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Neural progenitor cells labeling with microbubble contrast agent for ultrasound imaging in vivo.

ABSTRACT: Tracking neuroprogenitor cells (NPCs) that are used to target tumors, infarction or inflammation, is paramount for cell-based therapy. We employed ultrasound imaging that can detect a single microbubble because it can distinguish its unique signal from those of surrounding tissues. NPCs efficiently internalized positively charged microbubbles allowing a clinical ultrasound system to detect a single cell at 7 MHz. When injected intravenously, labeled NPCs traversed the lungs to be imaged in the left ventricle and the liver where they accumulated. Internalized microbubbles were not only less sensitive to destruction by ultrasound, but remained visible in vivo for days as compared to minutes when given free. The extended longevity provides ample time to allow cells to reach their intended target. We were also able to transfect NPCs in vitro when microbubbles were preloaded with GFP plasmid only when cells were insonated. Transfection efficiency and cell viability were both greater than 90%.

SUBMITTER: Cui W

PROVIDER: S-EPMC3742341 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Neural progenitor cells labeling with microbubble contrast agent for ultrasound imaging in vivo.

Cui Wenjin W Tavri Sidhartha S Benchimol Michael J MJ Itani Malak M Olson Emilia S ES Zhang Hong H Decyk Marika M Ramirez Rosemarie G RG Barback Christopher V CV Kono Yuko Y Mattrey Robert F RF

Biomaterials 20130408 21

Tracking neuroprogenitor cells (NPCs) that are used to target tumors, infarction or inflammation, is paramount for cell-based therapy. We employed ultrasound imaging that can detect a single microbubble because it can distinguish its unique signal from those of surrounding tissues. NPCs efficiently internalized positively charged microbubbles allowing a clinical ultrasound system to detect a single cell at 7 MHz. When injected intravenously, labeled NPCs traversed the lungs to be imaged in the l ...[more]

PMID: 23578557

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Project description:RationaleMicrobubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-(strept)avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld.ObjectiveTo develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging.Methods and resultsMicrobubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab')2 using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (|r|≥0.8), demonstrating a high degree of non-invasive molecular quantification.ConclusionsTargeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described, may possess properties (i)-(iii) desired for clinical applications.

Project description:PurposeThis study introduces a real-time contrast-enhanced ultrasound imaging method with recently developed laser-activated nanodroplets (LANDs), a new class of phase-change nanometer-scale contrast agents that provides perceptible, sustained high-contrast with ultrasound.MethodsIn response to pulsed laser irradiation, the LANDs-, which contain liquid perfluorohexane and optical fuses-blink (vaporize and recondense). That is, they change their state from liquid nanodroplets to gas microbubbles, and then back to liquid nanodroplets. In their gaseous microbubble state, the LANDs provide high-contrast ultrasound, but the microbubbles formed in situ typically recondense in tens of milliseconds. As a result, LAND visualization by standard, real-time ultrasound is limited. However, the periodic optical triggering of LANDs allows us to observe corresponding transient, periodic changes in ultrasound contrast. This study formulates a probability function that measures how ultrasound temporal signals vary in periodicity. Then, the estimated probability is mapped onto a B-scan image to construct a LAND-localized, contrast-enhanced image. We verified our method through phantom and in vivo experiments using an ultrasound system (Vevo 2100, FUJIFILM VisualSonics, Inc., Toronto, ON, Canada) operating with a 40-MHz linear array and interfaced with a 10 Hz Nd:YAG laser (Phocus, Opotek Inc., Carlsbad, CA, USA) operating at the fundamental 1064 nm wavelength.ResultsFrom the phantom study, the results showed improvements in the contrast-to-noise ratio of our approach over conventional ultrasound ranging from 129% to 267%, with corresponding execution times of 0.10 to 0.29 s, meaning that the developed method is computationally efficient while yielding high-contrast ultrasound. Furthermore, in vivo sentinel lymph node (SLN) imaging results demonstrated that our technique could accurately identify the SLN.ConclusionsThe results indicate that our approach enables efficient and robust LAND localization in real time with substantially improved contrast, which is essential for the successful translation of this contrast agent platform to clinical settings.

Project description:Ultrasound imaging presents many positive attributes, including safety, real-time imaging, universal accessibility, and cost. However, inherent difficulties in discrimination between soft tissues and tumors prompted development of stabilized microbubble contrast agents. This presents the opportunity to develop agents in which drug is entrapped in the microbubble shell. We describe preparation and characterization of theranostic poly(lactide) (PLA) and pegylated PLA (PEG-PLA) shelled microbubbles that entrap gemcitabine, a commonly used drug for pancreatic cancer (PDAC). Entrapping 6 wt% gemcitabine did not significantly affect drug activity, microbubble morphology, or ultrasound contrast activity compared with unmodified microbubbles. In vitro microbubble concentrations yielding ≥ 500nM entrapped gemcitabine were needed for complete cell death in MIA PaCa-2 PDAC drug sensitivity assays, compared with 62.5 nM free gemcitabine. In vivo administration of gemcitabine-loaded microbubbles to xenograft MIA PaCa-2 PDAC tumors in athymic mice was well tolerated and provided substantial tumoral image enhancement before and after destructive ultrasound pulses. However, no significant differences in tumor growth were observed among treatment groups, in keeping with the in vitro observation that much higher doses of gemcitabine are required to mirror free gemcitabine activity. STATEMENT OF SIGNIFICANCE: The preliminary results shown here are encouraging and support further investigation into increased gemcitabine loading. Encapsulation of gemcitabine within polylactic acid (PLA) microbubbles does not damage its activity towards pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) cells. Excellent imaging and evidence of penetration into the highly desmoplastic PDAC tumors is demonstrated. Microbubble destruction was confirmed in vivo, showing that elevated mechanical index shatters the microbubbles for enhanced delivery. The potential to slow PDAC growth in vivo is shown, but higher gemcitabine concentrations are required. Current efforts are directed at increasing drug loading by inclusion of drug-carrying nanoparticles for effective in vivo treatment.

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Neural progenitor cells labeling with microbubble contrast agent for ultrasound imaging in vivo.

Publications

Neural progenitor cells labeling with microbubble contrast agent for ultrasound imaging in vivo.

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