Ultrasound-mediated drug-free theranostics for treatment of prostate cancer

Lipid-shelled nanobubbles(NBs)can be visualized and activated using noninvasive ultrasound(US)stimulation,leading to significant bioeffects.Prior work demonstrates that active targeting of NBs to prostate-specific membrane antigen(PSMA)overexpressed in prostate cancer(PCa)results in enhanced cellular internalization and prolongs NB retention with persistent,cancer-cell specific acoustic activity.In this work,we hypothesized that tumor-accumulated PSMA-NBs combined with low frequency unfocused therapeutic US(TUS)will lead to selective damage and induce a specific therapeutic effect in PSMA-expressing tumors compared to PSMA-negative tumors.We observed that the internalized NBs and cellular compartments were disrupted after the PSMA-NB+TUS(targeted NB therapy or TNT)application,yet treated cells remained intact and viable.In vivo,PSMA-expressing tumors in mice receiving TNT treatment demonstrated a significantly greater extent of apoptosis(78.4±9.3%,p<0.01)compared to controls.TNT treatment significantly inhibited the PSMA expressing tumor growth and increased median survival time by 103%,p<0.001).A significant reduction in tumor progression compared to untreated control was also seen in an orthotopic rabbit PCa model.Results demonstrate that cavitation of PSMA-NBs internalized via receptor-mediated endocytosis into target PCa cells using unfocused ultrasound results in significant,tumor-specific bioeffects.The effects,while not lethal to PSMA-expressing cancer cells in vitro,result in significant in vivo reduction in tumor progression in two models of PCa.While the mechanism of action of these effects is yet unclear,it is likely related to a locally-induced immune response,opening the door to future investigations in this area.

Use of cationic microbubbles targeted to P-selectin to improve ultrasound-mediated gene transfection of hVEGF_(165) to the ischemic myocardium

Gene therapies have been applied to the treatment of cardiovascular disease, but their use is limited by the need to deliver them to the right target. We have employed targeted contrast ultrasound-mediated gene transfection （TCUMGT） via ultrasound-targeted microbubble destruction （UTMD） to transfer therapeutic genes to specific anatomic and pathological targets. Phospholipid microbubbles （MBs） with pcDNA3.l-human vascular endothelial growth factor 165 （pcDNA3.I-hVEGFls5） plasmids targeted to P-selectin （MB＋P＋VEGFp） were created by conjugating monoclonal antibodies against P-selectin to the lipid shell. These microbubbles were divided into four groups： microbubble only （MB）, microbubble＋P-selectin （MB＋P）, microbubble＋pcDNA3.l-hVEGF185 plasmid （MB＋VEGFp）, and microbubbie＋ P-selectin＋pcDNA3.1-hVEGF185 piasmid （MB＋P＋VEGFp）. The reverse transcription polymerase chain reaction （RT-PCR） and enzyme-linked immunosorbent assay （ELISA） results showed that the VEGF gene was successfully transfected by TCUMGT and the efficiency is increased with P-selectin targeting moiety. UTMD-mediated delivery of VEGF increased myocardial vascular density and improved cardiac function, and MB＋P＋VEGFp delivery showed greater improvement than MB＋VEGFp. This study drew support from TCUGMT technology and took advantage of targeted ultrasound contrast agent to identify ischemic myocardium, release pcDNA3.1-hVEGF165 recombinant plasmid, and improve the myocardial microenvironment, so promoting the restoration of myocardial function.

Ultrasound-mediated targeted microbubbles： a new vehicle for cancer therapy

With the hope of overcoming the serious side effects, great endeavor has been made in tumor-targeted chemotherapy, and various drug delivery modalities and drug carriers have been made to decrease systemic toxicity caused by chemotherapeutic agents. Scientists from home and abroad focus on the research of targeted microbubbles contrast agent, and the use of the targeted ultrasound microbubble contrast agent can carry gene drugs and so on to the target tissue, as well as mediated tumor cell apoptosis and tumor microvascular thrombosis block, etc., thus plays the role of targeted therapy. Recent studies have elucidated the mechanisms of drug release and absorption, however, much work remains to be done in order to develop a successful and optimal system. In this review, we summarized the continuing efforts in under-standing the usage of the ultrasound triggered target microbubbles in cancer therapy, from release mechanism to preparation methods. The latest applications of ultra-sound-triggered targeted microbubbles in cancer therapy, especially in gene therapy and antiangiogenic cancer therapy were discussed. Moreover, we concluded that as a new technology, ultrasound-triggered targeted microbubbles used as drug carriers and imaging agents are still energetic and are very likely to be translated into clinic in the near future.

Preparation of fluorescence starch-nanoparticle and its application as plant transgenic vehicle

Starch-nanoparticles were synthesized in water-in-oil microemusion at room temperature, and the starch-nanoparticles were coated with poly-L-lysine. The surface of the starch-nanoparticles was combined with fluorescence material Ru(bpy)32+·6H2O, and then the particles were characterized via transmission electron microscope. The fluorescence nanoparticles were conjugated with plasmid DNA to form complexes, and then treated with ultrasound and DNase I. pEGAD plasmid DNA-nanoparticle complexes were co-cultured with plant suspension cells of Dioscrea Zigiberensis G H Wright, and treated with ultrasound. The results show that the diameter of the fluorescence starch-nanoparticles is 50-100 nm. DNA-nanoparticle complexes can protect DNA from ultrasound damage as well as from DNase I cleavage. Mediated by ultrasound, pEGAD plasmid DNA-nanoparticle complexes can pierce into the cell wall, cell membrane and nucleus membrane of plant suspension cells. The green fluorescence protein(GFP) gene at a high frequency exceeds 5%. This nano-biomaterial can efficiently solve the problem that exterior genes cannot traverse the plant cell wall easily.