The miR-184-3p promotes rice black-streaked dwarf virus infection by suppressing Ken in Laodelphax striatellus (Fallén).

BACKGROUND: MicroRNAs (miRNAs) play a key role in various biological processes by influencing the translation of target messenger RNAs (mRNAs) through post-transcriptional regulation. The miR-184-3p has been identified as an abundant conserved miRNA in insects. However, less is known about its functions in insect-plant virus interactions. RESULTS: The function of miR-184-3p in regulation of plant viral infection in insects was investigated using a rice black-streaked dwarf virus (RBSDV) and Laodelphax striatellus (Fallén) interaction system. We found that the expression of miR-184-3p increased in L. striatellus after RBSDV infection. Injection of miR-184-3p mimics increased RBSDV accumulation, while treatment with miR-184-3p antagomirs inhibits the viral accumulation in L. striatellus. Ken, a zinc finger protein, was identified as a target of miR-184-3p. Knockdown of Ken increased the virus accumulation and promoted RBSDV transmission by L. striatellus. CONCLUSION: This study demonstrates that RBSDV infection induces the expression of miR-184-3p in its insect vector L. striatellus. The miR-184-3p targets Ken to promote RBSDV accumulation and transmission. These findings provide a new insight into the function of the miRNAs in regulating plant viral infection in its insect vector. © 2023 Society of Chemical Industry.

Acoustofluidic dynamic interfacial tensiometry.

The interfacial tension (IFT) of fluids plays an essential role in industrial, biomedical, and synthetic chemistry applications; however, measuring IFT at ultralow volumes is challenging. Here, we report a novel method for sessile drop tensiometry using surface acoustic waves (SAWs). The IFT of the fluids was determined by acquiring the silhouette of an axisymmetric sessile drop and applying iterative fitting using Taylor's deformation equation. Owing to physiochemical differences, upon interacting with acoustic waves, each microfluid has a different streaming velocity. This streaming velocity dictates any subsequent changes in droplet shape (i.e., height and width). We demonstrate the effectiveness of the proposed SAW-based tensiometry technique using blood plasma to screen for high leptin levels. The proposed device can measure the IFT of microscale liquid volumes (up to 1 µL) with an error margin of only ±5% (at 25 °C), which deviates from previous reported results. As such, this method provides pathologists with a solution for the pre-diagnosis of various blood-related diseases.

Ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-ß-induced neurotoxicity.

Background: Extracellular vesicles, including exosomes, are secreted by a variety of cell types in the central nervous system. Exosomes play a role in removing intracellular materials from the endosomal system. Alzheimer's disease (AD) is caused by an overproduction or reduced amyloid-beta (Aß) peptide clearance. Increased Aß levels in the brain may impair the exosome-mediated Aß clearance pathway. Therapeutic ultrasound stimulation demonstrated its potential for promoting Aß degradation efficiency in clinical trials. However, the underlying mechanism of ultrasound stimulation is still unclear. Methods: In this study, astrocytes, the most abundant glial cells in the brain, were used for exosome production. Post insonation, exosomes from ultrasound-stimulated HA cells (US-HA-Exo) were collected, nanoparticle tracking analysis and protein analysis were used to measure and characterize exosomes. Neuroprotective effect of US-HA-Exo in oligomeric Aß42 toxicated SH-SY5Y cells was tested. Cellular uptake and distribution of exosomes were observed by flow cytometry and confocal laser scanning microscopy. Focused ultrasound (FUS) with microbubbles was employed for blood-brain-barrier opening to achieve brain-targeted exosome delivery. After US-HA-Exo/FUS treatment, amyloid-ß plaque in APP/PS1 mice were evaluated by Aß immunostaining and thioflavin-S staining. Results: We showed that ultrasound resulted in an almost 5-fold increase in the exosome release from human astrocytes. Exosomes were rapidly internalized in SH-SY5Y cells, and colocalized with FITC-Aß42, causing a decreased uptake of FITC-Aß42. CCk-8 test results showed that US-HA-Exo could mitigate Aß toxicity to neurons in vitro. The therapeutic potential of US-HA-Exo/FUS delivery was demonstrated by a decrease in thioflavin-S-positive amyloid plaques and Aß immuno-staining, a therapeutic target for AD in APP/PS1 transgenic mice. The iTRAQ-based proteomic quantification was performed to gain mechanistic insight into the ultrasound effect on astrocyte-derived exosomes and their ability to alleviate Aß neurotoxicity. Conclusion: Our results imply that US-HA-Exo have the potential to provide neuroprotective effects to reverse oligomeric amyloid-ß-induced cytotoxicity in vitro and, when combined with FUS-induced BBB opening, enable the clearance of amyloid-ß plaques in vivo.

Real-Time Imaging Tracking of Mesenchymal Stem Cells Labeled with Lipid-Poly(lactic-co-glycolic acid) Nanobubbles.

Stem-cell-based therapy has attracted considerable attention due to the significant benefits to patients experiencing a wide range of diseases and injuries. However, their underlying mechanism of action is not completely understood. One main reason is the lack of imaging tools for real-time tracking of deep-seated transplanted stem cells. For the present study, we exploited a lipid poly(lactic-co-glycolic acid) nanobubble (LPN) probe with nanoscale size, good compatibility, and strong contrast-enhanced ultrasound signals. Due to the nanoscale particle size, cellular labeling of mesenchymal stem cells can be achieved via incubation with LPNs. Significantly enhanced ultrasound images of these labeled stem cells were obtained in vitro and in vivo. More importantly, the labeled stem cells could be tracked by ultrasound imaging for up to 5 days. Additional evaluation found that the in vivo detection limit achieved 2,000 labeled stem cells in the subcutaneous tissues of living mice. Our study presents a strategy to achieve real-time ultrasound imaging tracking, paving the way for an investigation on the underlying mechanism and future clinical application of stem cell therapy.

Ultrasound-Induced Blood-Brain-Barrier Opening Enhances Anticancer Efficacy in the Treatment of Glioblastoma: Current Status and Future Prospects.

Glioblastoma multiforme (GBM) diffusely infiltrates normal brain tissue. The presence of the blood-brain barrier (BBB) poses difficulties for targeted delivery of currently available antitumor drugs. Novel brain drug delivery strategies are far from satisfactory for glioma treatment. Recently, focused ultrasound (FUS) combined with microbubbles presents a transient, reversible, and noninvasive approach for local induction of BBB opening. This strategy demonstrated its potential to increase local concentrations of both diagnostic and therapeutic agents in glioma therapy. Current status and related physic mechanisms of this drug delivery technique are discussed in this review. Delivery efficiency enhancement in many preclinical glioma models was obtained by FUS-BBB opening combined with various nanoparticles. And, the clinical translational status of FUS-BBB will be discussed.

Ultrasound Molecular Imaging of Lymphocyte-endothelium Adhesion Cascade in Acute Cellular Rejection of Cardiac Allografts.

BACKGROUND: Acute cellular rejection is one of the main reasons for graft failure after heart transplantation. A precise diagnosis at the early stage of acute cellular rejection is a big challenge for clinicians. Given the importance of the interaction between T cells and graft endothelia in initiating rejection, we developed T cell-microbubble complexes (cell-MBs) as ultrasound molecular imaging probes to monitor the lymphocyte-endothelium adhesion cascade in cardiac acute cellular rejection. METHODS: Cell-MBs were fabricated by incubating lymphocytes with anti-CD4 antibody-conjugated MBs (MBCD4). The potential of cell-MBs as probes for detecting acute cardiac rejection was examined. Donor hearts from Brown Norway or Lewis rats were transplanted into Lewis recipients. Ultrasound molecular imaging was performed on allografts of untreated or cyclosporin A (CsA)-treated recipients, and isografts on posttransplantation day 3. Histology was used to assess rejection grades. RESULTS: We detected a significantly stronger ultrasound molecular imaging signal of cell-MBs than that of MBCD4 or plain MBs in allografts of untreated and CsA-treated recipients. No signal enhancement was observed in isografts with cell-MBs. The signal of cell-MBs in allografts of the untreated group was significantly higher than that in the CsA-treated group, and the signal in the CsA-treated group was higher than that in isografts. Histology confirmed grade 3R rejection in the untreated group, grade 2R rejection in CsA-treated group, and no rejection in isografts. CONCLUSIONS: Our study suggests that cell-MBs can function as a promising probe to image the dynamic lymphocyte-endothelium adhesion cascade for noninvasive diagnosis of cardiac acute cellular rejection.

Biosynthetic nanobubbles for targeted gene delivery by focused ultrasound.

Ultrasound-targeted microbubble destruction (UTMD) has recently drawn considerable attention in biomedicine applications due to its great potential to locally enhance gene delivery. However, conventional microbubbles have a microscale particle size and polydisperse particle size distribution, which makes it difficult for them to directly come into contact with tumor cells and to efficiently deliver therapeutic genes via ultrasound cavitation effects. In the current study, we developed a kind of novel cationic biosynthetic nanobubble (CBNB) as an ultrasonic gene delivery carrier through coating PEI on the surface of these biosynthetic nanobubbles (BNBs). The BNBs, produced from an extremely halophilic archaeon (Halobacterium NRC-1), possess a nanoscale size and can produce stable contrast signals both in vitro and in vivo. Surface modification with PEI polymer greatly increased the DNA loading capability of BNBs, leading to significantly improved gene transfection efficiency when combining with ultrasound. To our knowledge, this is the first report to apply biosynthetic bubbles as non-viral gene carriers which can effectively deliver genes into tumor cells with the aid of ultrasound cavitation. Our study provides a powerful tool for image-guided and efficient gene delivery using biosynthetic nanoscale contrast agents.

Acoustic Characteristics of Biosynthetic Bubbles for Ultrasound Contrast Imaging.

Biosynthetic bubbles produced by floating microorganisms, such as bacteria and algae, have recently attracted wide attention as novel ultrasound contrast agents owing to their significant potential in ultrasound imaging and acoustic reporter gene-based imaging. However, the acoustics properties of these bubbles are unclear. In this study, we developed a finite-element model to describe the oscillation of nonspherical biosynthetic bubbles composed of a gas core encapsulated in a protein shell. In this model, the elastic properties of the bubble shells were characterized in terms of the density, thickness, Young's modulus, and Poisson's ratio. Theoretical calculations were performed for a single bubble and an assembly of randomly oriented bubbles. Our results demonstrate that (1) there are many types of surface oscillation modes for nonspherical biosynthetic bubbles, and a systematic relationship exists between the surface modes and the resonance frequencies; (2) the bubble shell shape has a significant effect on the acoustic behavior; (3) the resonance frequency of an ellipsoidal bubble decreases with the decrease in its polar radius-to-equatorial axis ratio; and (4) the acoustic scattering of a randomly oriented suspension is isotropic at and below the first resonance frequency. Our findings provide physical insight into the biomedical applications of biosynthetic bubbles and can be used to optimize the acoustics properties of such bubbles.

Noninvasive Ultrasonic Neuromodulation in Freely Moving Mice.

Neuromodulation is a fundamental method for obtaining basic information about neuronal circuits for use in treatments for neurological and psychiatric disorders. Ultrasound stimulation has become a promising approach for noninvasively inducing neuromodulation in animals and humans. However, the previous investigations were subject to substantial limitations, due to most of them involving anesthetized and fixed small-animal models. Studies of awake and freely moving animals are needed, but the currently used ultrasound devices are too bulky to be applied to a freely moving animal. This study is the first time to design and fabricate a miniature and lightweight head-mounted ultrasound stimulator for inducing neuromodulation in freely moving mice. The main components of the stimulator include a miniature piezoelectric ceramic, a concave epoxy acoustic lens, and housing and connection components. The device was able to induce action potentials recorded in situ and evoke head-turning behaviors by stimulating the primary somatosensory cortex barrel field of the mouse. These findings indicate that the proposed method can be used to induce noninvasive neuromodulation in freely moving mice. This novel method could potentially lead to the application of ultrasonic neuromodulation in more-extensive neuroscience investigations.

MR imaging tracking of inflammation-activatable engineered neutrophils for targeted therapy of surgically treated glioma.

Cell-based drug delivery systems have shown promising capability for tumor-targeted therapy owing to the intrinsic tumor-homing and drug-carrying property of some living cells. However, imaging tracking of their migration and bio-effects is urgently needed for clinical application, especially for glioma. Here, we report the inflammation-activatable engineered neutrophils by internalizing doxorubicin-loaded magnetic mesoporous silica nanoparticles (ND-MMSNs) which can provide the potential for magnetic resonance (MR) imaging tracking of the drug-loaded cells to actively target inflamed brain tumor after surgical resection of primary tumor. The phagocytized D-MMSNs possess high drug loading efficiency and do not affect the host neutrophils' viability, thus remarkably improving intratumoral drug concentration and delaying relapse of surgically treated glioma. Our study offers a new strategy in targeted cancer theranostics through combining the merits of living cells and nanoparticle carriers.

Noninvasive and Local Delivery of Adenoviral-Mediated Herpes Simplex Virus Thymidine Kinase to Treat Glioma Through Focused Ultrasound-Induced Blood-Brain Barrier Opening in Rats.

Adenoviral-mediated gene therapy has been shown great prospects for tumor treatment. However, it is still a great challenge for its application in the glioma. A main cause is the blood-brain barrier (BBB) limits the delivery of adenoviral vectors, greatly compromising their efficacy. Here, we used focused ultrasound (FUS) induced microbubble cavitation to locally and reversibly open BBB for enhancing gene delivery. In this study, Ad-CMV-TK-IRES-EGFP (Ad-HSV-TK-EGFP) carrying the herpes simplex virus thymidine kinase (HSV-TK) and EGFP transgenes was chose as gendicine and Ad-CMV-IRES-EGFP (Ad-EGFP) as the control. The in vitro experiments showed that Ad-HSV-TK-EGFP had a high infection efficiency for C6 glioma cells, producing good tumor cell killing effects when these cells were exposed to more than 10 µg/ml ganciclovir (GCV). Taking advantage of FUS-induced BBB opening, Ad-HSV-TK-EGFP could be effectively delivered into the brain tumors, getting the overexpression of HSV-TK gene in the tumor cells. After exposure to GCV, the significantly stronger anti-tumor efficacy and longer survival time were observed in tumor-bearing mice treated with Ad-HSV-TK-EGFP + FUS than those treated with Ad-EGFP + FUS or only Ad-HSV-TK-EGFP. Histological examination indicated that the reduced expression level of Ki67 proteins and the increased apoptotic tumor cells in tumor xenografts, causing the inhibition of tumor growth. In conclusion, our study provided a new strategy to efficiently and locally deliver recombinant adenoviral vector-mediated HSV-TK gene into the brain to treat glioma.

Ultrasound-Triggered Drug Delivery for Breast Tumor Therapy Through iRGD-Targeted Paclitaxel-Loaded Liposome-Microbubble Complexes.

Liposome-microbubble complexes (LMC) have become a promising therapeutic carrier for ultrasound-triggered local drug release. However, it is still desirable for the released drugs to be delivered to tumors as effectively as possible. Here, we fabricated iRGD-targeted paclitaxel-loaded liposome-microbubble complexes (iRGD-PTX-LMC) and investigated the feasibility of enhancing the local drug delivery to breast tumors by using these complexes along with ultrasound irradiation. Our results showed that iRGD-modified PTX-loaded liposomes (iRGD-PTX-PL) were successfully conjugated to the surface of microbubbles (MBs) through biotin-avidin linkage. The resulting iRGD-PTX-LMC retained the ultrasound imaging capability and showed effective ultrasound-triggered drug release. High cell affinity and enhanced drug delivery into tumor cells was confirmed for iRGD-PTX-LMC upon ultrasound exposure. Additionally, our data revealed that iRGD-PTX-LMC with ultrasound had a significantly better tumor growth inhibition effect than iRGD-PTX-PL or nontargeted PTX-LMC in not only in vitro but also in vivo studies. Histological examination indicated that the inhibition of tumor growth was caused by the increases in the drug concentration and the number of apoptotic tumor cells in tumor xenografts. In conclusion, our study revealed the great potential of iRGD-PTX-LMC as a new tool to enhance local drug delivery and significantly improve antitumor efficacy.

Focused Ultrasound-Augmented Delivery of Biodegradable Multifunctional Nanoplatforms for Imaging-Guided Brain Tumor Treatment.

The blood brain barrier is the main obstacle to delivering diagnostic and therapeutic agents to the diseased sites of brain. It is still of great challenge for the combined use of focused ultrasound (FUS) and theranostic nanotechnology to achieve noninvasive and localized delivery of chemotherapeutic drugs into orthotopic brain tumor. In this work, a unique theranostic nanoplatform for highly efficient photoacoustic imaging-guided chemotherapy of brain tumor both in vitro and in vivo, which is based on the utilization of hollow mesoporous organosilica nanoparticles (HMONs) to integrate ultrasmall Cu2-x Se particles on the surface and doxorubicin inside the hollow interior, is synthesized. The developed multifunctional theranostic nanosystems exhibit tumor-triggered programmed destruction due to the reducing microenvironment-responsive cleavage of disulfide bonds that are incorporated into the framework of HMONs and linked between HMONs and Cu2-x Se, resulting in tumor-specific biodegradation and on-demand drug-releasing behavior. Such tumor microenvironment-responsive biodegradable and biocompatible theranostic nanosystems in combination with FUS provide a promising delivery nanoplatform with high performance for orthotopic brain tumor imaging and therapy.

Ultrasound Molecular Imaging of Atherosclerosis for Early Diagnosis and Therapeutic Evaluation through Leucocyte-like Multiple Targeted Microbubbles.

Cardiovascular diseases resulting from atherosclerosis have become a serious threat to human health. It is well-known that an ongoing inflammatory response is involved during atherosclerosis progression that ultimately results in the accumulation of lipids and formation of plaques. Monitoring the pathological changes during the inflammatory response will be of great significance for early diagnosis and therapeutic evaluation of atherosclerosis. Targeted contrast-enhanced ultrasonography has been shown to be a promising noninvasive imaging technique for evaluating the degree of atherosclerosis and may potentially be translated to clinical imaging in the future. However, inadequate cell adhesion of targeted microbubbles (MBs) in large arterial vessels still remains a great challenge. Methods: By mimicking the leucocytes that are recruited to the vessel wall during the initiation of atherosclerosis through selectin-dependent arrest and cell adhesion molecule-mediated firm cell adhesion, we developed VCAM-1/ICAM-1/P-selectin-targeted MBVIS by integrating VCAM-1 and ICAM-1 antibodies and synthetic polymeric sialyl Lewis X (sLex) onto the MB surface. Results: The resulting MBVIS had a high affinity to inflammatory bEnd.3 cells in both static and dynamic flow conditions. Significantly enhanced ultrasound imaging signals were achieved by MBVIS in detecting the atherosclerosis progress when compared with the single- or dual-targeted MBs. Taking advantage of the artificial MBVIS, less ultrasound imaging signals were found in the atorvastatin-treated, but not placebo-treated, ApoE-deficient mice with atherosclerosis, revealing a potential therapeutic efficacy of atorvastatin for early stage atherosclerosis. This was further confirmed by histologic staining examination. Conclusions: Our study provides a promising ultrasound molecular imaging probe for early-stage diagnosis and therapeutic evaluation of atherosclerosis.

Tumor-penetrating Peptide-integrated Thermally Sensitive Liposomal Doxorubicin Enhances Efficacy of Radiofrequency Ablation in Liver Tumors.

Purpose To investigate the role of a tumor-penetrating peptide (internalizing CRGDRGPDC [iRGD])-integrated thermally sensitive liposomal (TSL) doxorubicin (DOX) in combination with radiofrequency (RF) ablation of liver tumors in an animal model. Materials and Methods Approval from the institutional animal care and use committee was obtained. Characterization of iRGD-TSL-DOX was performed in vitro. Next, H22 liver adenocarcinomas were implanted in 138 mice in vivo. The DOX accumulation and cell apoptosis of iRGD-TSL-DOX and TSL-DOX with or without RF were evaluated (n = 5) at different time points after treatment with quantitative analysis or pathologic staining. Mice bearing tumors were randomized into the following six groups (each group, eight mice): no treatment, iRGD-TSL-DOX, TSL-DOX, RF alone, RF ablation followed by TSL-DOX at 30 minutes (TSL-DOX combined with RF), and RF ablation followed by iRGD-TSL-DOX (iRGD-TSL-DOX combined with RF). Kaplan-Meier method was used to estimate the survival curves and log-rank test was used for comparison with statistical software. Results DOX encapsulation efficiency in iRGD-TSL-DOX was 97.5% ± 1.3 (standard deviation) with temperature-dependent drug release capability confirmed in vitro. In vivo, the iRGD-TSL-DOX group had overall higher DOX concentration in the tumor and had maximal difference at 24 hours compared with TSL-DOX group (2.7-fold). RF caused more intense cell apoptosis at 24 hours (median, 65% vs 21%, respectively; P < .001). For end-point survival, the iRGD-TSL-DOX combined with RF group had better survival (median, 32 days) than TSL-DOX combined with RF (median, 27 days; P = .035) or RF alone (median, 21 days; P < .001). Conclusion Conjugation to iRGD helped to improve intratumoral DOX accumulation and further enhanced the activity of TSL-DOX in RF ablation of liver tumors. © RSNA, 2017 Online supplemental material is available for this article.

Hyperthermia-triggered drug delivery from iRGD-modified temperature-sensitive liposomes enhances the anti-tumor efficacy using high intensity focused ultrasound.

An important limitation to successful cancer treatment with chemotherapeutics is the inability to achieve therapeutically effective drug concentrations while avoiding healthy tissue damage. In this work, a new tumor-targeting peptide iRGD (CCRGDKGPDC) was used to modify drug-loaded low temperature-sensitive liposomes (iRGD-LTSL-DOX) to explore the anti-tumor effects in combination with high intensity focused ultrasound (HIFU) in vitro and in vivo. iRGD-LTSL-DOX can specifically target to ανß3-positive cells and locally release the encapsulated doxorubicin (DOX) in a hyperthermia-triggered manner. In vivo results showed that DOX from iRGD-LTSL-DOX was intravascularly released and rapidly penetrated into tumor interstitial space after HIFU-triggered heat treatment, thereby overcoming the limited tumor penetration of anticancer drugs. Significantly stronger anti-tumor efficacy further supported the effective combination of iRGD-LTSL-DOX with HIFU-induced hyperthermia. Our study provided a novel tumor-targeting LTSL-DOX and demonstrated its usefulness in HIFU-induced hyperthermia-triggered drug delivery.

IR-780 Dye as a Sonosensitizer for Sonodynamic Therapy of Breast Tumor.

Sonodynamic therapy (SDT) has become a new modality for cancer therapy through activating certain chemical sensitizers by ultrasound (US). Discovery and development of novel sonosensitizers are attracting extensive attentions. Here, we introduce IR-780 iodide, a lipophilic heptamethine dye with a peak optical absorption of 780 nm wavelength, which can function as SDT agents for breast cancer treatment. The in vitro cellular uptake, cell viability, and the generation levels of reactive oxygen species (ROS) were examined by using 4T1 breast cancer cells incubated with various concentrations of IR-780 followed by US irradiation. Our results showed a dose- and time-dependent cellular uptake of IR-780 iodide in 4T1 cancer cells. Significant lower viabilities and more necrotic/apoptotic cells were found when these cancer cells were treated with IR-780 iodide with US irradiation. Further analyzing the generation of ROS demonstrated significant increase of (1)O2 level and H2O2, but not ⋅OH in the SDT-treated cells. The in vivo anti-tumor efficacy of SDT with IR-780 revealed significant tumor growth inhibition of xenografts of 4T1 cancer cells; it was further confirmed by histological analysis and TUNEL staining. Our results strongly suggest that SDT combined with IR-780 may provide a promising strategy for tumor treatment with minimal side effects.

Molecular imaging-guided photothermal/photodynamic therapy against tumor by iRGD-modified indocyanine green nanoparticles.

Multifunctional near-infrared (NIR) nanoparticles demonstrate great potential in tumor theranostic applications. To achieve the sensitive detection and effective phototherapy in the early stage of tumor genesis, it is highly desirable to improve the targeting of NIR theranostic agents to biomarkers and to enhance their accumulation in tumor. Here we report a novel targeted multifunctional theranostic nanoparticle, internalized RGD (iRGD)-modified indocyanine green (ICG) liposomes (iRGD-ICG-LPs), for molecular imaging-guided photothermal therapy (PTT) and photodynamic therapy (PDT) therapy against breast tumor. The iRGD peptides with high affinity to αvß3 integrin and effective tumor-internalized property were firstly used to synthesize iRGD-PEG2000-DSPE lipopeptides, which were further utilized to fabricate the targeted ICG liposomes. The results indicated that iRGD-ICG-LPs exhibited excellent stability and could provide an accurate and sensitive detection of breast tumor through NIR fluorescence molecular imaging. We further employed this nanoparticle for tumor theranostic application, demonstrating significantly higher tumor accumulation and tumor inhibition efficacy through PTT/PDT effects. Histological analysis further revealed much more apoptotic cells, confirming the advantageous anti-tumor effect of iRGD-ICG-LPs over non-targeted ICG-LPs. Notably, the targeting therapy mediated by iRGD provides almost equivalent anti-tumor efficacy at a 12.5-fold lower drug dose than that by monoclonal antibody, and no tumor recurrence and obvious treatment-induced toxicity were observed in our study. Our study provides a promising strategy to realize the sensitive detection and effective treatment of tumors by integrating molecular imaging into PTT/PDT therapy.

A Disposable Microfluidic Device for Controlled Drug Release from Thermal-Sensitive Liposomes by High Intensity Focused Ultrasound.

The drug release triggered thermally by high intensity focused ultrasound (HIFU) has been considered a promising drug delivery strategy due to its localized energy and non-invasive characters. However, the mechanism underlying the HIFU-mediated drug delivery remains unclear due to its complexity at the cellular level. In this paper, micro-HIFU (MHIFU) generated by a microfluidic device is introduced which is able to control the drug release from temperature-sensitive liposomes (TSL) and evaluate the thermal and mechanical effects of ultrasound on the cellular drug uptake and apoptosis. By simply adjusting the input electrical signal to the device, the temperature of sample can be maintained at 37 °C, 42 °C and 50 °C with the deviation of ± 0.3 °C as desired. The flow cytometry results show that the drug delivery under MHIFU sonication leads to a significant increase in apoptosis compared to the drug release by incubation alone at elevated temperature of 42 °C. Furthermore, increased squamous and protruding structures on the surface membrane of cells were detected by atomic force microscopy (AFM) after MHIFU irradiation of TSL. We demonstrate that compared to the routine HIFU treatment, MHIFU enables monitoring of in situ interactions between the ultrasound and cell in real time. Furthermore, it can quantitatively analyze and characterize the alterations of the cell membrane as a function of the treatment time.