<p><a>Molecular imaging revolutionized the way researchers and clinicians visualize and investigate complex biochemical phenomena, and it is beneficial </a><a>for disease diagnosis, drug design and therapy assessment</a>. Among a variety of different imaging techniques, the non-ionizing and non-invasive photoacoustic (PA) imaging is attracting increased attentions, owing to its high spatial and temporal resolutions with reasonable penetration depth in tissue. Parallel efforts have been the preparation of PA imaging agents which has high PA efficacy and can specifically label the targets at cellular or molecular level. Particularly, there is exponentially growing interest in imaging in the second near-infrared (NIR-II) window (1000–1700 nm), where offers reduced tissue background and improved penetration depth. However, study of PA imaging in the NIR-II window is incomplete, partly due to the lack of suitable materials. Therefore, in my dissertation work I studied NIR-II PA imaging through semiconducting polymer. </p> <p>Firstly, the performance of PA imaging in the NIR-II window is explored by using a semiconducting polymer nanoparticle (SPN) which has strong absorption in the NIR-II window. Compared with lipid, blood and water, such SPN shows outstanding PA contrast in the NIR-II window <i>in situ</i> and <i>in vivo</i>, and an imaging depth of more than 5 cm at 1064 nm excitation is achieved in chicken-breast tissue. These results suggest that SPN as a PA contrast in the NIR-II window opens new opportunities for biomedical imaging with improved imaging contrast and centimeter-deep imaging depth.</p> <p>Next, targeted PA imaging of prostate cancer is achieved by functionalizing a NIR-II absorbing SPN with prostate-specific membrane antigen (PSMA)-targeted ligands. Insights into the interaction of the imaging probes with the biological targets are obtained from single-cell to whole-organ by transient absorption (TA) microscopy and PA imaging. TA microscopy reveals the targeting efficiency, kinetics, and specificity of the functionalized SPN to PSMA-positive prostate cancer at cellular level. Meanwhile, the functionalized SPN demonstrates selective accumulation and retention in the PSMA-positive tumor after intravenous administration <i>in vivo</i>. Taken together, it is demonstrated that BTII-DUPA SPN is a promising targeted probe for prostate cancer diagnosis by PA imaging. </p> <p>Lastly, PA imaging in the NIR-II window is also achieved water-soluble semiconducting polymer, which is prepared by oxygen-doping. After doping, it shows broadband absorption in the entire NIR-II window, with great chemical stability, photostability and biocompatibility. Owing to its merit of broadband absorption, the imaging depth comparison among different NIR-II wavelengths is also achieved. Moreover, this doped semiconducting polymer is readily soluble in normal physiological pH by virtue of carboxyl groups on side chains and tends to aggregate at an acidic environment which results in a 7.6-fold PA enhancement at pH 5.0. Importantly, a 3.4±1.0-fold greater signal in tumor tissue than that in muscle is revealed <i>in vivo</i>. This study provides a more attainable yet effective platform to the field for achieving water-soluble NIR-II absorbing contrast agents for activatable PA imaging. </p>

Nous avons synthétisé des polymères possédant des terminaisons fluorées afin de formuler des nanocapsules comme agents de contraste ultrasonores (ACUs) pour l’imagerie des tumeurs. Ces nanocapsules sont composées d’un cœur de bromure de perfluorooctyle (PFOB), un liquide perfluoré biocompatible et échogène, et d’une coque polymère possédant trois blocs d’affinités différentes. Le bloc hydrophile de polyéthylène glycol (PEG) présent en surface des nanocapsules permet de prolonger leur temps de circulation dans le compartiment sanguin et de favoriser leur accumulation dans les tumeurs par l’effet de perméabilité et de rétention accrue. Le bloc hydrophobe de polylactide (PLA) permet de générer une coque dégradable plus stable que les membranes de lipides ou de tensioactifs qui composent les ACUs utilisés en clinique. Finalement, la terminaison fluorée permet de favoriser l’ancrage du polymère autour de la goutte de liquide perfluoré et d’augmenter l’échogénicité des nanocapsules. Deux stratégies différentes ont été développées pour introduire ce bloc fluoré. La première consistait à synthétiser un PLA terminé par un chaînon fluoré linéaire court (C3F7 à C13F27) et à le mélanger à un polymère dibloc PLA-PEG pour formuler les nanocapsules. Nous avons montré que l’efficacité d’encapsulation du PFOB augmente avec la longueur de chaîne fluorée jusqu’à C8F17. La deuxième stratégie consistait à synthétiser directement un polymère tribloc composé des trois parties PEG, PLA et fluorée sur la même chaîne, la partie fluorée étant constituée de 4 à 15 chaînons C8F17 pendants (structure en peigne). Des mesures de tension interfaciale ont montré que ces polymères triblocs s’adsorbent à l’interface PFOB/solvant organique et encapsulent le PFOB plus efficacement que le PLA-PEG non fluoré. La morphologie des capsules est fortement influencée par le nombre de chaînons fluorés présents dans le polymère et par la quantité de polymère utilisée lors de la formulation. Une masse élevée du polymère contenant 15 chaînons fluorés favorisera ainsi la formation de nanocapsules possédant plusieurs cœurs de PFOB. La diminution de la quantité de polymère fluoré a finalement permis de produire des capsules avec un seul cœur, une coque fine, et de forme légèrement ellipsoïdale. Ces capsules diffusent les ultrasons plus efficacement que les capsules de PLA-PEG non fluoré. Alors que la présence de chaînes de PEG atténue considérablement la réponse acoustique des capsules, l’addition des chaînons fluorés permet de contrebalancer cet effet. Cette amélioration provient de plusieurs paramètres : l’augmentation de la quantité de PFOB encapsulé, l’augmentation de la densité de la capsule, et la diminution de l’épaisseur de la coque des capsules. Par ailleurs, les polymères fluorés et leurs produits de dégradation n’induisent pas de cytotoxicité in vitro comparé à leurs analogues non fluorés. Ces nanocapsules apparaissent donc comme des agents de contraste prometteurs pour permettre de mieux visualiser les tumeurs par échographie. / We have synthesized polymers with fluorinated end chains to formulate nanocapsules as ultrasound contrast agents (UCAs) for tumor imaging. These nanocapsules are composed of a core of perfluorooctyl bromide (PFOB), a biocompatible and echogenic perfluorinated liquid, and a polymeric shell made of three blocks of different affinities. The hydrophilic block of poly(ethylene glycol) (PEG) at the surface of the nanocapsules allows increasing their circulation time in the blood and promoting their accumulation into tumors by the enhanced permeation and retention effect. The hydrophobic block of polylactide (PLA) allows generating a degradable shell with higher stability as compared to the surfactant- and lipid-based membranes of commercialized UCAs. Finally, the fluorinated block favors the wetting of the polymer around the perfluorinated liquid and improves the nanocapsules echogenicity. Two different strategies have been developed to introduce this fluorinated part. The first one consisted in synthesizing a PLA terminated by a short linear fluorinated chain (from C3F7 to C13F27) and mixing it with a PLA-PEG diblock polymer to formulate the nanocapsules. The encapsulation efficiency of PFOB was found to increase with the fluorinated chain length up to C8F17. The second strategy consisted in synthesizing directly a triblock polymer composed of the three parts (PEG, PLA and fluorinated) on the same chain, the fluorinated part consisting of 4 to 15 pendant C8F17 chains (with a comb-like structure). Interfacial tension measurements showed that these triblock polymers adsorb at the PFOB/organic solvent interface and encapsulate PFOB more efficiently than non-fluorinated PLA-PEG. The capsules morphology was strongly influenced by the number of fluorinated chains and the amount of polymer used for formulation. Formulation with a high quantity of the polymer containing 15 fluorinated pendants thus favored the formation of nanocapsules with several PFOB cores. Decreasing the fluorinated polymer quantity then allowed producing capsules with a single core, a thin shell, and a slightly ellipsoidal shape. These capsules were more efficient ultrasound scatterers than non-fluorinated PLA-PEG capsules. While the presence of PEG chains considerably attenuates the capsules acoustic response, addition of fluorinated chains seems to counterbalance this effect. Such improvement arises from several contributions: a higher encapsulated PFOB content, a higher density due to the presence of fluorinated chains, and a lower shell thickness. Furthermore, the fluorinated polymers and their degradation products did not induce any in vitro cytotoxicity as compared to their non-fluorinated analogues. These nanocapsules therefore appear as promising UCAs for tumor imaging.

Acoustic droplet vaporization (ADV) is a process in which a phase shift of a liquified droplet into a gaseous microbubble, is triggered using an ultrasonic wave. In contrast to utilizing conventional contrast agents in ultrasound, the phase change contrast agents used in ADV can extravasate into tumor tissue, and they offer a greater circulatory lifespan, thereby increasing the potential applications in which they can be utilized. In this project, the impact of different ultrasound parameters on the efficiency of ADV was investigated, using a programmable ultrasound system. Two different ultrasound sequences were designed, for imaging and vaporization of droplets. Furthermore, three different sets of experiments were performed. Firstly, the vaporization effect of different imaging voltages was investigated, whereby a setting of 15V was identified as an able voltage for the remaining experiments. Secondly, experiments concerning the effect of vaporizing frequency on the ADV efficiency were performed, including the use of single and dual frequencies. Lastly, different frequency settings were combined with varying the number of cycles, to assess how the choice of pulse length influences the vaporization. The results from the project indicate that no substantial difference in ADV efficiency is achieved when using different frequency settings for perfluoropentane droplets encapsulated by cellulose nanofibers. However, the results provide clear indications of the benefit of using longer pulse durations on the vaporization efficiency. In conclusion, further studies are required before ADV can be translated into a clinical setting.

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Please note: we were unable to immediately open the spreadsheet below. We repaired the spreadsheet file with Excel, and have a copy of it in storage. If you have difficulty opening the spreadsheet, please write to us at open-help@bu.edu. / Osteoarthritis (OA) is a painful, chronic, non-inflammatory disease affecting 140 million people worldwide that alters synovial joint structure and function. OA progressively breaks down hyaline cartilage, the hydrated tissue that provides a smooth, nearly frictionless surface and distributes loads applied to articulating joint surfaces. The loss of glycosaminoglycans (GAGs) from the extracellular matrix of cartilage is an early marker of OA. Therefore, imaging methods that quantify the GAG content of cartilage are of interest. This work investigates the synthesis and development of three cationic contrast agents (CAs) for imaging articular cartilage (AC): CA4+, an iodinated small molecule, and tantalum oxide nanoparticles (Ta2O5 NPs) for x-ray Computed Tomography (CT) imaging; and Gadopentetate-dilysine (Gd(DTPA)Lys2), a gadolinium small molecule for Magnetic Resonance (MR) imaging. These cationic contrast agents are attracted to the strong negative fixed charge of extracellular GAG and, therefore, infiltrate cartilage. This work begins with an overview of CT and MR imaging basic principles, current clinical CAs and contrast enhanced imaging of AC. First, the large-scale (50 g) synthesis of CA4+ is described and the partitioning over time of CA4+ into ex vivo AC is correlated to GAG content and cartilage mechanical properties. Similar partitioning studies are applied to anionic, neutral and cationic Ta2O5 NPs, where the cationic NP exhibited substantially greater affinity for AC. Moreover, by maintaining the positive charge on the NP surface and introducing a polyethylene glycol coating, a NP formulation is described for successful in vivo cartilage imaging. Next described is the MRI CA, Gd(DTPA)Lys2, which affords an equivalent T1 signal in cartilage at 1/10th the effective dosage of anionic gadopentetate. Finally, the equilibrium partitioning of the small molecule CT and MRI CAs is directly compared to GAG content and mechanical properties in human finger AC. In summary, results show cationic CAs strongly correlate to both GAG and mechanical properties and distribute in direct proportion to GAG unlike anionic CAs. The use of cationic CAs to quantify the biochemical and mechanical changes of AC may aid drug discovery and improve clinical assessment and intervention of OA for future patients. / 2017-11-03T00:00:00Z

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Nowadays hybrid imaging modalities are new trends in medical imaging. To improve the diagnostic outcome of hybrid imaging, multimodal contrast agents need to be developed. For example, hybrid contrast agents for computer tomography and ultrasound (CACTUS) are one of those desirable hybrid contrast agents for the modern medical imaging. Polyvinyl alcohol (PVA) micro-bubbles (MBs) are one of the latest generations of ultrasound contrast agents (UCAs). PVA MBs are more stable and offer longer circulation and on-shelf storage time compare to other UCAs. However, the current use as contrast agent is limited only to ultrasound imaging. In this project, we fabricated and characterized hybrid contrast agents based on PVA MBs. Two methods for developing hybrid contrast agents were proposed. The first method is to combine MBs, currently used as an ultrasound contrast agent, with gold nanoparticles that are used as a preclinical contrast agent for computer tomography (CT). The second method is to determine at which concentration plain MBs suspension has both considerable negative contrast in CT and enhancement of the backscattered signal in ultrasound imaging. Both methods were evaluated and optimized. A scenario to achieve promising hybrid contrast agent was described in this report.