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Objective. The aim of this paper is to show an algorithm for the automatic computer-based tracing (ACT) of common carotid artery (CCA) in longitudinal B-mode ultrasound images characterized by four main features: (i) user-independence; (ii) suitability to normal and pathological images; (iii) robustness to noise; and (iv) independent of ultrasound OEM scanner. Methods. Three hundred longitudinal B-mode images (100 normal CCAs, 100 CCAs with increased intima-media thickness, 60 stable plaques, and 40 echolucent plaques) were acquired using three different (GE, Siemens, and Biosound) OEM ultrasound image scanners. The algorithm processed each image to delineate the region of interest containing the CCA. Output of the algorithm are three segmentation lines representing (a) distal (far) and (b) near adventitia layers, and (c) lumen of the CCA. Three operators qualitatively scored the ACTs. Results. The CCA was correctly automatically traced in all the 300 B-mode images. The performance was independent on the image scanner used to acquire the image or on the type of the CCA (healthy versus pathologic). Eight ACTs out of 300 received a poor score after visual inspection due to an automated adventitia tracing that did not correctly follow the CCA wall in a small portion of the image. Conclusions. The proposed algorithm is robust in ACTs of CCA since it is independent of scanner and normal/abnormal wall. This approach could constitute a general basis for a completely automated segmentation procedure.

Please cite this article as: R. Cavalli, M. Argenziano, E. Vigna, P. Giustetto, E. Torres, S. Aime, E. Terreno, Preparation and in vitro characterization of chitosan nanobubbles as theranostic agents, Colloids and Surfaces B: Biointerfaces (2015), http://dx.doi.org/10. 1016/j.colsurfb.2015.03.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 27 A c c e p t e d M a n u s c r i p A c c e p t e d M a n u s c r i p t 2 ABSTRACT Theranostic delivery systems are nanostructures that combine the modality of therapy and diagnostic imaging. Polymeric micro-and nanobubbles, spherical vesicles containing a gas core, have been proposed as new theranostic carriers for MRI-guided therapy. In this study, chitosan nanobubbles were purposely tuned for the co-delivery of prednisolone phosphate and a Gd (III) complex, as therapeutic and MRI diagnostic agent, respectively. Perfluoropentane was used for filling up the internal core of the formulation. These theranostic nanobubbles showed diameters of about 500 nm and a positive surface charge that allows the interaction with the negatively charged Gd-DOTP complex. Pluronic F68 was added to the nanobubble aqueous suspension as stabilizer agent. The encapsulation efficiency was good for both the active compounds, and a prolonged drug release profile was observed in vitro. The effect of ultrasound stimulation on prednisolone phosphate release was evaluated at 37 °C. A marked increase on drug release kinetics with no burst effect was obtained after the exposure of the system to ultrasound. Furthermore, the relaxivity of the MRI probe changed upon incorporation in the nanobubble shell, thereby offering interesting opportunity in dual MRI-US experiments. The ultrasound characterization showed a good in vitro echogenicity of the theranostic nanobubbles.In summary, chitosan drug-loaded nanobubbles with Gd (III) complex bound to their shell might be considered a new platform for imaging and drug delivery with the potential of improving anticancer treatments.

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Chitosan-coated oxygen microbubbles of average diameter 2.5 mum, narrow size distribution and spherical shape were prepared. A core-shell structure was evidenced by fluorescence microscopy using fluorescent microbubbles. Such microbubbles can be a therapeutic device for vehiculating oxygen to hypoxic tissues, provided they show proper permeability and diffusivity properties and are non-toxic. Our study proves that oxygen is efficiently delivered both in 'in vitro' and 'in vivo' preparations, and can be conveniently metabolized reversing the cellular hypoxic response. Moreover, toxic effects were investigated in human blood and in cultured cells and no evidence for them was found.

The work aimed at developing a novel MRI-based theranostic protocol for improving the anticancer efficacy of a Doxil-like liposomal formulation. The goal was achieved stimulating the intratumor release of the drug from the nanocarrier and favoring its diffusion in the lesion by the sequential application of low-intensity pulsed ultrasound. The protocol was tested on mice bearing a syngeneic breast cancer model. The combination of acoustic waves with different characteristics allowed for: i) the release of the drug and the co-encapsulated MRI agent (Gadoteridol) from the liposomes in the vessels of the tumor region, and ii) the extravasation of the released material, as well as intact liposomes, in the tumor stroma. The MR-T1 contrast enhancement measured in the tumor reported on the delivery and US-triggered release of Doxorubicin. The developed protocol resulted in a marked increase in the intratumor drug concentration that, in turn, led to the complete regression of the lesion. The protocol has a good clinical translatability because all the components of the theranostic agent (Doxorubicin, liposomes, Gadoteridol) are approved for human use. MRIJbased% procedure% for% the% in$ vivo% visualization% of% the% release% of% an% anticancer% drug% (Doxorubicin)% from% liposomes% stimulated% by% the% local% application% of% pulsed% lowJintensity% planar% ultrasound.% First,% we% investigated% the% in% vitro% release% properties% of% several% nanovesicular% carriers% under% US% application% and% demonstrated% that% the% release% was% i)% caused% by% the% mechanical% characteristics% of% the% US% stimulus,% ii)% very% sensitive% to% the% composition% of% the% particle% membrane,% and% iii)% MRI% detectable% (Giustetto% et$ al.,% J.$ Med.$ Imaging$Health$Inf.%3,%356J366%(2013)).%Next,%the%MRI%potential%of%the%method%was%demonstrated%in$vivo%on%a% mouse%model%of%melanoma% (Rizzitelli%et$al.,%Nanomedicine%10,%901J904%(2014)).%More%recently,%the%theranostic% protocol% was% implemented% by% the% encapsulation% of% Doxorubicin,% and% both% the% MRI% performance% and% the% therapeutic% benefits% associated% with% the% USJtriggered% intratumor% release% of% the% drug% on% a% mouse% model% of% breast%cancer%were%reported%(Rizzitelli%et$al.,%J.$Control.$Release%202,%21J30% (2015)).% In%the%submitted%paper,%we%further%improved%the%performance%of%the%method%through%the%sequential% application%of%two%different%low%intensity%US%stimuli,%one%inducing%a%permeabilization%of%the%tumor%vascular% endothelium,%and%the%other%stimulating%the%release%of%the%drug%from%the%nanocarrier.%The%synergy%between% the%two%short%stimuli%(only%3%minutes%in%total)%allowed%for%a%complete%tumor%regression%in%a%mouse%model%of% breast%cancer.%Furthermore,%also%the%MRI%detectability%of%the%process%was%improved.%% Though% several% examples% dealing% with% the% use% of% US% (but% mostly% focused% with% highJintensity)% for% triggering% drug% release% can% be% found% in% literature,% this% is,% to% our% knowledge,% the% case% with% the% highest% therap...