the unique features of different constituents.By joining HA polymer to the shell, Mary W.N.Burnset al.created targeted and bioresponsive MBs.HA transforms into a hydrogel and muffles the acoustic signal once it cross-linked.Based on this, they created a pHsensitive MB platform using a reversible pH-sensitive cross-linker[60].

    As previously noted, the backscattering capability reduced as the size of the nanosized MBs decreases [61].One solution to this issue is to change the makeup of the shells.Despite the impact of the bubble size, shell features have an important influence on bubble behaviors [62].The outcome demonstrates that there is a clear correlation between the nonlinear behavior of the shell under US and its stiffness.The stiffness variation has a significant influence on the pressure threshold.As a result, multiple attempts to employ relatively flexible shells have been made [63,64].

    4.2.2.Targeting

    The traditional MB circulates with bloodstream and cannot be employed for tissue-specific applications since it lacks a specialized capacity to react with specific sites.For tackling this challenge, targeted MB is made to promote the accumulation in only certain tissues, organs,etc.Targeted imaging, additionally, can significantly lower the injection volume of MBs and reduce the diffi-culty of imaging [20,59].

    Fig.3.Ultrasound imaging of tumor after injection of biotinylated ligand MBs.(a)Grayscale ultrasound imaging of tumor after injection of SonoVue MB, NB, NB-A,NB-R and NB-A/NB-R at various time points (10, 30, 60, 120 and 300 s).(b, c) Corresponding time-intensity curves and AUC analysis with data extracted from (a).The data represent the mean ± S.E.M.(n=3 per group).A one-way ANOVA test was used for statistical analysis; ns: no significance, ???P < 0.001, ????P < 0.0001 compared with the Sonovue group.Copied with permission [65].Copyright 2021,Elsevier.

    Different ligands, including antibodies, peptides, and carbohydrates, were attached to the MBs to improve their capacity to target.Additionally, the EPR effect is investigated, which also causes nanosized MBs to accumulate more in tumors.

    There are various conventional methods for specific ligands coupling to MB membranes [59].(1) Adding the targeted ligand to the bubble’s outer shell directly.This technique works well for ligands that are lipid-bound because they can resist the challenging MBs synthesis conditions (Fig.3) [65].(2) Using electrostatic adsorption, self-ionic bonding [66,67], or other techniques to attach antibodies or ligands to the MB shell membrane.However,in vivoenvironment has an influence on the connections, making the desired targeting action less likely to occur.(3) Coupling agents are a category of compounds with two ends that each has a unique set of characteristics.These various groups may interact with various organic molecules to create a strong connection.Certain ligands or antibodies can link to the MB shellviacoupling agents indirectly.(4) The MB shell’s formulation includes the bridging agent.The bridging agent’s composition is firstly modified by adding the required chemical groups, which will eventually create functional groups.The functional groups are triggered once the MB has formed, and they are then coupled with the ligand.(5)A biotinylated ligand is connected by incorporating biotin into the shell membrane layer and using avidin as a “bridging” agent.The strongest non-covalent interaction currently understood is that between biotin and avidin [68,69].

    Another commonly accepted technique to achieve targeting is to use membrane generated from natural cells, such as platelets,erythrocytes, cancer cells, and stem cells.Modern research has focused heavily on cell membrane-camouflaged drug delivery systems (CMCDDs), which are widely recognized for their superior biocompatibility and potential to improve the targeting effect [70].Additionally, MBs have been included to this targeting strategy.Because the membrane proteins and the original immune components are there, MBs can acquire the cells’innate capacity for multitargeting.This technique can also increase the biocompatibility of MBs and prolonged circulation time [71].For instance, in the case of sepsis-induced acute renal injury [72] and myocardial ischemia-reperfusion injury [73], platelet membrane-coated hybrid MBs were equipped with a variety of adhesive receptors (such as integrin IIb3), benefiting from selective adherence to injured endothelium.Similar to this, Natacha Jugniotet al.synthesized the first nanosized MBsviatriple-negative breast cancer cell membrane as a targeted diagnostic agent [74], taking use of the homotypic recognition of tumor cells.

    4.3. Delivery of contrast agents

    4.3.1.Strengths of multimodal imaging

    Multimodal imaging enables the combination of US imaging with other clinical imaging examinations.US imaging is a realtime, practical, and secure imaging option, but it is less accurate in detecting soft tissues than other imaging methods [75].Combing US with other imaging techniques, say, MRI, can provide more comprehensive understanding to the patients’condition.It is investigated if adding multimodal contrast agents to MBs can address this issue, delivering more precise information [76].

    4.3.2.Construction of multimodal imaging MBs

    The creation of multimodal MBs involves the use of components with various imaging capabilities.An US-responsive dualmodal US/T1-MRI MB was created by Young Il Yoonet al.for the effective diagnosis of prostate cancer.To identify malignancies using T1-MRI, Fe3+chelated-melanin nanoparticles (Fe3+MNPs) were created.The MB+Fe3+MNPPs complex was then createdviaa simple charge interaction between the MBs and Fe3+MNPPs [67].Furthermore, because of its paramagnetic characteristics and shorter T1 relaxation durations of hydrogens in nearby water molecules,which can provide high contrast on T1 images [77], gadolinium(Gd) has been used for MRI/US dual-modality molecular imaging in breast cancer animal models.

    5.Therapeutic MB

    The applications of MBs as UCAs have been highlighted above.MBs have also been thoroughly investigated as a tool to enhance drug delivery [78].

    5.1. Gas core

    The gas cores of MBs have the potential to improve therapeutic outcomes.Numerous different biological effects are induced by their synthesis, oscillation and collapse [79].

    5.1.1.US cavitation

    One of the effects US induces is cavitation, or MB oscillation.As mentioned above, when US waves are applied to an aqueous medium, the MBs within will compress and expand in accordance with the waves.This process, in which these tiny bubbles go through growth and collapse sessions or resonance in the medium when exposed to acoustic radiation, is known as the "cavitation process" [80].Scientists divided them into two types of cavitation bubbles basing on the acoustic pressure and the behavior of MBs.The bubbles in the US field will gradually grow to a crucial size known as resonance size [81].If the MB exceeds its resonance size within one or several acoustic cycles, becomes unstable and collapses violently, this phenomenon is called inertial cavitation.If, on the contrary, it oscillates for many cycles around its resonance size without collapse, it is called stable cavitation (or non-inertial cavitation) [82], as shown in Figs.4a and b.Relatively speaking, MBs undergo inertial cavitation under higher acoustic pressure and stable cavitation under lower acoustic pressure [83].

    Fig.4.MB cavitation.(a) Schematic of stable cavitation.Copied with permission [80].Copyright 2003, Ivyspring International.(b) Schematic of inertial cavitation.Copied with permission [80].Copyright 2003, Ivyspring International.(c) Impact of cavitation on cells.Copied with permission [84].Copyright 2021, Elsevier.

    As a mechanical effect, cavitation causes injury to the immediately adjacent tissue, including cell death and thrombolysis[11,84,85].Its applications in acute myocardial infarction, stroke,and peripheral arterial disease have seen positive outcomes [86].This effect is also explored in multiple malignant diseases.The treatment with MBs can induce vascular damage and blood flow disruption in tumor, and eventually reduce tumor growth and prolong survival [79].

    5.1.2.Sonoporation

    As mentioned above, during the cavitation process, MB produces great energy to its surroundings.This energy is transmitted to the surrounding cells in the form of mechanical streams or microjets, causing shear stress on their membranes, therefore increases the cell permeability, as shown in Fig.4c.This is because that it creates transient pores in cellular membranes when bubble dynamics become violent enough.This phenomenon is called sonoporation [78].In the majority of the experiments, sonoporation was used to increase the uptake of molecules or to penetrate biological barriers [87].However, different tissues and medications have their own ideal ultrasonic parameters respectively.Thus finding the ideal ultrasonic parameter and maximizing sonoporation effect also worth exploring.According to Qi Liuet al., the optimal parameters of the sonoporation effect for MDA-MB-231 cells were 300 mW/cm2of US intensity, 2 min of irradiation time, and 20%MBs concentration.In a specific range, the intake of fluorescence staining first increased and then decreased with the increase of US power intensity, irradiation time, and MB concentration [88].On the other hand, Quet al.investigated the effectiveness of sonoporation on several breast cancer cell lines and discovered that each cell line has its ideal combination of US parameters to increase the sonoporation efficiency respectively [89].To accelerate benchto-bedside translation, Kotopouliset al.compared three clinically available MBs and summarized that each kind of MBs had the optimal concentration and US parameters to fulfill the sonoporation effect, with SonoVue being best at lower intensities and SonazoidTMat higher intensities [90].

    US-targeted MB destruction (UTMD) is a type of US therapy combining ultrasonic cavitation and sonoporation.Drug-carrying MBs are injected into bloodstream, and when US is applied, the MBs will play as cavitation nuclei as well as sonoporation inducer,thus releasing the drug and enhance its effect [91].MBs are widely used in targeted drug delivery of drugs that have high systemic side effects or are easily degradedin vivo, ranging from nucleic acids, to proteins, chemotherapies, and even immunotherapy [92].For example, Liuet al.fabricated chitosan-based injectable hydrogel embedded with SDF-1α-carrying nanodroplets (PFP@NDs-PEGSDF-1α) that vaporize into MBs under the application of US, and proved them useful in enhancing the cartilage repairin vitroandin vivo[93].Moreover, a first clinical trial was performed based on UTMD-induced chemotherapy in which researchers combined US,MBs, and chemotherapy in a clinical setting using commercially available equipment.This joint treatment augmented the clinical efficacy of gemcitabine and extend survival time in patients with pancreatic ductal adenocarcinoma [94].Later, John R.Eisenbreyet al.combined UTMD with transarterial radioembolization in a slightly larger group of 28 patients with hepatocellular carcinoma,and found this approach feasible with an excellent safety profile and an improved hepatocellular carcinoma treatment response[95].However, there is still a long way to go to introduce it to clinical applications.More and larger trials are needed to fill this gap.

    16.She fell fast asleep: In this version of the story, Goldilocks falling asleep in a strange home gives her some sympathy. Either she is simply unrepentant or completely destitute41. When we view her intrusion as that of a homeless or vagrant child without a home, food, bed or civilized training, her pathos42, and consequently her sympathetic qualities, is heightened. Of course, she could just be a spoiled child who lives by the motto, What s mine is mine and what s yours is mine! The interpretation43 is up to the teller17 and the listener.Return to place in story.

    5.1.3.Gas therapy

    PFC makes up the majority of gas cores, since PFC gas cores are stable, thus can provide longerin vivocirculation time.Aside from these advantages, PFC has high oxygen-carrying capacity, which can be used to alleviate the hypoxic tumor environment and works as a synergistic treatment [96].

    MBs are also being explored as gas carriers to delivery therapeutic gasses.This approach has been investigated in alleviating cardiac allograft rejection by Tao Linet al.who concluded that nitric-oxide (NO) released from MBs significantly suppressed thrombosis and reduced inflammatory cell infiltration [97].Zhonget al., on the other hand, observed similar anti-inflammatory and thrombolysis effects by administrating H2S-loaded MBs in an ischemia-reperfusion injury model [98].

    5.2. Shell

    MBs are usually injected intravenously in clinical practice, and then they circulate throughout the body.This makes the distribution of MBs difficult to predict, and it is possible that the contents of the MBs may be deposited in undesired tissues, causing toxic side effects on the rest of the body.One way to overcome this problem is to combine ligands or receptors to the shells to create “target MBs” that deposit in the target tissues.Glucocorticoids are often the first-line therapy for patients with immuneassociated diseases.However, its dose-dependent side effects, such as the increased risk of infection and metabolic disturbances, hamper its clinical use.Kui Fanet al.fabricated a kind of visualized podocyte-targeting and focused US responsive glucocorticoid MBs that delivered dexamethasone (Dex) to podocyte specifically, thus reduced systemic side effects [99].Except for limiting side effects,targeted MB can also be useful for active drug delivery to target lesions.This approach has been investigated for targeted intracerebral delivery by Xue Miet al., who fabricated US-responsive NBs to load asparagine endopeptidase (AEP) inhibitor RR-11a, and modified the NB surface with either AEP recognizable peptide AAN or pro-transendothelial transversal motif RGD for AEP-targeted treatment of Alzheimer’s disease (AD).They effectively reduced amyloid plaque deposition in the hippocampus and tau cleavage, increased RR-11a molecule accumulation in the AD lesion, and subsequently improved cognitive performance in AD model mouse models [100].

    Besides combining targeting ligands to shell, adding environmentally responsive materials to MB shell is another way to produce MBs that deposit cargo at the target spot.By adjusting the fabrication technics of the shells, drugs within can only be released in specific condition.For instance, researchers created a hydroxychloroquine (HCQ)-carrying MB with dual pH and US responsiveness that selectively releases medications in acidic tumor microenvironment or when sufficient ultrasonic pressure is applied.This method prevented tumor lung metastasis and exhibits good tumor-targeting, biocompatibility, and biosafety with a tumor growth suppression value of 80.02% simultaneously (Fig.5) [101].

    5.3. Drug delivery

    Cell membranes can prohibit large molecules (e.g., drugs and genes) from entering cells.Some scientists are practicing lipid nanocarriers for their advantages of improving drug solubility and bioavailability [102].MBs are one of the commonly used nanocarriers, and drug delivery by targeted use of US to rupture drugcarrying MBs can result in local drug release, thus achieve better therapeutic effect [78].

    5.3.1.Chemotherapy

    Chemotherapy has an irreplaceable position in anti-cancer strategies, but conventional chemotherapy has substantial side effects and leads easily to cancer treatment failure [103].The shell of the MBs can help avoid direct exposure of chemotherapeutic drugs to internal environment, thus reducing their systemic toxicity and enhance the drug deposition in tumorous area.The use of encapsulated chemotherapeutic drugs has proved effective in breast cancer, ovarian cancer and several other kinds of solid tumors by increasing circulation time and tumor drug accumulation, while limiting bioavailability and toxicity in normal tissues,as shown in Fig.5 [101,104].To further enhance the efficacy, scientists combined Pt(IV), chloroquine (CQ) and anti-PD-L1 peptide(DPPA-1) by encapsulating all three of the anticancer drugs into the MBs, which achieved a superior synergistic effect of chemoimmunotherapy [105].

    A low-intensity US (US) combined with certain chemical agents called sonosensitizers in a process known as sonodynamic therapy (SDT) has been developed as a therapeutic modality since late 1980s [106] and is gaining widespread attention in the treatment of diseases.In SDT, US is used as the stimuli to trigger the production of reactive oxygen species (ROS) by sonosensitizers to affect the survival of target cells [107,108].The combination of MBs and SDT made it possible for US to treat disease in two different aspects, thus using US in a more efficient way.Loganet al.evaluated the potential to use MBs to deliver Rose Bengal, a sonosensitizer,together with paclitaxel (PTX) and doxorubicin (Dox) to combine SDT and chemotherapy as a potential treatment for breast cancer,and discovered a significant reduction in both the cancer cell viability and tumor volume compared to the ones treated with the drug-carrying MBs alone or a Cremophor EL suspension of PTX and Dox [109].Since ROS is produced in SDT, combining SDT with other antitumor therapy can effectively alleviate hypoxia in TME,and this approach to encapsulate sonosensitizers into MB has seen applausive results in many malignant as well as benign diseases[110-112].

    5.3.3.Gene therapy

    Gene therapy is a breakthrough in the management of many genetically defect illnesses, including cancer, and this kind of therapy paths the future direction for the treatment of ailments that cannot be cured by modern medicine.Because genes are too large to enter cells passively and easily degraded by enzymesin vivo,reliable and effective carriers are required to deliver them to target cells [112,113].To date, inducing the expression of a certain gene is realized through the introduction of plasmid DNA (pDNA)or messenger RNA (mRNA) into target cells, while the suppression a certain gene is realized through small interfering RNA (siRNA)or RNA interference (RNAi) technology [114].The most challenging part for it is to exploit safe and efficient gene delivery vectors to protect genetic cargos as well as facilitate their transfer to the target site of action [115], and the application of US-mediated gene delivery (UMGD) allows for a direct, site-specific transfer of genetic materials into the organ/site of interest.With the help of UTMD and sonoporation, this approach also enhances gene uptake by increasing cell membrane permeability [116].Wuet al.encapsulated plasmid DNA (pDNA) into a phase-changeable cationic MB, and discovered this kind of DNA-carrying MBs to possess favorable biocompatibility and its possibility to enhance gene transfection efficiency and therapeutic effect [117].For RNA delivery,Wanget al.synthesized the lipid MBs which were charge-coupled with galectin-7-siRNA, and utilized UTMD to locally enhance gene transfection efficiency and successfully inhibited galectin-7 expression through siRNA-mediated knockdown in a rat abdominal heterotopic heart transplantation acute rejection model [17].Jennifer C.Wischhusen also announced that UTMD-mediated delivery of microRNA-122 and anti-microRNA-21 modulated the immune microenvironment of Hepa1-6 tumors at the level of cytokine expressions in a murine hepatocellular carcinoma model [118].However,it is yet to discover the parameters of US transducers and protocols that can achieve efficient gene transfer in large animal models and humans, and optimizing the procedure to avoid potential tissue damageviaUMGD.

    Fig.5.US and MB enhance tumor inhibition in vivo.(a) Schematic illustration of the experiment.(b) Photographs of excised tumors at the experiment terminal.(c) The tumor growth curves of different groups in 14 days.(d) The weight of excised tumor in different groups.(e) Body weight changes of mice after different treatments.(f) HE staining, TUNEL and IHC analysis in different groups.Scale bar: 100 μm.All statistical data are expressed as means ± SD (n=5).Copied with permission [101].Copyright 2022, Elsevier.

    6.Theranostic MBs

    6.1. Strength

    The emergence of MBs has sparked creative approaches to both diagnosis and treatment.The characteristics of MBs allow them to act as a carrier for drug delivery while imaging.This makes it possible to monitor the lesion and administer drugs simultaneously to avoid any delayed treatment.Besides, the characteristic of MBs can visualize the traces of drugs for more precise treatment, and enhance their intake by UTMD.These methods address the critical clinical requirement for the creation of a more accurate and effective method of therapy in addition to a non-invasive assessment agent.

    6.2. Construction

    6.2.1.Combination of functional compositions

    Combining diagnostic compositions and therapeutic compositions to build one theranostic MB is the most direct way to achieve this goal.It is easy to understand that the integration of functional elements makes a multifunctional MB.Take Wang’s HCQNDs mentioned above as an example, they fabricated the bubble with HCQ as the cargo for tumor theranostics, which showed excellent tumor-targeting, biocompatibility, biosafety as well as contrast-enhanced ultrasound imaging properties.This approach avoided the insufficient response of traditional MBs to the TME,and paved the way for precise visualization and effective treatment of tumors [101].

    The basic structure of a MB—its gas core, is the most favorable elements for diagnosis.After MBs play as imaging contracts for imaging, they explode to release cargos within if US parameters are switched.In this way, the gas core helps not only imaging, but also drug release.As mentioned, scientists have encapsulated a series of drugs [9,78,79,99,103,104,109], even genes [17,114,117,118],into a basic MB, and this approach not only expanded their functions, enhanced their intake, protected irrelevant tissue, but also visualized the administration of the cargos by releasing them at the site they were just imaged.It is reported that gemcitabine MBs not only revealed significantly affect drug activity and efficacy, US contrast activity compared with unmodified MBs, but also provided substantial tumoral image enhancement before and after destructive US pulses [9].In addition to malignant diseases, combining urokinase (UK) with US and MBs also have a synergistic effect on thrombolysis by remarkably increased the thrombolysis rate deep vein thrombosis dogs [119].The UTMD effect has also been used to open some biological barriers, say, blood brain barrier, for MBs to enter central nervous system to image and administer drugs [100].These findings convincingly suggest that the combination of diagnostic compositions and therapeutic compositions in one MB not only fulfill both effects, but may also realize better therapeutic outcomes.

    Fig.6.Schematic of the effects of theranostic MBs.(a) Schematic of the MB combining SDT, fluorescence imaging and US imaging.Copied with permission [96].Copyright 2022, John Wiley and Sons.(b) Schematic of the imaging and treating utilities of Xe-NBs.Copied with permission [130].Copyright 2018, American Chemical Society.

    In additional to gas core, contrast agent for other kinds of imaging is another kind of functional composition scientists are loading onto MBs to have a better understanding of a patient’s condition.It is reported that the attempt to load thrombus-specific theranostic nanoparticles onto MBs significantly enhanced the photoacoustic contrast in thrombosed vessels specifically and suppressed thrombus formation [120].Lei Sunet al.chose to load temoporfin, a SDT agent, into their MBs.In this way, the tumors can be monitored in real time by temoporfin-mediated fluorescence imaging and PFCMB-enhanced ultrasound imaging while reaching complete obliteration of tumors and efficient extension of the survival time of tumor-bearing mice with minimal systemic adverse effects (Fig.6a)[96].These loaded contrast agents, especially the ones for photoacoustic imaging, are always adopted to PTT as well.In another research, scientists encapsulated IR780-ND into MBs for photoacoustic and fluorescence imaging, as well as for its SDT effect [121].Yet, most of the contrast agents loaded are photoacoustic agents,and this method is far from mature.

    6.2.2.Multifunctional compositions

    Concentrating on a single component with several functions is an additional method of creating theranostic MBs.Numerous studies focusing on the gas core have been proposed in light of the structure of MBs.

    Inertial cavitation has been extensively exploited in this field due to its potent effects upon remote activation, as was previously indicated.Previous studies have suggested that genetically altered bacteria and cells may heterologously produce designed GVs, allowing for non-invasive gene expression imaging [122].Additionally, the use of GVs as cavitation sources has been investigated.It was shown that these biomolecules may be transformed into micrometer-scale cavitating bubbles by low-frequency US, which then unleashes powerful local mechanical effects.As a result, in addition to acting as US imaging contrasts, manufactured GVs can operate as distantly actuated cell-eradicating agents [123].

    Likely, high intensity focused ultrasound (HIFU) and radiofrequency ablation (RFA) may be improved by bubble-caused cavitation [124].For instance, l-menthol was used to create a biocompatible "tri-phase transitional" platform [125].The packed IR-780 would turn light into heat energy when faced an NIR laser, which would cause the enclosed l-menthol to vaporize.The continually created l-menthol bubbles could improve US imaging contrast.lmenthol bubble may also provide a cavitation effect that makes tumor cell membranes more permeable and subsequently enhances the PTT effect.

    Gas therapy, which uses physiologically important gasses, is another way to make use of the therapeutic effects of gas core and has inspired novel, inventive ways to construct MBs [126].The gas can still function as the gas core for imaging in addition to its biological impact.For example, H2O2is now developing as a novel stimuli-responsive modality, with its capacity to produce O2bubbles for US imaging, attenuate tumor hypoxia and improve the therapeutic effectiveness of various treatment subsequently [127].

    Regarding anti-inflammatory gasses, it has been demonstrated that high levels of NO have a crucial impact on the immune system, with their main effects being anti-inflammatory and immunosuppressive [128].For the simultaneous detection and precise therapy of antibody-mediated cardiac allograft rejection (AMR)in cardiac allografts, a new C4d-targeted NO-loaded MB was created.MBs are proved to stay in cardiac allografts with AMR, noninvasively sensing C4d deposition and accurately administering NO[97].

    Similar work has also been pursued using Xenon (Xe).Xe has a strong therapeutic ability to treat neuronal damage and has been shown to be neuroprotective [129].For the real-time US imageguided preventive therapy of the early stroke, Xe-enclosed nanosized MBs have been produced [129].In vivo, the MBs at the site of the ischemic lesion provides the region US contrast imaging effect.Additionally, local neuroprotective Xe administration can restore neurological function with lessened neuron destruction from apoptosis (Fig.6b) [130].

    7.Conclusion

    MBs is proven to be a promising tool for the integration of diagnosis and treatment for a variety of diseases.In this review, we summarized the functions of each component of MBs in diagnosis or treatment, and also proposed several methods to integrate these components to create theranostic MBs.Advances in theranostic MBs have expanded their use mainly to cancers, vascular diseases and CNS diseases.During the past decades, scientists have created more stable MBs, with the ability to circulate longer, target more precisely and carry more therapeutic components.However,there are still some limitations await to be tackled to fully unleash the potential of theranostic MBs.Although it is possible for some kinds of MBs to penetrate to deep tissue, how to balance the bubble size to guarantee both imaging effect and penetration ability is not entirely solved yet.Since imaging and therapeutic US require different US parameters, it will be more convenient if a theranostic US machine is manufactured to image and treat with one US probe.After all, US is the most widely used imaging modality, and the development of theranostic US will be beneficial for all.

    Declaration of competing interest

    The authors declared that they have no financial and personal relationships with other people or organizations that can inappropriately influence their work.

    Acknowledgments

    This work was supported by the National Natural Science Foundation of China-Sichuan Joint Fund Key Program (No.NSFCU21A20417), the National Natural Science Foundation of China(Nos.NSFC31930067, 81971622, 82272003), and the 135 Project for Disciplines of Excellence, West China Hospital, Sichuan University(No.ZYGD18002, China).

    国产单亲对白刺激| 欧美一区二区亚洲| 黄色日韩在线| 欧美潮喷喷水| 女人被狂操c到高潮| 国产成人a∨麻豆精品| 97人妻精品一区二区三区麻豆| 一个人看视频在线观看www免费| 久热久热在线精品观看| 亚洲国产最新在线播放| 国产成人福利小说| 婷婷色麻豆天堂久久| 免费av不卡在线播放| 国产精品不卡视频一区二区| 一级av片app| 熟女人妻精品中文字幕| 国产视频首页在线观看| 亚洲成人中文字幕在线播放| 亚洲av电影在线观看一区二区三区 | 久久鲁丝午夜福利片| 成年免费大片在线观看| 男女视频在线观看网站免费| 永久网站在线| a级一级毛片免费在线观看| 日本黄色片子视频| 国产av国产精品国产| 亚洲精品乱久久久久久| 久久久久久九九精品二区国产| 中文字幕av在线有码专区| 蜜桃久久精品国产亚洲av| 精品一区二区三区视频在线| 69人妻影院| 国产av不卡久久| 精品久久久久久久久亚洲| 美女脱内裤让男人舔精品视频| 日韩在线高清观看一区二区三区| 亚洲图色成人| av女优亚洲男人天堂| 69人妻影院| 久久精品综合一区二区三区| 九九久久精品国产亚洲av麻豆| 日韩av不卡免费在线播放| 欧美人与善性xxx| 日韩视频在线欧美| 成人亚洲精品av一区二区| 国产精品久久久久久精品电影小说 | 亚洲欧美中文字幕日韩二区| 色播亚洲综合网| 综合色av麻豆| 国产精品久久久久久精品电影| 2021天堂中文幕一二区在线观| 国产熟女欧美一区二区| 99re6热这里在线精品视频| 联通29元200g的流量卡| 午夜精品国产一区二区电影 | 一边亲一边摸免费视频| 在线观看一区二区三区| 男女边摸边吃奶| 精品不卡国产一区二区三区| 高清视频免费观看一区二区 | 美女黄网站色视频| 91av网一区二区| 久久久亚洲精品成人影院| 99视频精品全部免费 在线| 久久精品国产亚洲av涩爱| 国产激情偷乱视频一区二区| 亚洲天堂国产精品一区在线| 久热久热在线精品观看| 午夜激情欧美在线| 春色校园在线视频观看| 69av精品久久久久久| 国产高清国产精品国产三级 | 一级毛片aaaaaa免费看小| 亚洲不卡免费看| 麻豆av噜噜一区二区三区| 成人鲁丝片一二三区免费| 水蜜桃什么品种好| 国产精品久久久久久精品电影小说 | 成人鲁丝片一二三区免费| 国产成人aa在线观看| 男插女下体视频免费在线播放| 欧美zozozo另类| 国产精品女同一区二区软件| 色哟哟·www| 美女黄网站色视频| 亚洲美女视频黄频| 哪个播放器可以免费观看大片| 亚洲精品亚洲一区二区| 亚洲欧美一区二区三区黑人 | 在线免费观看不下载黄p国产| 性色avwww在线观看| 免费观看无遮挡的男女| 国产午夜福利久久久久久| 三级经典国产精品| 伦精品一区二区三区| 赤兔流量卡办理| 黄色欧美视频在线观看| 最近最新中文字幕大全电影3| 九九爱精品视频在线观看| 亚洲一区高清亚洲精品| 国产麻豆成人av免费视频| 国产老妇伦熟女老妇高清| 插阴视频在线观看视频| 国产成人a∨麻豆精品| 观看美女的网站| 久久久精品欧美日韩精品| 国产黄a三级三级三级人| 亚州av有码| 国产精品一及| 久久久久久久久大av| 热99在线观看视频| 少妇被粗大猛烈的视频| 国产一区二区三区av在线| 日日啪夜夜撸| 日日啪夜夜撸| 日日啪夜夜撸| 午夜福利在线在线| 精品人妻偷拍中文字幕| 成人毛片a级毛片在线播放| av在线蜜桃| 亚洲欧美精品自产自拍| 欧美日韩综合久久久久久| 国产高清不卡午夜福利| 亚洲经典国产精华液单| 黄色一级大片看看| 亚洲欧美日韩东京热| 久久精品国产亚洲av涩爱| 熟妇人妻久久中文字幕3abv| 国产伦一二天堂av在线观看| 亚洲国产日韩欧美精品在线观看| 亚洲精品一二三| 成人午夜精彩视频在线观看| 99久久精品一区二区三区| 久久精品熟女亚洲av麻豆精品 | 日本-黄色视频高清免费观看| 国产高清三级在线| 亚洲成人一二三区av| 欧美成人a在线观看| 国产精品久久视频播放| 最后的刺客免费高清国语| 国语对白做爰xxxⅹ性视频网站| 午夜福利在线观看吧| 一区二区三区乱码不卡18| 亚洲欧美清纯卡通| 18禁裸乳无遮挡免费网站照片| 国产精品久久视频播放| 日韩欧美精品免费久久| 亚洲va在线va天堂va国产| 午夜免费激情av| 亚洲四区av| 简卡轻食公司| 一级黄片播放器| 久久精品夜色国产| 天堂俺去俺来也www色官网 | 免费看不卡的av| 国产伦理片在线播放av一区| 搞女人的毛片| 黄色一级大片看看| 国产高清不卡午夜福利| av.在线天堂| ponron亚洲| 久久久亚洲精品成人影院| 2022亚洲国产成人精品| 亚洲成人精品中文字幕电影| 美女大奶头视频| 精品国产三级普通话版| 亚洲av电影在线观看一区二区三区 | 内射极品少妇av片p| 看免费成人av毛片| .国产精品久久| 亚洲第一区二区三区不卡| 国产女主播在线喷水免费视频网站 | 日韩制服骚丝袜av| 日韩伦理黄色片| 七月丁香在线播放| 亚洲av免费在线观看| 久久久久久国产a免费观看| 亚洲最大成人av| 欧美性感艳星| 两个人视频免费观看高清| 亚洲婷婷狠狠爱综合网| 男人和女人高潮做爰伦理| 最近2019中文字幕mv第一页| 建设人人有责人人尽责人人享有的 | 国产精品一二三区在线看| 九九久久精品国产亚洲av麻豆| 最近最新中文字幕免费大全7| 国产国拍精品亚洲av在线观看| 国产高清国产精品国产三级 | 国产毛片a区久久久久| 欧美区成人在线视频| 1000部很黄的大片| 日本与韩国留学比较| 久久这里只有精品中国| 美女国产视频在线观看| 高清av免费在线| 欧美一区二区亚洲| 久久韩国三级中文字幕| 久久国内精品自在自线图片| 午夜爱爱视频在线播放| 亚洲精品中文字幕在线视频 | 国内精品宾馆在线| 在线免费观看不下载黄p国产| 国产v大片淫在线免费观看| 极品少妇高潮喷水抽搐| 啦啦啦韩国在线观看视频| 日日摸夜夜添夜夜添av毛片| h日本视频在线播放| 亚洲第一区二区三区不卡| 久久久午夜欧美精品| 最新中文字幕久久久久| 亚洲自偷自拍三级| 偷拍熟女少妇极品色| 大片免费播放器 马上看| 成年人午夜在线观看视频 | 秋霞伦理黄片| 伊人久久精品亚洲午夜| 一级毛片黄色毛片免费观看视频| av在线蜜桃| 少妇人妻一区二区三区视频| 国产精品久久久久久精品电影| 亚洲国产欧美人成| 一夜夜www| 大香蕉97超碰在线| 三级国产精品片| 亚洲不卡免费看| 亚洲av中文字字幕乱码综合| 免费大片黄手机在线观看| 日本黄大片高清| 自拍偷自拍亚洲精品老妇| 精品久久久久久电影网| 亚洲av成人av| 91在线精品国自产拍蜜月| 日本一二三区视频观看| 99热这里只有是精品在线观看| 高清在线视频一区二区三区| 中文字幕av在线有码专区| 一个人看的www免费观看视频| 国产高潮美女av| 26uuu在线亚洲综合色| 日本猛色少妇xxxxx猛交久久| 欧美zozozo另类| 国产精品一区www在线观看| 国产v大片淫在线免费观看| 成人综合一区亚洲| 搞女人的毛片| 麻豆久久精品国产亚洲av| 日韩中字成人| 国产精品日韩av在线免费观看| 在线观看免费高清a一片| 精品人妻熟女av久视频| 欧美高清性xxxxhd video| 国产午夜精品一二区理论片| 黄色日韩在线| 婷婷色麻豆天堂久久| 日韩大片免费观看网站| 国产精品女同一区二区软件| 日本欧美国产在线视频| 99久国产av精品| 成人欧美大片| 国产男女超爽视频在线观看| 日产精品乱码卡一卡2卡三| 日韩欧美三级三区| 视频中文字幕在线观看| 国内精品宾馆在线| 亚洲人成网站在线播| 国产午夜精品一二区理论片| 人体艺术视频欧美日本| 亚洲av男天堂| 春色校园在线视频观看| 亚洲不卡免费看| 久久久欧美国产精品| 夜夜看夜夜爽夜夜摸| 五月伊人婷婷丁香| 久久精品综合一区二区三区| 精品久久久精品久久久| 免费看日本二区| 成年女人在线观看亚洲视频 | 黄色配什么色好看| 天天躁夜夜躁狠狠久久av| 国产成人91sexporn| 免费大片18禁| 蜜桃久久精品国产亚洲av| 联通29元200g的流量卡| av天堂中文字幕网| 亚洲国产精品sss在线观看| 亚洲成人中文字幕在线播放| 欧美另类一区| 国内精品宾馆在线| 丝瓜视频免费看黄片| 日韩成人伦理影院| 国产免费一级a男人的天堂| 黄片wwwwww| 国产色爽女视频免费观看| 黄色一级大片看看| 国产三级在线视频| 亚洲欧洲日产国产| 亚洲婷婷狠狠爱综合网| 男人狂女人下面高潮的视频| 欧美变态另类bdsm刘玥| 身体一侧抽搐| 亚洲国产精品专区欧美| 成人午夜高清在线视频| 青春草国产在线视频| 免费人成在线观看视频色| 国产老妇女一区| 久久精品久久久久久噜噜老黄| 国产高清国产精品国产三级 | 亚洲欧美一区二区三区黑人 | 中文资源天堂在线| 亚洲激情五月婷婷啪啪| 在线观看三级黄色| 国语对白做爰xxxⅹ性视频网站| 狠狠精品人妻久久久久久综合| 久久av网站| 丝袜人妻中文字幕| 夫妻午夜视频| av女优亚洲男人天堂| 欧美av亚洲av综合av国产av | av有码第一页| 波多野结衣一区麻豆| 成人18禁高潮啪啪吃奶动态图| 国产成人aa在线观看| 国产xxxxx性猛交| 免费观看av网站的网址| 久久久久久伊人网av| av卡一久久| 天天躁夜夜躁狠狠躁躁| 国产在线视频一区二区| 国产精品成人在线| 国产高清国产精品国产三级| 国产黄色视频一区二区在线观看| 国产成人精品一,二区| 欧美激情高清一区二区三区 | 久久久久精品久久久久真实原创| 黄色怎么调成土黄色| 精品国产超薄肉色丝袜足j| 亚洲精品一二三| 视频在线观看一区二区三区| 多毛熟女@视频| 欧美日韩精品网址| 久久婷婷青草| 天天操日日干夜夜撸| 啦啦啦在线观看免费高清www| 2021少妇久久久久久久久久久| videos熟女内射| 精品国产露脸久久av麻豆| 色婷婷av一区二区三区视频| 久久午夜福利片| 日日啪夜夜爽| 美女脱内裤让男人舔精品视频| 国产一区二区在线观看av| 在线观看免费高清a一片| 久久久久久人妻| 亚洲经典国产精华液单| 久久这里只有精品19| 王馨瑶露胸无遮挡在线观看| 老熟女久久久| 国产成人精品在线电影| 少妇人妻久久综合中文| 欧美日韩国产mv在线观看视频| 十八禁高潮呻吟视频| 夫妻性生交免费视频一级片| 极品人妻少妇av视频| 日韩欧美精品免费久久| 在线观看人妻少妇| 中文字幕人妻丝袜制服| av又黄又爽大尺度在线免费看| 亚洲av免费高清在线观看| 国产又爽黄色视频| 欧美精品一区二区大全| 男女高潮啪啪啪动态图| 人妻系列 视频| 99re6热这里在线精品视频| 99香蕉大伊视频| 男男h啪啪无遮挡| 国产日韩欧美亚洲二区| 日本-黄色视频高清免费观看| 又粗又硬又长又爽又黄的视频| 欧美日韩av久久| kizo精华| 亚洲熟女精品中文字幕| 少妇猛男粗大的猛烈进出视频| av线在线观看网站| 欧美日韩一区二区视频在线观看视频在线| 一级毛片电影观看| 新久久久久国产一级毛片| 永久网站在线| 高清av免费在线| 精品少妇一区二区三区视频日本电影 | 自拍欧美九色日韩亚洲蝌蚪91| 午夜激情av网站| 亚洲精品一二三| 日韩中字成人| 亚洲国产最新在线播放| 久久久久久久亚洲中文字幕| 交换朋友夫妻互换小说| 中文字幕最新亚洲高清| 欧美亚洲日本最大视频资源| 国产在线免费精品| 亚洲av男天堂| 男人爽女人下面视频在线观看| 免费看不卡的av| 欧美人与性动交α欧美精品济南到 | 久久久久人妻精品一区果冻| 国产成人欧美| 波野结衣二区三区在线| 成年女人毛片免费观看观看9 | 久久韩国三级中文字幕| 亚洲精品av麻豆狂野| 美女视频免费永久观看网站| 国产成人精品在线电影| av又黄又爽大尺度在线免费看| 日韩 亚洲 欧美在线| 亚洲,欧美,日韩| 国产麻豆69| 国产老妇伦熟女老妇高清| 国产精品不卡视频一区二区| 看非洲黑人一级黄片| av电影中文网址| av视频免费观看在线观看| 制服诱惑二区| 性色avwww在线观看| 国产精品香港三级国产av潘金莲 | 国产乱来视频区| 看十八女毛片水多多多| 国产男人的电影天堂91| 久久久精品区二区三区| 久久国产精品大桥未久av| 有码 亚洲区| 老汉色∧v一级毛片| 国产av码专区亚洲av| 丰满乱子伦码专区| 如何舔出高潮| 日本-黄色视频高清免费观看| 国产人伦9x9x在线观看 | 亚洲美女黄色视频免费看| av国产久精品久网站免费入址| 精品一区二区三卡| 国产一区二区三区av在线| 人妻人人澡人人爽人人| 国产精品国产av在线观看| 99热国产这里只有精品6| 色婷婷久久久亚洲欧美| 伦精品一区二区三区| 日韩大片免费观看网站| 麻豆乱淫一区二区| 黑丝袜美女国产一区| 男女国产视频网站| 中文字幕制服av| 午夜福利网站1000一区二区三区| 久久人人爽av亚洲精品天堂| 国产亚洲精品第一综合不卡| 午夜日本视频在线| 久久国产亚洲av麻豆专区| 精品一区二区三卡| 国产熟女午夜一区二区三区| 亚洲四区av| 国产在线视频一区二区| 国产男人的电影天堂91| 国产一级毛片在线| 大话2 男鬼变身卡| 久久精品久久精品一区二区三区| 亚洲第一av免费看| 一区在线观看完整版| 女性被躁到高潮视频| 日韩,欧美,国产一区二区三区| 在线观看三级黄色| 欧美日韩亚洲高清精品| 男女免费视频国产| 久久 成人 亚洲| 亚洲三级黄色毛片| 国产熟女午夜一区二区三区| 美女国产高潮福利片在线看| 九草在线视频观看| 国产亚洲午夜精品一区二区久久| 久久久久久人妻| 亚洲一区二区三区欧美精品| 丰满少妇做爰视频| 欧美黄色片欧美黄色片| 成年女人毛片免费观看观看9 | 我要看黄色一级片免费的| 91精品三级在线观看| 国产亚洲欧美精品永久| 国产爽快片一区二区三区| a级毛片在线看网站| videossex国产| 秋霞伦理黄片| 色婷婷av一区二区三区视频| 久久久精品区二区三区| 高清黄色对白视频在线免费看| 啦啦啦视频在线资源免费观看| 国产av一区二区精品久久| 女人精品久久久久毛片| 蜜桃国产av成人99| 美女大奶头黄色视频| 午夜91福利影院| 十八禁网站网址无遮挡| 欧美日韩亚洲国产一区二区在线观看 | 亚洲av.av天堂| 国产成人欧美| 国产精品国产三级专区第一集| 亚洲精品成人av观看孕妇| 日韩一本色道免费dvd| 亚洲国产色片| 亚洲经典国产精华液单| 两个人看的免费小视频| 日韩视频在线欧美| 精品一区二区三区四区五区乱码 | 精品人妻熟女毛片av久久网站| 国产男女内射视频| 精品亚洲成国产av| 久久精品久久久久久噜噜老黄| 一边摸一边做爽爽视频免费| 午夜福利在线观看免费完整高清在| 啦啦啦在线免费观看视频4| 久久久欧美国产精品| av又黄又爽大尺度在线免费看| 熟妇人妻不卡中文字幕| 成人手机av| 久久精品夜色国产| 大话2 男鬼变身卡| 咕卡用的链子| 黄色一级大片看看| 国产精品女同一区二区软件| 久久这里有精品视频免费| 国产精品亚洲av一区麻豆 | 女人被躁到高潮嗷嗷叫费观| 这个男人来自地球电影免费观看 | 日本欧美国产在线视频| 波野结衣二区三区在线| 日本av手机在线免费观看| 国产又色又爽无遮挡免| 午夜激情久久久久久久| 精品亚洲成a人片在线观看| 在线免费观看不下载黄p国产| 男女免费视频国产| 亚洲国产最新在线播放| 国产成人精品福利久久| 国产综合精华液| 国产又色又爽无遮挡免| 2018国产大陆天天弄谢| 天天躁狠狠躁夜夜躁狠狠躁| 搡女人真爽免费视频火全软件| 国产精品久久久久久精品古装| 麻豆av在线久日| 国产老妇伦熟女老妇高清| 香蕉丝袜av| 午夜老司机福利剧场| 人人妻人人澡人人爽人人夜夜| 国产av国产精品国产| 亚洲精品美女久久久久99蜜臀 | 国产精品国产av在线观看| 2018国产大陆天天弄谢| 午夜影院在线不卡| 日韩大片免费观看网站| 女人高潮潮喷娇喘18禁视频| 久久久精品国产亚洲av高清涩受| 女的被弄到高潮叫床怎么办| 欧美日韩视频精品一区| 在线观看www视频免费| 只有这里有精品99| 麻豆乱淫一区二区| 丝袜人妻中文字幕| 亚洲精品成人av观看孕妇| 久久久亚洲精品成人影院| 人妻少妇偷人精品九色| 国产女主播在线喷水免费视频网站| 2021少妇久久久久久久久久久| 香蕉丝袜av| 又黄又粗又硬又大视频| 日本免费在线观看一区| 午夜老司机福利剧场| 国产男女超爽视频在线观看| 精品少妇内射三级| 久久女婷五月综合色啪小说| 亚洲成人手机| 久久久久久久久久人人人人人人| 看免费av毛片| 亚洲精品美女久久久久99蜜臀 | 91精品三级在线观看| 人人妻人人添人人爽欧美一区卜| 亚洲,欧美,日韩| 天美传媒精品一区二区| 不卡视频在线观看欧美| 久久青草综合色| 岛国毛片在线播放| 免费观看无遮挡的男女| 日韩熟女老妇一区二区性免费视频| 午夜福利视频精品| 欧美最新免费一区二区三区| 亚洲国产最新在线播放| 欧美激情高清一区二区三区 | 性色avwww在线观看| 你懂的网址亚洲精品在线观看| 春色校园在线视频观看| 制服丝袜香蕉在线| 人妻少妇偷人精品九色| 麻豆av在线久日| 国产亚洲一区二区精品| 午夜av观看不卡| 天天躁夜夜躁狠狠躁躁| 日本vs欧美在线观看视频| av在线老鸭窝| 久久久国产一区二区| 考比视频在线观看| 国产精品女同一区二区软件| 亚洲精品美女久久av网站| 在线观看免费高清a一片| 国产高清不卡午夜福利| 性色avwww在线观看| 国产成人精品久久久久久| 欧美日韩av久久| 超色免费av| 女的被弄到高潮叫床怎么办|