Jesus Pacheco-Torres^1,2, Paloma Ballesteros², Pilar Lopez-Larrubia¹, and Sebastian Cerdan^1
1Biomedical Research Institute "Alberto Sols" - CSIC/UAM, Madrid, Spain, ²Laboratory of Organic Synthesis and Molecular Imaging, UNED, Madrid, Spain

Nitroimidazolyl derivatives (Pimonidazole, Misonidazole, EF5) have been traditionally used by different imaging methods as markers for hypoxia due to their preferential reduction and subsequent trapping in vivo under hypoxic conditions. However, these results remained difficult to interpret since the reduction mechanism and its rate determining steps remained largely unexplored. We address here the latter two aspects. We show that it is the intracellular redox state (NADP/NADPH, GSSG/GSH), rather than the oxygen tension, what determines the reduction rate of these compounds, the rection rate being limited mainly by the GSH concentration. This is a general mechanism occurring in all nitromidazolyl derivatives investigated.

Todd C. Soesbe¹, Osamu Togao¹, Masaya Takahashi¹, and A. Dean Sherry^1,2
1Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TX, United States, ²Department of Chemistry, The University of Texas at Dallas, Dallas, TX, United States

Paramagnetic chemical exchange saturation transfer (PARACEST) agents use water molecule exchange with lanthanide ions and radiofrequency (RF) spin saturation to create negative contrast in MRI. One advantage that PARACEST agents have over Gd-based T1 agents is that image contrast can be turned off and on via the RF saturation pulse frequency. We have recently shown that chemical exchange of water molecules between Eu3+-based PARACEST agents and bulk water can also facilitate T2 exchange (T2exch). T2exch causes a significant reduction in the bulk water T2 (i.e. negative contrast) for agents with high local concentrations, intermediate exchange rates, and large chemical shifts. The negative contrast is present even when the RF saturation pulse is omitted, causing the PARACEST agents to behave like susceptibility or T2 agents. We hypothesized that the ultra-short TE (<10 μs) used in the SWIFT sequence could reclaim the loss in signal due to T2exch and enable fast and sensitive in vivo PARECEST imaging.

Chih-Lung Chen¹, Cheng-Hung Chou², Ming-Huang Lin², Wen-Yuan Hsieh¹, Hsin-Hsin Shen¹, Shian-Jy Wang¹, and C. Chang^2
1Industrial Technology Research Institute, Hsinchu, 310, Taiwan, ²Academic Sinica, Taiwan

The activation of T-cells correlates with the pathogenesis of rheumatoid arthritis (RA). Understanding the genesis, migration, and distribution of the T-cells provides important perspectives regarding RA. To monitor T-cells noninvasively and repeatedly, an in vivo labeling technique using a new nanoparticle contrast agent, IOPC, was employed. The IOPC had a longer blood circulation time that allowed uptake by cells over a longer duration. Noticeable IOPC-induced hypointensities was observed in the growth plate of the RA rat one day following in vivo IOPC labeling. Double immunohistology against IOPC and CD3 confirmed the presence of T-cells in the growth plate in RA.

Veronica Clavijo Jordan¹, and Kevin M Bennett^1
1School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, United States

Nanoparticles have been developed as T₂ contrast agents for molecular MRI. However, there is still a need to develop agents with higher relaxivities in order to increase sensitivity to delivered agents in vivo. In this work, we formed a tungsten-iron alloy in the interior cavitiy of apoferritin. The use of the protein to form a crystal core enhances the magnetic properties of the particle. The yield of the process when compared to magnetoferritin was enhanced by 200%. The W-Magnetoferritin nanoparticles had a per-iron and per-particle transverse relaxivity of 27,666mM^-1s^-1and 433,651mM^-1s^-1 respectively, which is a ~10% increase over magnetoferritin nanoparticles.

Eliana Gianolio¹, Luca Maciocco², Daniela Imperio³, Giovanni Battista Giovenzana³, Federica Simonelli⁴, Kamel Abbas⁴, Gianni Bisi⁵, and Silvio Aime^1
1Dept. Chemistry IFM & Molecular Imaging Center, University of Torino, Torino, Italy, Italy, ²Advanced Accelerator Applications (AAA), St. Genis Pouilly, France, ³DiSCAFF, University of Eastern Piedmont “A. Avogadro", Novara, Italy, ⁴European Commission Cyclotron, Institute for Health and Consumer Protection Joint Research Centre, Ispra (VA), Italy, ⁵, Nucl Med Serv, Azienda Osped San Giovanni Battista, Dipartimento Med Interna, University of Torino, Torino, Italy

In vitro study of a dual MRI/SPECT pH-responsive agent where the SPECT-active moiety (based on a Ho(III) containing complex) acts as a reporter of the concentration of the MRI active one (based on a Gd(III) containing complex) thus allowing the transformation of the observed 1H-relaxation rates into relaxivities to recover the information relative to the pH determination.

Praveen Kumar Gulaka¹, Federico A Rojas-Quijano², Zoltan Kovacs², Ralph P Mason^1,3, A D Sherry^2,3, and Vikram D Kodibagkar^1,3
1Joint graduate program in Biomedical Engineering, UT Arlington and UT Southwestern Medical Center, Dallas, Tx, United States, ²Advanced Imaging Research Center, UT Southwestern Medical Center, ³Radiology, UT Southwestern Medical Center

Hypoxic regions in tumors are known to affect radiation sensitivity and promote development of metastases. Therefore the ability to image the tumor hypoxia in vivo will provide useful prognostic information and help tailor therapy. Previous research demonstrated that 2-nitroimidazole accumulated in hypoxic tissues due to an enzyme mediated reduction of the nitro group in hypoxic conditions. In this work, we report both in vitro and in vivo evidence for accumulation of a T1 shortening agent, a GdDOTA monoamide conjugate of 2-nitroimidazole abbreviated as GdDO3NI, in hypoxic tumor tissue.

Vipul R Sheth¹, Yuguo Li², Liu Qi Chen³, Christine A Howison⁴, and Mark D Pagel^5
1Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States, ²Radiology, Case Western Reserve University, Cleveland, OH, United States, ³Chemistry and Biochemistry, University of Arizona, Tucson, AZ, United States, ⁴Arizona Research Laboratories, University of Arizona, Tucson, AZ, United States, ⁵Biomedical Engineering and Chemistry & Biochemistry, University of Arizona, Tucson, AZ, United States

A PARACEST MRI contrast agent, Yb-DO3A-oAA, can measure pH over a range of 6-7.9 pH units, with a precision of 0.206 pH units and an accuracy of 0.089 pH units. This measurement is based on a ratio of the two CEST effects of the PARACEST agent, which is independent of the agent's concentration or the samples T_1sat relaxation time. Combined with a CEST-FISP acquisition protocol, the PARACEST agent was used to measure the extracellular pH (pHe) within a subcutaneous tumor and muscle of a MDA-MB-231 breast cancer model.

Ashwini A Ketkar-Atre¹, Stefaan J. Soenen², Philip Roelandt³, Tineke Notelaers³, Greetje Vande Velde¹, Catherine Verfaillie³, Marcel De Cuyper⁴, and Uwe Himmelreich^1
1Biomedical NMR Unit/MoSAIC, KULeuven Campus Gasthuisberg, Leuven, Flanders, Belgium, ²Department of Pharmaceutical Sciences, Ghent University, Belgium, ³Interdepartmental Stem Cell Institute, KULeuven Campus Gasthuisberg, ⁴Lab of BioNanoColloids, KULeuven Campus Kortrijk, IRC, Belgium

In diseases like liver cirrhosis or hepatitis where hepatocytes are damaged and healing is difficult, it is necessary to isolate hepatocytes from mixed population of endo- and mesodermal cells differentiated from stem cells. We labelled HepG2s, C17.2 (negative control) and mixture of cells containing hepatocytes like cells with Cationic MLs (unspecific uptake), Anionic MLs (negative control) and Lac MLs with galactose-terminal entities which are recognized by asialoglycoprotein receptors (ASGPR). Higher specificity in uptake was observed with Lac MLs labelling with hepatocytes. And In vivo experiments revealed the potential use of Lac MLs as a contrast agent for liver therapy evaluation.

Yuguo Li¹, Vipul R Sheth², Guanshu Liu^3,4, and Mark D Pagel^5
1Radiology, Case Western Reserve University, Cleveland, OH, United States, ²Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States, ³Department of Radiology, Johns Hopkins University, Baltimore, MD, United States, ⁴F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States, ⁵Biomedical Engineering and Chemistry & Biochemistry, University of Arizona, Tucson, AZ, United States

We have developed a new esterase-responsive PARACEST MRI contrast agent. Before esterase cleavage, the agent Yb-DO3A-oAA-TML-ester has only one CEST signal at -11 ppm from an amide proton. Esterase de-esterification forms an amine in the product Yb-DO3A-oAA, which creates a second PARACEST signal at +9 ppm. The two CEST effects of the product endows self-calibration with respect to pharmacokinetic factors such as the concentration of agent and resulting possible shortening of T_1sat relaxation time, providing a more accurate way to detect esterase enzyme activity without needing a reference agent.

Ryan Miller Davis¹, Shingo Matsumoto¹, Marcelino Bernardo^2,3, Anastasia Sowers¹, Ken-Ichiro Matsumoto⁴, Murali C Krishna¹, and James B Mitchell^1
1Radiation Biology Branch, National Cancer Institute, Bethesda, Maryland, United States, ²Molecular Imaging Program, National Cancer Institute, Bethesda, Maryland, United States, ³National Cancer Institute-Frederick, Frederick, Maryland, United States, ⁴National Institute of Radiological Sciences, Molecular Imaging Center, Chiba, Japan

Nitroxides are a diverse class of organic small molecular weight (170-400 Da) paramagnetic radioprotectors. Because nitroxides are paramagnetic, their pharmacodynamics can be monitored indirectly with MRI. This study uses a 3 Tesla human scanner to measure pharmacodynamics of various nitroxides after tail vein injection in mice. In addition, radioprotection studies of those nitroxides were carried out with 300kVp x-rays in a dose range of 6-12.5 Gy. The results of this study provide invaluable information regarding possible causes of nitroxide toxicity, the relationship between nitroxide pharmacokinetics and radioprotective potency, and healthy tissue and tumor redox status.

Michael K Nkansah¹, and Erik M Shapiro^1,2
1Department of Biomedical Engineering, Yale University, New Haven, CT, United States, ²Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, United States

While magnetic relaxation switches (MRSws) have been developed using iron-oxide particles that cluster in the presence of an extracellular stimulus, the potential of using such systems to monitor intracellular events in vivo via MRI has not been investigated. Granot et al first demonstrated an MRSw operating in cellulo and in vivo via MRI using a Feridex®/dextranase system. We demonstrate the fabrication of magnetic cellulose particles that are relaxometrically sensitive to cellulase digestion. In the ‘off’ state, the particle remains intact. When switched ‘on’ through the cleavage action of cellulase, the iron-oxide cores get dispersed, changing the relaxivity of the agent.

Bhavna S Paratala¹, Lindsay K Hill², Lilliane Mujica-Parodi¹, Elisabeth de Castro Caparelli^3,4, Youssef Zaim Wadghiri², and Balaji Sitharaman^1
1Biomedical Engineering, Stony Brook University, Stony Brook, New York, United States, ²Department of Radiology, New York University Langone Medical Center, New York, New York, United States, ³Medical Department, Brookhaven National Laboratory, Upton, New York, United States, ⁴Social, Cognitive and Affective Neuroscience Center, Stony Brook University, Stony Brook, New York, United States

We report the synthesis, characterization (structure, magnetism and relaxometry) and in vitro MRI of graphene oxide nanoribbon (GONR)-based MRI contrast agents (CAs) for cellular and molecular MRI. GONRs were synthesized by chemical “unzipping” of multiwalled carbon nanotubes using the oxidizing agent potassium permanganate. HRTEM and Raman spectroscopy confirm the presence of GONRs. Magnetic (SQUID), and NMR relaxatometry studies reveal room temperature superparamagnetism, and relaxivities of r1 = 45mM-1s-1 and r2 = 234mM-1s-1, respectively. T1-, T2- weighted MRI phantom images show significant contrast enhancement compared to Manganese chloride, widely used preclinical CA .

Enzo Terreno¹, Pierangela Giustetto¹, Daniela Delli Castelli¹, Cinzia Boffa¹, Davide Durando¹, and Silvio Aime^1
1Molecular and Preclinical Imaging Center, University of Torino, Torino, Italy

The mechanical (i.e. non-thermic) release of the liposomal content (MRI agent and/or drug) by using pulsed low-frequency low-intense ultrasound is strongly affected by small changes in the bilayer composition, payload of imaging probe (or drug), size and shape of the nanovesicles. This finding offers the opportunity to selectively trigger the release of imaging reporters, as well as drugs, from a mixture of different nanocarriers, thus opening new therapeutic schemes to improve the overall efficacy of a pharmacological treatment.

Ki-Hye Jung¹, Hee-Kyung Kim², Min-Kyoung Kang², Ji-Ae Park³, Seung-Tae Woo⁴, Joo-Hyun Kim⁴, Tae-Jeong Kim¹, and Yongmin Chang^2,5
1Department of Applied Chemistry, Kyungpook National University, Daegu, Korea, Republic of, ²Department of Medical & Biological Engineering, Kyungpook National University, Daegu, Korea, Republic of, ³Laboratory of Nuclear Medicine Research, Molecular Imaging Center, Korea Institute of Radiological & Medical Science, Seoul, Korea, Republic of, ⁴Bayer Schering Pharma Korea, Seoul, Korea, Republic of, ⁵Department of Diagnostic Radiology and Molecular Medicine, Kyungpook National University, Daegu, Korea, Republic of

We report the synthesis of Gd-complex of macrocyclic DTPA conjugate of 2,2¡¯-diaminobiphenyl (GdL) for use as a new MR contrast agent for both angiography and brain-tumor imaging. GdL exhibits very high R₁ relaxivity (= 12.15 mM^-1sec^-1) which is 3.3 times as high as that of structurally related macrocyclic analogue, Dotarem^® R₁(= 3.7 mM^-1sec^-1). Also observed is the greater kinetic stability than those of commercially available Omniscan^® and Multihance^®. The present system shows a very strong blood-pool effect for as long as 2 h, and most uniquely demonstrates brain-tumor imaging capability which is absent from the ordinary ECF MRI CAs.

Hee-Kyung Kim¹, Ki-Hye Jung², Min-Kyoung Kang¹, Ji-Ae Park³, Seung-Tae Woo⁴, Joo-Hyun Kim⁴, Tae-Jeong Kim², and Yongmin Chang^1,5
1Department of Medical & Biological Engineering, Kyungpook National University, Daegu, Korea, Republic of, ²Department of Applied Chemistry, Kyungpook National University, Daegu, Korea, Republic of, ³Laboratory of Nuclear Medicine Research, Molecular Imaging Center, Korea Institute of Radiological & Medical Science, Seoul, Korea, Republic of, ⁴Bayer Schering Pharma Korea, Seoul, Korea, Republic of, ⁵Department of Diagnostic Radiology and Molecular Medicine, Kyungpook National University, Daegu, Korea, Republic of

Gd-complexes of the type [Gd(L)(H₂O)]·H₂O(5a-c), where L is DOTA conjugates of tranexamic acid (4a)and tranexamic esters (4b-c), have been prepared as a new class of MRI BPCAs. Thermodynamic stability (K_GdL) and pharmacokinetic inertness of 5 are compared well with or better than those of analogous MRI CAs such as Gd-DOTA and Gd-DTPA-BMA. Their R₁-relaxivities are significantly higher than any of the clinically used MRI CAs. T₁-weighted MR images of mice administered by 5c demonstrate high blood-pool effect with simultaneous contrast enhancement in liver.

Simone S Williams^1,2, Tricia L Lobo³, and Erik M Shapiro^1,3
1Department of Biomedical Engineering, Yale University, New Haven, CT, United States, ²Xavier University of Louisiana, New Orleans, LA, United States, ³Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, United States

We investigated the use of gadolinium oxide (Gd₂O₃) based contrast agents for MRI-based cell tracking. Gd₂O₃ nanocrystals were synthesized and encapsulated within PLGA to form 150 nm nanoparticles. While PLGA encapsulated Gd2O3 nanoparticles had good r1 molar relaxivity, 1.9 mM^-1sec^-1, Gd₂O₃ nanocrystals rapidly dissolved to form gadolinium ions in solutions mimicking lysosomal chemical environment within cells. Thus, while Gd₂O₃ does have favorable MRI properties, the rapid dissolution of Gd₂O₃ to form gadolinium ions is dangerous and needs to be accounted for when using Gd₂O₃ as an MRI contrast agent.

Debbie Anaby¹, Liat Avram¹, Amnon Bar-Shir², Ofer Sadan³, Smadar Cohen⁴, Niva Segev-Amzaleg⁵, Dan Frenkel⁵, Daniel Offen³, and Yoram Cohen^1
1School of Chemistry, Tel Aviv University, Tel Aviv, Israel, ²Johns Hopkins University, Baltimore, Maryland, United States, ³Department of neurology, Rabin Medical Center, Tel Aviv University, Tel Aviv, ⁴Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben Gurion University of the Negev, Beer Sheva, Israel, ⁵Department of Neurobiology, the Goerge Weiss Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

Calcium cations are involved in myriad of biological processes and pathologies. Despite the crucial role played by calcium in living systems, the noninvasive determination or imaging of calcium levels in opaque samples and deep tissues remains a formidable challenge. Here we describe a new platform based on superparamagnetic iron oxide nanoparticles coated with mono-disperse alginate, which enables specific detection of Calcium, by MRI. These nanoparticles were shown to detect calcium secreted in Quinolinic Acid lesions in rats brains in vivo. This new non-invasive MRI biomarker for calcium has the potential to act as a calcium probe in in vivo settings.

Rajat K. Ghosh¹, Stephen J. Kadlecek¹, Kiarash Emami¹, Benjamin M. Pullinger¹, Giuseppe Pileio², Malcolm H. Levitt², Nicholas N. Kuzma^1,3, and Rahim R. Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, PA, United States, ²School of Chemistry, Southampton University, Southampton, Hampshire, United Kingdom, ³Departments of Biomedical Engineering and Imaging Sciences, University of Rochester, Rochester, NY, United States

Development of hyperpolarized MRI tracers is often limited by the longitudinal relaxation rate due to dipolar interactions. It has been previously demonstrated that the effect of dipolar interactions in solution can be removed by storing the nuclear polarization of molecules in long-lived, singlet-like spin states. In the case of doubly-enriched ¹⁵N₂O storing the polarization of ¹⁵N nuclei in the singlet state has been shown to substantially increase their polarization lifetime. The feasibility of utilizing ¹⁵N₂O as a tracer is investigated by measuring the singlet lifetime of¹⁵N₂O when dissolved in a variety of solvents including whole blood. Comparing the singlet lifetime to the T₁ relaxation in deuterated and natural solvents sheds light on the mechanism of the singlet state relaxation

Kelly Catherine McPhee¹, Jennifer E.H. Baker^1,2, Katayoun Saatchi³, Urs O Häfeli³, and Stefan A Reinsberg^1
1Physics and Astronomy, University of British Columbia, Vancouver, British Columbia, Canada, ²Radiation Biology Unit, BC Cancer Research Centre, Vancouver, British Columbia, Canada,³Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada

In this pilot study, we investigate a novel, high-molecular weight (HMW) contrast agent, hyperbranched polyglycerol (HPG), doubly labeled with Gd and a fluorescent marker. Longitudinal measures of T1 were made in vivo. We observed accumulation of HPG over several days, followed by a drop after about a week both in MRI (via changes in T1 baseline), and in histology (via the fluorescent tag). Histology shows HPG remains within or proximal to vasculature at early time points, but extravasates and accumulates at greater distances from vessels over time.

Ji-Ae Park¹, Jung Young Kim¹, Byoung Soo Kim¹, Wonho Lee¹, In Ok Ko¹, Joo Hyun Kang¹, Sang Moo Lim², Hee-Kyung Kim³, Yongmin Chang³, Tae-Jeong Kim⁴, and Kyeong Min Kim^1
1Molecular Imaging Research Center, Korea Institute of Radiological & Medical Science, Seoul, Nowon-Gu, Korea, Republic of, ²Department of nuclear Medicine, Korea Institute of Radiological & Medical Science, ³Department of Medical & Biological Engineering, Kyungpook National University, ⁴Department of Applied Chemistry, Kyungpook National University, Korea, Republic of

The combination of magnetic resonance imaging (MRI) and nuclear medicine imaging can be representative synergistic approach for providing anatomical and functional information together, because of the high resolution of MRI and the high detector sensitivity of radionuclide imaging, respectively. In this study, we report the Gd-DTPA-histidine conjugated of ^99mTc complexes [GdLHis_^99mTc] as MR/SPECT dual modality contrast agents. To overcome problems in hybrid imaging due to the huge difference (~10³) of imaging sensitivity between MRI and SPECT, we suggest the mixed-usage of [GdLHis_^99mTc] with Gd-DTPA-histidine conjugated of Re complexes [GdLHis_Re] that is an alternative substance(cold-form) having chemical characteristics equivalent with [GdLHis_^99mTc]. A new hybrid ^99mTc labeled MR contrast could be made and be suitable to both MRI and SPECT imaging. The identical characteristics of [GdLHis_^99mTc] and [GdLHis_Re] showed the same bio-functional change of hybrid contrast agents, with the additional merit of improved MRI image quality. Therefore, the hybrid-usage of both [GdLHis_Re] and [GdLHis_^99mTc] should be useful in the optimal acquisition of MR/SPECT imaging that is prerequisite for precise interpretation of bio-function.

Zhaoda Zhang¹, Matthew Greenfield², Andrew Kolodziej², and Peter Caravan^1
1A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States, ²Epix Pharmaceuticals, Lexington, MA, United States

Fibrin-specific peptides conjugated to multiple Gd-chelates, e.g. EP-2104R and EP-1242, have shown efficacy in MR detection of thrombus. We hypothesized that a second small binding group at the N-terminus may provide additional fibrin affinity, while at the same time would restrict internal motion at the N-terminus upon fibrin binding and this would result in higher relaxivity. We demonstrate that a minor perturbation (addition of a thymine moiety at the N-terminus) in probe structure can result in a 50% increase in relaxivity at the target, but does not increase off-target relaxivity. This heteroditopic binding approach is generalizable to other protein-targeted probes.

Meser M. Ali¹, Parvez Ismail Bhuiyan¹, Hassan Bagher-Ebadian^2,3, Branislava Janic¹, Robert A knight^2,3, James R. Ewing^2,3, and Ali Syed Arbab^1
1Radiology, Henry Ford Hospital, Detroit, MI, United States, ²Neurology, Henry Ford Hospital, ³Physics, Oakland University

We have recently developed a new pH-responsive dendrimer-based MRI contrast agent with excellent improvements in both overall sensitivity and responsiveness of relaxivities to pH. Therefore, the R2/R1 ratio of this dendritic MR agent has been used to measure pH and the ratio (r2/r1) showed pH-response. This pH measurement is independent of the absolute concentration of the agent so that a single MRI agent can measure pH without requiring a second MRI to account for pharmacokinetics.

Francisco Perez-Balderas^1,2, Benjamin G Davis², Sander I vanKasteren², Alexandr Khrapichev¹, Andrew Jefferson³, Claire Bristow¹, Sebastien Serres¹, Robin P Choudhury³, Daniel C Anthony⁴, and Nicola R Sibson^1
1CR/UK Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford, Oxfordshire, United Kingdom, ²Chemistry Research Laboratory, University of Oxford, Oxford, Oxfordshire, United Kingdom, ³Department of Cardiovascular Medicine, University of Oxford, Oxford, Oxfordshire, United Kingdom, ⁴Department of Pharmacology, University of Oxford, Oxford, Oxfordshire, United Kingdom

Superparamagnetic iron oxide (SPIO) nanoparticles have been extensively used for several biomedical applications. Recently, microparticles of iron oxide (MPIO) have been advantageously employed in cellular tracking and early detection of endovascular pathologies. Unfortunately, the commercially available MPIO used suffer from a lack of biodegradability that precludes their medical use. We have developed fully biodegradable multimeric MPIO (mMPIO) with a size ca. 1 m that combine the superior imaging capabilities of MPIO with the excellent biodegradability and clearance of SPIO. We demonstrate here both in vitro and in vivo degradation of our novel mMPIO, and their sensitive in vivo contrast effects.

Mojmir Suchy^1,2, Alex X. Li², Mark Milne¹, Robert Bartha², and Robert H. E. Hudson^1
1Chemistry, University of Western Ontario, London, Ontario, Canada, ²Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

A new synthetic methodology for the preparation of Tm3+-derived PARACEST MRI contrast agents containing an amino acid arginine has been developed. The CEST sensitivity of these molecules has been evaluated and found to be comparable to that of Tm3+ DOTAM-Gly-Lys-OH, a PARACEST MRI contrast agent previously detected in mouse kidneys and mouse brain tumours.

Robert Ta^1,2, Alex X Li¹, Mojmir Suchy³, Robert H.E Hudson³, Stephen Pasternak^4,5, and Robert Bartha^1,2
1Imaging Research Laboratories, Robarts Research Institute, London, Ontario, Canada, ²Medical Biophysics, The University of Western Ontario, London, Ontario, Canada, ³Chemistry, The University of Western Ontario, London, Ontario, Canada, ⁴Molecular Brain Research Group, Robarts Research Institute, London, Ontario, Canada, ⁵Clinical Neurological Sciences, The University of Western Ontario, London, Ontario, Canada

A novel contrast agent, Gd³⁺-DOTA-CAT, has been developed for in-vivo magnetic resonance imaging of Cathepsin-D activity in Alzheimer’s disease. A cell-penetrating-peptide was attached to increase the agent’s ability to cross the blood-brain-barrier. A Cathepsin-D recognition site was used for enzymatic detection of Gd³⁺-DOTA-CAT upon brain tissue penetration. We compared the MR sensitivity of Gd³⁺-DOTA-CAT to Gd³⁺-DTPA(Magnevist®) to evaluate the potential in-vivo imaging of this compound. Injection of 10 mM Gd³⁺-DOTA-CAT in a transgenic Alzheimer’s disease mouse produced increased signal intensity within the brain, cerebral and non-cerebral vasculature. Gd³⁺-DOTA-CAT demonstrates significant potential as a MRI contrast agent for Cathepsin-D activity in-vivo.

Garrett William Astary¹, Svetlana Kantorovich², Paul Richard Carney^1,3, Malisa Sarntinoranont⁴, and Thomas Harold Mareci^5
1Biomedical Engineering, University of Florida, Gainesville, FL, United States, ²Neuroscience, University of Florida, ³Division of Pediatric Neurology, University of Florida, ⁴Mechanical and Aerospace Engineering, University of Florida, ⁵Biochemistry and Molecular Biology, University of Florida

A priori knowledge of contrast agent (CA) relaxivity (R₁ and R₂), which parameterizes how a CA alters neighboring water proton relaxation times (T₁ and T₂), can be used to determine the CA concentration in tissue, using pre- and post-contrast T₁-weighted scans and knowledge of inherent tissue T₁ values. The relaxivity of the CA gadolinium-labeled albumin (Gd-albumin) was measured in rat thalamus in vivo at 11.1 T and compared to the relaxivity of this CA measured in solution. R₁ and R₂ values in tissue were found to be reduced by 78% and 32%, respectively relative to solution values.

Geralda A.F. van Tilborg¹, David P. Cormode², Peter A. Jarzyna², Annette van der Toorn¹, Susanne M.A. van der Pol³, Louis van Bloois⁴, Gert Storm⁴, Willem J.M. Mulder², Helga E. de Vries³, and Rick M. Dijkhuizen^1
1Image Sciences Institute, University Medical Center Utrecht, Utrecht, Netherlands, ²Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, New York, New York, United States, ³3Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands, ⁴Department of Pharmaceutics, Institute for Pharmaceutical Sciences, Utrecht, Netherlands

MRI-based in vivo cell tracking studies require potent and biocompatible contrast agents with high labeling efficiency, and, preferentially, inclusion of fluorescent entities for additional microscopic analyses. In the present study we compared three different types of fluorescent lipid-coated nanoclusters of iron oxide, with or without inclusion of an oil phase. Nanoparticles without oil showed superior properties in terms of relaxivity r2, shelf-life, labeling efficiency of murine macrophages and biocompatibility. In conclusion, lipid-coated nanoclusters of iron oxide represent an attractive, potent and flexible platform with, in the absence of an oil phase, excellent properties for cellular imaging.

Shelton D. Caruthers¹, Dipanjan Pan¹, Angana Senpan¹, Anne H. Schmieder¹, Patrick J. Gaffney², Samuel A Wickline¹, and Gregory M Lanza^1
1C-TRAIN, Washington University School of Medicine, St. Louis, MO, United States, ²Dept. of Surgery, St. Thomas' Hospital, London, United Kingdom

Based on a nanocolloidal suspension of lipid-encapsulated, organically-soluble copper oleate, a new site-targeted molecular imaging contrast agent is presented. Concentrating ~100,000 copper atoms per nanoparticle, this agent provides a high per-particle r1 relaxivity allowing sensitive detection on T1-weighted MRI as is demonstrated herein targeted to fibrin clots in vitro.

Shelton D. Caruthers¹, Monica Shokeen², Ricardo Ferdani², Hua Pan¹, Samuel A Wickline¹, and Carolyn J. Anderson^2
1C-TRAIN, Washington University School of Medicine, St. Louis, MO, United States, ²Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

The combination of PET and MRI is a major step in the evolution of molecular imaging. This work introduces a novel multi-modality contrast agent detected by both PET and MRI. Based on a lipid-encapuslated liquid perfluorocarbon nanoparticle platform, the agent uses a self-inserting chelator with a linker peptide derived from melittin to allow straightforward labeling with ⁶⁴Cu. Quantitative MR imaging results from direct detection of the ¹⁹F signal from the nanoparticle core.

Zhen Ye^1,2, Xueming Wu², Mingqian Tan², and Zheng-Rong Lu^2
1Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, United States, ²Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States

This study designed, synthesized and evaluated a novel biodegradable polymeric MRI contrast agent with high kinetic stability for clinical cancer diagnosis using contrast-enhanced MRI. The new agent showed high relaxivity and good degradability in vitro. The MR contrast-enhancing effect of the new agent was evaluated on mice bearing orthotopic 4T1 breast cancer tumor. Our in vivo preliminary results demonstrated the agent was able to generate significantly prolonged and higher tumor enhancement than clinical agents. The novel contrast agent is of great clinical potential for MR cancer diagnosis.

Stefaan Soenen J.H. Soenen¹, Michel Hodenius¹, Marcel De Cuyper¹, and Uwe Himmelreich^2
1Lab of BioNanoColloids, IRC, Katholieke Universiteit Leuven Campus Kortrijk, Kortrijk, Belgium, ²Biomedical NMR Unit/ MoSAIC, Katholieke Universiteit Leuven, Leuven, Flandern, Belgium

Magnetoliposomes (ML) have been developped and studied) for stable, non-toxic, longitudinal cell labelling and monitoring. In contrast to other iron oxide based nanoparticles, MLs are stable intracellularly for a long time, don't cause adverse effects on cell biology and result in stronger T2* contrast. The later is due to gradual, intracellular degredation of the outer lipid layer and subsequent clustering of the monolayer-coated iron oxide particles.

Byunghee Yoo¹, Vipul R Sheth², Christine A Howison³, Matthew Douglas⁴, Carlos T Pineda⁵, Amanda F Baker⁶, and Mark D Pagel^7
1Biomedical Engineering, University of Arizona, Tucson, AZ, United States, ²Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States, ³Arizona Research Laboratories, University of Arizona, Tucson, AZ, United States, ⁴College of Medicine, University of Arizona, Tucson, AZ, United States, ⁵Arizona Cancer Center, University of Arizona, Tucson, AZ, United States, ⁶Hematology/Oncology, Arizona Cancer Center, University of Arizona, Tucson, AZ, United States, ⁷Biomedical Engineering and Chemistry & Biochemistry, University of Arizona, Tucson, AZ, United States

We have detected the enzyme activity of urokinase Plasminogen Activator within a Capan-2 pancreatic tumor model. After i.v. injection of a mixture of a uPA-responsive PARACEST agent and an unresponsive "control" PARACEST agent, CEST-FISP MR images were acquired for 18 minutes to monitor both agents. The initial increase in CEST effects in the tumor from both agents was equivalent indicating equivalent pharmacokinetics, but the CEST effect of the enzyme-responsive agent decreased more rapidly than the CEST effect of the control agent after 6 minutes, indicating that the agent was being cleaved by uPA.

Elizabeth A Osborne¹, and Angelique Y Louie^2
1Chemistry, University of California, Davis, Davis, CA, United States, ²Biomedical Engineering, University of California, Davis, Davis, CA, United States

We have developed MRI contrast agents based on paramagnetic nanoparticles functionalized with “molecular switches”, that are capable of reporting on redox conditions. The “molecular switches”, spirooxazine, change conformation between hydrophilic and hydrophobic isomers in response to NADH and peroxide. This isomerization directs aggregation and dispersion of the nanoparticles yielding a modulation of MR signal. We have synthesized and characterized iron oxide nanoparticles coated with dextran that has been cross-linked and aminated thus allowing attachment of spirooxazine. Preliminary results indicate successful preparation of the particles, and size and relaxivity differences have been observed upon reaction with NADH/peroxide in solution studies.

Dong-Hyuk Kim¹, Yong-Hee Han¹, Moo-Young Jang¹, and Chi -Woong Mun^1,2
1Biomedical Engineering, Inje University, KimHae, KyeongNam, Korea, Republic of, ²UHRC

This study, typical MR variables such as T1-and T2-relaxation times of the tissue-mimic phantoms which include the lab-made gold nanoparticles(GNP) were measured according to their morphological characteristics and synthesis conditions.