Clinical study of ultrasound and microbubbles for enhancing chemotherapeutic sensitivity of malignant tumors in digestive system

Objective： To explore the safety of ultrasound and microbubbles for enhancing the chemotherapeutic sensitivity of malignant tumors in the digestive system in a clinical trial, as well as its efficacy.Methods： From October 2014 to June 2016, twelve patients volunteered to participate in this study. Eleven patients had hepatic metastases from tumors of the digestive system, and one patient had pancreatic carcinoma. According to the mechanical index （MI） in the ultrasound field, patients were classified into four groups with MIs of 0.4, 0.6, 0.8 and 1.0. Within half an hour after chemotherapy, patients underwent ultrasound scanning with ultrasound microbubbles （SonoVue） to enhance the efficacy of chemotherapy. All adverse reactions were recorded and were classified in 4 grades according to the Common Terminology Criteria for Adverse Events version 4.03 （CTCAE V4.03）. Tumor responses were evaluated by the Response Evaluation Criteria in Solid Tumors version 1.1 criteria. All the patients were followed up until progression.Results： All the adverse reactions recorded were level 1 or level 2. No local pain occurred in any of the patients. Among all the adverse reactions, fever might be related to the treatment with ultrasound combined with microbubbles. Six patients had stable disease （SD）, and one patient had a partial response （PR） after the first cycle of treatment. At the end of follow-up, tumor progression was restricted to the original sites, and no new lesions had appeared.Conclusions： Our preliminary data showed the potential role of a combined treatment with ultrasound and microbubbles in enhancing the chemotherapeutic sensitivity of malignant tumors of the digestive system. This technique is safe when the MI is no greater than 1.0.

Microstreaming velocity field and shear stress created by an oscillating encapsulated microbubble near a cell membrane

Sonoporation mediated by microbubbles is being extensively studied as a promising technology to facilitate gene/drug delivery to cells. However, the theoretical study regarding the mechanisms involved in sonoporation is still in its infancy.Microstreaming generated by pulsating microbubble near the cell membrane is regarded as one of the most important mechanisms in the sonoporation process. Here, based on an encapsulated microbubble dynamic model with considering nonlinear rheological effects of both shell elasticity and viscosity, the microstreaming velocity field and shear stress generated by an oscillating microbubble near the cell membrane are theoretically simulated. Some factors that might affect the behaviors of microstreaming are thoroughly investigated, including the distance between the bubble center and cell membrane（d）, shell elasticity（χ）, and shell viscosity（κ）. The results show that（i） the presence of cell membrane can result in asymmetric microstreaming velocity field, while the constrained effect of the membrane wall decays with increasing the bubble-cell distance;（ii） the bubble resonance frequency increases with the increase in d and χ, and the decrease in κ,although it is more dominated by the variation of shell elasticity; and（iii） the maximal microstreaming shear stress on the cell membrane increases rapidly with reducing the d, χ, and κ. The results suggest that microbubbles with softer and less viscous shell materials might be preferred to achieve more efficient sonoporation outcomes, and it is better to have bubbles located in the immediate vicinity of the cell membrane.

Microflow-induced shear stress on biomaterial wall by ultrasound-induced encapsulated microbubble oscillation

A model of an ultrasound-driven encapsulated microbubble（EMB） oscillation near biomaterial wall is presented and used for describing the microflow-induced shear stress on the wall by means of a numerical method. The characteristic of the model lies in the explicit treatment of different types of wall for the EMB responses. The simulation results show that the radius-time change trends obtained by our model are consistent with the existing models and experimental results. In addition, the effect of the elastic wall on the acoustic EMB response is stronger than that of the rigid wall, and the shear stress on the elastic wall is larger than that of the rigid wall. The closer the EMB to the wall, the greater the shear stress on the wall. The substantial shear stress on the wall surface occurs inside a circular zone with a radius about two-thirds of the bubble radius. This paper may be of interest in the study of potential damage mechanisms to the microvessel for drug and gene delivery due to sonoporation.

Development of exosome membrane materialsfused microbubbles for enhanced stability and efficient drug delivery of ultrasound contrast agent

Lipid-coated microbubbles are widely used as an ultrasound contrast agent,as well as drug delivery carriers.However,the two main limitations in ultrasound diagnosis and drug delivery using microbubbles are the short half-life in the blood system,and the difficulty of surface modification of microbubbles for active targeting.The exosome,a type of extracellular vesicle,has a preferentially targeting ability for its original cell.In this study,exosome-fused microbubbles(Exo-MBs)were developed by embedding the exosome membrane proteins into microbubbles.As a result,the stability of Exo-MBs is improved over the conventional microbubbles.On the same principle that under the exposure of ultrasound,microbubbles are cavitated and self-assembled into nano-sized particles,and Exo-MBs are self-assembled into exosome membrane proteins-embedded nanoparticles(Exo-NPs).The Exo-NPs showed favorable targeting properties to their original cells.A photosensitizer,chlorin e6,was loaded into Exo-MBs to evaluate therapeutic efficacy as a drug carrier.Much higher therapeutic efficacy of photodynamic therapy was confirmed,followed by cancer immunotherapy from immunogenic cell death.We have therefore developed a novel ultrasound image-guided drug delivery platform that overcomes the shortcomings of the conventional ultrasound contrast agent and is capable of simultaneous photodynamic therapy and cancer immunotherapy.

Advances in ultrasound-targeted microbubble-mediated gene therapy for liver fibrosis

Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix(ECM) and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications.However, fibrosis can be reversed before developing into cirrhosis and has thus been the subject of extensive researches particularly at the gene level. Currently, therapeutic genes are imported into the damaged liver to delay or prevent the development of liver fi brosis by regulating the expression of exogenous genes. One technique of gene delivery uses ultrasound targeting of microbubbles combined with therapeutic genes where the time and intensity of the ultrasound can control the release process.Ultrasound irradiation of microbubbles in the vicinity of cells changes the permeability of the cell membrane by its cavitation effect and enhances gene transfection. In this paper, recent progress in the field is reviewed with emphasis on the following aspects: the types of ultrasound microbubbles, the construction of an ultrasound-mediated gene delivery system, the mechanism of ultrasound microbubble–mediated gene transfer and the application of ultrasound microbubbles in the treatment of liver fibrosis.