Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhu X
PROVIDER: S-EPMC4761943 | biostudies-other | 2016 Feb
REPOSITORIES: biostudies-other
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Project description:Noble gases, especially xenon (Xe), have been shown to have antiapoptotic effects in treating hypoxia ischemia related injuries. Currently, in vivo gas delivery is systemic and performed through inhalation, leading to reduced efficacy at the injury site. This report provides a first demonstration of the encapsulation of pure Xe, Ar, or He in phospholipid-coated sub-10 µm microbubbles, without the necessity of stabilizing perfluorocarbon additives. Optimization of shell compositions and preparation techniques show that distearoylphosphatidylcholine (DSPC) with DSPE-PEG5000 can produce stable microbubbles upon shaking, while dibehenoylphosphatidylcholine (DBPC) blended with either DSPE-PEG2000 or DSPE-PEG5000 produces a high yield of microbubbles via a sonication/centrifugation method. Xe and Ar concentrations released into the microbubble suspension headspace are measured using GC-MS, while Xe released directly in solution is detected by the fluorescence quenching of a Xe-sensitive cryptophane molecule. Bubble production is found to be amenable to scale-up while maintaining their size distribution and stability. Excellent ultrasound contrast is observed in a phantom for several minutes under physiological conditions, while an intravenous administration of a bolus of pure Xe microbubbles provides significant contrast in a mouse in pre- and post-lung settings (heart and kidney, respectively), paving the way for image-guided, localized gas delivery for theranostic applications.
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Project description:Background/objectiveAccurate disease diagnosis and staging are essential for patients suspected of having lung cancer. The state-of-the-art minimally invasive tools used by physicians to perform these operations are bronchoscopy, for navigating the lung airways, and endobronchial ultrasound (EBUS), for localizing suspect extraluminal cancer lesions. While new image-guided systems enable accurate bronchoscope navigation close to a lesion, no means exists for guiding the final EBUS localization of an extraluminal lesion. We propose an EBUS simulation method to assist with EBUS localization.MethodsThe method draws on a patient's chest computed-tomography (CT) scan to model the ultrasound signal propagation through the tissue media. The method, which is suitable for simulating EBUS images for both radial-probe and convex-probe EBUS devices, entails three steps: 1) image preprocessing, which generates a 2D CT equivalent of the EBUS scan plane; 2) EBUS scan-line computation, which models ultrasound transmission to map the CT plane into a preliminary simulated EBUS image; and 3) image post-processing, which increases realism by introducing simulated EBUS imaging effects and artifacts.ResultsResults show that the method produces simulated EBUS images that strongly resemble images generated live by a real device and compares favorably to an existing ultrasound simulation method. It also produces images at a rate greater than real time (i.e., 53 frames/sec). We also demonstrate a successful integration of the method into an image-guided EBUS bronchoscopy system.Conclusion/significanceThe method is effective and practical for procedure planning/preview and follow-on live guidance of EBUS bronchoscopy.
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Project description:Recently, liposomes-microbubble conjugates have emerged as a promising ultrasound (US)-responsive platform for cancer therapeutics. However, these are limited by their size in terms of tumor penetration. Additionally, there have been no attempts to enhance the smartness of such conjugates which have been used only as passive carriers. The present study explores submicron sized (756?±?180.0?nm), US-responsive, phosphatidylserine (PS)-based paclitaxel-liposomes-nanobubble conjugates (PSPLBC) with an additional pro-apoptotic effect towards enhanced anti-cancer efficacy and image-guidance. The developed PSPLBC underwent cavitation in response to US-trigger, exhibiting in vitro pulsatile release with a 10-fold increase in cellular internalization as compared to control. The PS-containing formulations were found to be pro-apoptotic and exhibited strong synergism between PS and paclitaxel (Combination Index, CI?<?0.1). This resulted in significantly high anti-tumor efficacy both in vitro and in vivo conditions (98.3?±?0.8% tumor growth inhibition, TGI). Significant reduction in tumor proliferation index and MVD, as well as significant increase in apoptosis, were observed for the treated tumor sections. Further, the intravenous (i.v.) administration of PSPLBC enhanced the tumor US-contrast by 2-fold as compared to SonoVue. These results, show the potential of PSPLBC as a promising non-invasive, pro-apoptotic, smart DDS for US-responsive, image-guided cancer therapeutics.
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Project description:Xenon (Xe) is a bioactive gas capable of reducing and stabilizing neurologic injury in stroke. The goal of this work was to develop lipid-shelled microbubbles for xenon loading and ultrasound-triggered release. Microbubbles loaded with either xenon (Xe-MB) or xenon and octafluoropropane (Xe-OFP-MB) (9:1 v/v) were synthesized by high-shear mixing. The size distribution and the frequency-dependent attenuation coefficient of Xe-MB and Xe-OFP-MB were measured using a Coulter counter and a broadband acoustic attenuation spectroscopy system, respectively. The Xe dose was evaluated using gas chromatography/mass spectrometry. The total Xe doses in Xe-MB and Xe-OFP-MB were 113.1 ± 13.5 and 145.6 ± 25.5 μl per mg of lipid, respectively. Co-encapsulation of OFP increased the total xenon dose, attenuation coefficient, microbubble stability (in an undersaturated solution), and shelf life of the agent. Triggered release of gas payload was demonstrated with 6-MHz duplex Doppler and 220-kHz pulsed ultrasound. These results constitute the first step toward the use of lipid-shelled microbubbles for applications such as neuroprotection in stroke.
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Project description:ObjectivesUltrasound-mediated gene delivery can be amplified by acoustic disruption of microbubble carriers that undergo cavitation. We hypothesized that endothelial targeting of microbubbles bearing cDNA is feasible and, through optimizing proximity to the vessel wall, increases the efficacy of gene transfection.BackgroundContrast ultrasound-mediated gene delivery is a promising approach for site-specific gene therapy, although there are concerns with the reproducibility of this technique and the safety when using high-power ultrasound.MethodsCationic lipid-shelled decafluorobutane microbubbles bearing a targeting moiety were prepared and compared with nontargeted microbubbles. Microbubble targeting efficiency to endothelial adhesion molecules (P-selectin or intercellular adhesion molecule [ICAM]-1) was tested using in vitro flow chamber studies, intravital microscopy of tumor necrosis factor-alpha (TNF-α)-stimulated murine cremaster muscle, and targeted contrast ultrasound imaging of P-selectin in a model of murine limb ischemia. Ultrasound-mediated transfection of luciferase reporter plasmid charge coupled to microbubbles in the post-ischemic hindlimb muscle was assessed by in vivo optical imaging.ResultsCharge coupling of cDNA to the microbubble surface was not influenced by the presence of targeting ligand, and did not alter the cavitation properties of cationic microbubbles. In flow chamber studies, surface conjugation of cDNA did not affect attachment of targeted microbubbles at microvascular shear stresses (0.6 and 1.5 dyne/cm(2)). Attachment in vivo was also not affected by cDNA according to intravital microscopy observations of venular adhesion of ICAM-1-targeted microbubbles and by ultrasound molecular imaging of P-selectin-targeted microbubbles in the post-ischemic hindlimb in mice. Transfection at the site of high acoustic pressures (1.0 and 1.8 MPa) was similar for control and P-selectin-targeted microbubbles but was associated with vascular rupture and hemorrhage. At 0.6 MPa, there were no adverse bioeffects, and transfection was 5-fold greater with P-selectin-targeted microbubbles.ConclusionsWe conclude that ultrasound-mediated transfection at safe acoustic pressures can be markedly augmented by endothelial juxtaposition.
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Project description:This study investigated the effects of free paclitaxel (PTX) and PTX-loaded in pyromellitic nanosponges (PTX-PNS) in reducing in vitro and in vivo melanoma cell growth and invasivity, and in inhibiting angiogenesis. To test the response of cells to the two PTX formulations, the cell viability was evaluated by MTT assay in seven continuous cell lines, in primary melanoma cells, both in 2D and 3D cultures, and in human umbilical vein endothelial cells (HUVECs) after exposure to different concentrations of PTX or PTX-PNS. Cell motility was assessed by a scratch assay or Boyden chamber assay, evaluating cell migration in presence or absence of diverse concentrations of PTX or PTX-PNS. The effect of PTX and PTX-PNS on angiogenesis was evaluated as endothelial tube formation assay, a test able to estimate the formation of three-dimensional vessels in vitro. To assess the anticancer effect of PTX and PTX-PNS in in vivo experiments, the two drug formulations were tested in a melanoma mouse model obtained by B16-BL6 cell implantation in C57/BL6 mice. Results obtained were as follows: 1) MTT analysis revealed that cell proliferation was more affected by PTX-PNS than by PTX in all tested cell lines, in both 2D and 3D cultures; 2) the analysis of the cell migration showed that PTX-PNS acted at very lower concentrations than PTX; 3) tube formation assay showed that PTX-PNS were more effective in inhibiting tube formation than free PTX; and 4) in vivo experiments demonstrated that tumor weights, volumes, and growth were significantly reduced by PTX-PNS treatment with respect to PTX; the angiogenesis and the cell proliferation, detected in the tumor samples with CD31 and Ki-67 antibodies, respectively, indicated that, in the PTX-PNS-treated tumors, the tube formation was inhibited, and a low amount of proliferating cells was present. Taken together, our data demonstrated that our new PTX nanoformulation can respond to some important issues related to PTX treatment, lowering the anti-tumor effective doses and increasing the effectiveness in inhibiting melanoma growth in vivo.
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