Dendron based antifouling, MRI and magnetic hyperthermia properties of different shaped iron oxide nanoparticles.

Owing to the great potential of iron oxide nanoparticles (NPs) for nanomedicine, large efforts have been made to better control their magnetic properties, especially their magnetic anisotropy to provide NPs able to combine imaging by MRI and therapy by magnetic hyperthermia. In that context, the design of anisotropic NPs appears as a very promising and efficient strategy. Furthermore, their bioactive coating also remains a challenge as it should provide colloidal stability, biocompatibility, furtivity along with good water diffusion for MRI. By taking advantage of our controlled synthesis method of iron oxide NPs with different shapes (cubic, spherical, octopod and nanoplate), we demonstrate here that the dendron coating, shown previously to be very suitable for 10 nm sized iron oxide, also provided very good colloidal, MRI and antifouling properties to the anisotropic shaped NPs. These antifouling properties, demonstrated through several experiments and characterizations, are very promising to achieve specific targeting of disease tissues without affecting healthy organs. On the other hand, the magnetic hyperthermia properties were shown to depend on the saturation magnetization and the ability of NPs to self-align, confirming the need of a balance between crystalline and dipolar magnetic anisotropies.

Evaluation of the Active Targeting of Melanin Granules after Intravenous Injection of Dendronized Nanoparticles.

The biodistribution of dendronized iron oxides, NPs10@D1_DOTAGA and melanin-targeting NPs10@D1_ICF_DOTAGA, was studied in vivo using magnetic resonance imaging (MRI) and planar scintigraphy through [177Lu]Lu-radiolabeling. MRI experiments showed high contrast power of both dendronized nanoparticles (DPs) and hepatobiliary and urinary excretions. Little tumor uptake could be highlighted after intravenous injection probably as a consequence of the negatively charged DOTAGA-derivatized shell, which reduces the diffusion across the cells' membrane. Planar scintigraphy images demonstrated a moderate specific tumor uptake of melanoma-targeted [177Lu]Lu-NPs10@D1_ICF_DOTAGA at 2 h post-intravenous injection (pi), and the highest tumor uptake of the control probe [177Lu]Lu-NPs10@D1_DOTAGA at 30 min pi, probably due to the enhanced permeability and retention effect. In addition, ex vivo confocal microscopy studies showed a high specific targeting of human melanoma samples impregnated with NPs10@D1_ICF_Alexa647_ DOTAGA.

VSION as high field MRI T1 contrast agent: evidence of their potential as positive contrast agent for magnetic resonance angiography.

Because of their outstanding magnetic properties, iron oxide nanoparticles have already been the subject of numerous studies in the biomedical field, in particular as a negative contrast agent for T2-weighted nuclear magnetic resonance imaging, or as therapeutic agents in hyperthermia experiments. Recent studies have shown that below a given particle size (i.e. 5 nm), iron oxide may be used to provide a significant positive (brightening) effect on T1-weighted MRI. In such an application, not only the size of the crystal, but also the control of the coating process is essential to ensure optimal properties, especially at a very high field (> 3 T). In this work, we focused on the development of very small iron oxide nanoparticles as a potential platform for high field T1 magnetic resonance angiography (MRA) applications. The feasibility has been evaluated in vivo at 9.4 T, demonstrating the usefulness of the developed system for MRA applications.

Characterization of Gd loaded chitosan-TPP nanohydrogels by a multi-technique approach combining dynamic light scattering (DLS), asymetrical flow-field-flow-fractionation (AF4) and atomic force microscopy (AFM) and design of positive contrast agents for molecular resonance imaging (MRI).

Chitosan CS-tripolyphosphate TPP/hyaluronic acid HA nanohydrogels loaded with gadolinium chelates (GdDOTA ⊂ CS-TPP/HA NGs) synthesized by ionic gelation were designed for lymph node (LN) MRI. In order to be efficiently drained to LNs, nanogels (NGs) needed to exhibit a diameter ϕ < 100 nm. For that, formulation parameters were tuned, using (i) CS of two different molecular weights (51 and 37 kDa) and (ii) variable CS/TPP ratio (2 < CS/TPP < 8). Characterization of NG size distribution by dynamic light scattering (DLS) and asymetrical flow-field-flow-fractionation (AF4) showed discrepancies since DLS diameters were consistently above 200 nm while AF4 showed individual nano-objects with ϕ < 100 nm. Such a difference could be correlated to the presence of aggregates inherent to ionic gelation. This point was clarified by atomic force microscopy (AFM) in liquid mode which highlighted the main presence of individual nano-objects in nanosuspensions. Thus, combination of DLS, AF4 and AFM provided a more precise characterization of GdDOTA ⊂ CS-TPP/HA nanohydrogels which, in turn, allowed to select formulations leading to NGs of suitable mean sizes showing good MRI efficiency and negligible toxicity.

Multimodal assessment of early tumor response to chemotherapy: comparison between diffusion-weighted MRI, 1H-MR spectroscopy of choline and USPIO particles targeted at cell death.

The aim of this study was to determine the value of different magnetic resonance (MR) protocols to assess early tumor response to chemotherapy. We used a murine tumor model (TLT) presenting different degrees of response to three different cytotoxic agents. As shown in survival curves, cyclophosphamide (CP) was the most efficient drug followed by 5-fluorouracil (5-FU), whereas the etoposide treatment had little impact on TLT tumors. Three different MR protocols were used at 9.4 Tesla 24 h post-treatment: diffusion-weighted (DW)-MRI, choline measurement by (1) H MRS, and contrast-enhanced MRI using ultrasmall iron oxide nanoparticles (USPIO) targeted at phosphatidylserine. Accumulation of contrast agent in apoptotic tumors was monitored by T(2) -weighted images and quantified by EPR spectroscopy. Necrosis and apoptosis were assessed by histology. Large variations were observed in the measurement of choline peak areas and could not be directly correlated to tumor response. Although the targeted USPIO particles were able to significantly differentiate between the efficiency of each cytotoxic agent and best correlated with survival endpoint, they present the main disadvantage of non-specific tumor accumulation, which could be problematic when transferring the method to the clinic. DW-MRI presents a better compromise by combining longitudinal studies with a high dynamic range; however, DW-MRI was unable to show any significant effect for 5-FU. This study illustrates the need for multimodal imaging in assessing tumor response to treatment to compensate for individual limitations.

Role of Erythronium americanum Ker. in Energy Flow and Nutrient Dynamics of a Northern Hardwood Forest Ecosystem.

The aboveground activity of the spring herb, Erythronium americanum, is restricted to the period between snowmelt and forest canopy development. Its phenology and production capacity closely adapt the species to this temporal niche in northern deciduous forests. While E. americanum has a minor effect on energy flow, it may reduce losses of potassium and nitrogen from the ecosystem during the period of maximum removal by incorporating these elements in accumulating biomass. Later, during the summer, these nutrients are made available when the above-ground, nonperennating tissues decay.

The paramagnetic properties of malaria pigment, hemozoin, yield clues to a low-cost system for its trapping and determination.

The binding of malaria pigment, hemozoin, by a gradient magnetic field has been investigated in a manual trapping column system. Two types of magnetic filling have been tested to produce field gradients: nickel-plated steel wires, wrapped around a steel core, and superparamagnetic microbeads. The latter system allows an efficient trapping (> 80%) of ß-hematin (a synthetic pigment with physical and paramagnetic properties analogous to those of hemozoin). Tests with a Plasmodium falciparum 3D7 culture indicate that hemozoin is similarly trapped. Off-line optical spectroscopy measurements present limited sensitivity as the hemozoin we detected from in vitro cultured parasites would correspond to only a theoretical 0.02% parasitemia (1000 parasites/µL). Further work needs to be undertaken to reduce this threshold to a practical detectability level. Based on these data, a magneto-chromatographic on-line system with reduced dead volumes is proposed as a possible low-cost instrument to be tested as a malaria diagnosis system.

Prevalence, management and ethnobotanical investigation of hypertension in two Guinean urban districts.

ETHNOPHARMACOLOGICAL RELEVANCE: Hypertension is an important public health challenge in low- and middle-income countries, and in many African countries including Guinea medicinal plants are still widely used for its treatment. MATERIALS AND METHODS: The objective of this study was to determine the prevalence of hypertension in two Guinean urban districts (Pounthioun and Dowsare), to describe its management and to collect information on traditional herbal remedies. A total of 316 participants entered the study, 28.2% (89/316) men and 71.8% (227/316) women. Of these, 181 were from Dowsare (50 men and 131 women) and 135 from Pounthioun (39 men and 96 women). The mean age of subjects was 40.8 ±â€¯14.0 years (range18 - 88years), while the majority of subjects (63.3% or 200/316) were 45-74 years old. RESULTS: The overall prevalence of hypertension was 44.9% (142/316): 46.4% (84/181) from Dowsare and 43.0% (58/135) from Pounthioun. Ethnobotanical investigations among hypertensive patients led to the collection of 15 plant species, among which Hymenocardia acida leaves and Uapaca togoensis stem bark were the most cited. Phytochemical investigation of these two plant species led to the isolation and identification of isovitexin and isoorientin from H. acida, and betulinic acid and lupeol from U. togoensis. CONCLUSION: The presence of these constituents in Hymenocardia acida leaves and Uapaca togoensis stem bark may at least in part support their traditional use against hypertension in Guinea.

Synthesis of a new gadolinium complex with a high affinity for human serum albumin and its manifold physicochemical characterization by proton relaxation rate analysis, NMR diffusometry and electrospray mass spectrometry.

A novel gadolinium complex, derived from Gd-DTPA (DTPA: diethylenetriaminepentaacetic acid) and sulfaphenazole, intended to be a potential MRI contrast agent and to interact with human serum albumin (HSA), was synthesized and characterized. Its relaxometric properties were evaluated in water, and its binding to HSA was investigated by three techniques: proton relaxation rate analysis, NMR diffusometry, and electrospray mass spectrometry. The complex has a higher relaxivity than the parent compound (r(1)=7.8s(-1)mM(-1) at 310K and 0.47T and 7.7s(-1)mM(-1) at 310K and 1.41T), a fast water exchange, and a very good stability versus zinc(II) transmetallation. All techniques agree with a high affinity of the complex for HSA, and competition experiments indicate that this contrast agent competes with ibuprofen for HSA.

Comparative analysis of the 1H NMR relaxation enhancement produced by iron oxide and core-shell iron-iron oxide nanoparticles.

Physicochemical and magnetorelaxometric characterization of the colloidal suspensions consisting of Fe-based nanoparticles coated with dextran have been carried out. Iron oxide and iron core/iron oxide shell nanoparticles were obtained by laser-induced pyrolysis of Fe(CO)5 vapours. Under different magnetic field strengths, the colloidal suspension formed by iron oxide nanoparticles showed longitudinal (R1) and transverse (R2) nuclear magnetic relaxation suspension (NMRD) profiles, similar to those previously reported for other commercial magnetic resonance imaging (MRI) contrast agents. However, colloidal suspension formed by ferromagnetic iron-core nanoparticles showed a strong increase of the R1 values at low applied magnetic fields and a strong increase of the R2 measured at high applied magnetic field. This behaviour was explained considering the larger magnetic aggregate size and saturation magnetization values measured for this sample, 92 nm and 31 emu/g Fe, respectively, with respect to those measured for the colloidal suspensions of iron oxide nanoparticles (61 nm and 23 emu/g Fe). This suspension can be used both as T1 and T2 contrast agent.

How a grafting anchor tailors the cellular uptake and in vivo fate of dendronized iron oxide nanoparticles.

Superparamagnetic spherical iron oxide nanoparticles of 10 nm diameter have been synthesized by thermal decomposition and grafted through a direct ligand exchange protocol with two dendrons bearing respectively a monophosphonic anchor (D2) or a biphosphonic tweezer (D2-2P) at their focal point. Physico-chemical characterization techniques such as dynamic light scattering (DLS), zeta potential, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and superconducting quantum interference device (SQUID) magnetometry were used to assess their composition, colloidal stability and magnetic properties. High-resolution magic angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy studies have been conducted to understand the organic shell composition and to determine both the grafting rate of the dendrons onto the nanoparticle surface and the influence of the remaining oleic acid originating from the synthesis protocol on the cellular uptake. Both dendronized IONPs showed moderate in vitro toxicity (MTT and LDH tests) in human cancer and primary cell lines. Furthermore, in vivo MRI studies showed high contrast enhancement as well as renal and hepatobiliary excretions and highlighted the influence of the grafting anchor (mono- versus bi-phosphonate) on the in vivo fate of dendronized magnetic iron oxides.

Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer.

Myoferlin is a multiple C2-domain-containing protein that regulates membrane repair, tyrosine kinase receptor function and endocytosis in myoblasts and endothelial cells. Recently it has been reported as overexpressed in several cancers and shown to contribute to proliferation, migration and invasion of cancer cells. We have previously demonstrated that myoferlin regulates epidermal growth factor receptor activity in breast cancer. In the current study, we report a consistent overexpression of myoferlin in triple-negative breast cancer cells (TNBC) over cells originating from other breast cancer subtypes. Using a combination of proteomics, metabolomics and electron microscopy, we demonstrate that myoferlin depletion results in marked alteration of endosomal system and metabolism. Mechanistically, myoferlin depletion caused impaired vesicle traffic that led to a misbalance of saturated/unsaturated fatty acids. This provoked mitochondrial dysfunction in TNBC cells. As a consequence of the major metabolic stress, TNBC cells rapidly triggered AMP activated protein kinase-mediated metabolic reprogramming to glycolysis. This reduced their ability to balance between oxidative phosphorylation and glycolysis, rendering TNBC cells metabolically inflexible, and more sensitive to metabolic drug targeting in vitro. In line with this, our in vivo findings demonstrated a significantly reduced capacity of myoferlin-deficient TNBC cells to metastasise to lungs. The significance of this observation was further supported by clinical data, showing that TNBC patients whose tumors overexpress myoferlin have worst distant metastasis-free and overall survivals. This novel insight into myoferlin function establishes an important link between vesicle traffic, cancer metabolism and progression, offering new diagnostic and therapeutic concepts to develop treatments for TNBC patients.

HDAC7 inhibition resets STAT3 tumorigenic activity in human glioblastoma independently of EGFR and PTEN: new opportunities for selected targeted therapies.

To date, the mutational status of EGFR and PTEN has been shown as relevant for favoring pro- or anti-tumor functions of STAT3 in human glioblastoma multiforme (GBM). We have screened genomic data from 154 patients and have identified a strong positive correlation between STAT3 and HDAC7 expression. In the current work we show the existence of a subpopulation of patients overexpressing HDAC7 and STAT3 that has particularly poor clinical outcome. Surprisingly, the somatic mutation rate of both STAT3 and HDAC7 was insignificant in GBM comparing with EGFR, PTEN or TP53. Depletion of HDAC7 in a range of GBM cells induced the expression of tyrosine kinase JAK1 and the tumor suppressor AKAP12. Both proteins synergistically sustained the activity of STAT3 by inducing its phosphorylation (JAK1) and protein expression (AKAP12). In absence of HDAC7, activated STAT3 was responsible for significant imbalance of secreted pro-/anti-angiogenic factors. This inhibited the migration and sprouting of endothelial cells in paracrine fashion in vitro as well as angiogenesis in vivo. In a murine model of GBM, induced HDAC7-silencing decreased the tumor burden by threefold. The current data show for the first time that silencing HDAC7 can reset the tumor suppressor activity of STAT3, independently of the EGFR/PTEN/TP53 background of the GBM. This effect could be exploited to overcome tumor heterogeneity and provide a new rationale behind the development of specific HDAC7 inhibitors for clinical use.

Validation of a dendron concept to tune colloidal stability, MRI relaxivity and bioelimination of functional nanoparticles.

The functionalization of spherical superparamagnetic iron oxide nanoparticles (SPION) of 10 nm with a linear monophosphonate (L1) and also PEGylated mono-phosphonated dendrons of growing generation (D2-G1, -G2 and -G3) yielded dendritic nano-objects of 15 to 30 nm in size, stable in physiological media and showing both renal and hepatobiliary elimination. The grafting of the different molecules has been confirmed by IR spectroscopy and elemental analysis. The colloidal stability of functionalized NS10 has been evaluated in water and in different physiological media. All functionalized NS10 were stable over a long period of time and displayed a mean hydrodynamic diameter smaller than 50 nm whatever the molecule architecture or dendron generation. Only the NS10@L1 showed less stability in biological media at high ionic concentration. NMRD profiles and relaxivity measurements highlighted the influence of the molecule architecture on the water diffusion close to the magnetic core thus influencing the relaxation properties at low magnetic field. Coupling of a fluorescent dye on the functionalized NS10 allowed investigating their biodistribution and highlighting urinary and hepato-biliary eliminations.

Multinuclear magnetic resonance characterization of paramagnetic contrast agents. The manifold effects of concentration and counterions.

RATIONALE AND OBJECTIVES: Proper fitting of the nuclear magnetic resonance dispersion (NMRD) profiles to the numerous factors governing nuclear relaxation in paramagnetic systems requires knowledge of some parameters usually obtained by other techniques. The rotational correlation time (tau R) for example can be measured by carbon-13, hydrogen-2, or oxygen-17 NMR. Discrepancies between values reported in the literature might be attributed to the different concentration ranges used so far in these modalities. In the present work focussing on commercial nonspecific contrast agents, the influence of the solution composition (type and concentration of the complexes and of the counterions) has been examined with regard to the water proton relaxation enhancement and molecular dynamics. METHODS: The proton relaxation rate enhancement of Magnevist, Dotarem, Omniscan, and ProHance was measured in aqueous solution up to a concentration of 0.5 M. In the same concentration window, the rotational correlation times were obtained from the study of deuterium relaxation rates of the diamagnetic deuterated analogs (lanthanum complexes) of the gadolinium chelates. RESULTS: Above 50 mM, the relaxation rate enhancement versus concentrations strongly deviates from linearity. Magnevist, a clinical formulation containing two meglumine counterions per molecule of paramagnetic complex, exhibits the largest concentration effect. A slowing down of the molecular dynamics accounts for this behavior as confirmed by the analysis of the rotational correlation times obtained by deuterium relaxometry. At low concentrations (< or = 50 mM), tau R values obtained by proton NMRD analysis and by deuterium relaxation are in very good agreement. CONCLUSIONS: This study shows that NMR analyses of small molecular weight complexes should be carried out on solutions containing no more than 50 mM to avoid the biaising effects of concentration. On the other hand, the benefitting relaxivity enhancement induced by highly concentrated solutions has to be taken into account in the context of bolus injection or vesicular entrapment.

Mechanical and biochemical cardiac disturbances induced by bolus administration of iodinated contrast media and noniodinated solutions.

RATIONALE AND OBJECTIVES: Bolus injection of iodinated contrast media has been observed to alter myocardial mechanical function, but the consequences on cellular metabolism are poorly documented. Modifications of metabolic parameters (intracellular pH as well as adenosine triphosphate [ATP], phosphocreatine, and inorganic phosphate contents) and of mechanical function (coronary flow, heart rate, and left ventricular developed pressure) were simultaneously recorded on isolated rat hearts perfused over 2 minutes with a high osmolality contrast medium (HOCM) and two low osmolality contrast media (LOCM). In addition, the effects of test solutions mimicking the ionicity and the osmolality of LOCM were evaluated. METHODS: Isovolumic rat hearts were submitted to a 2-minute perfusion with oxygenated Radioselectan, Hexabrix, and Omnipaque (320 mgI/mL) at 37 degrees C. Metabolic parameters were obtained by P-31 nuclear magnetic resonance spectroscopy at 4.7 Tesla. Noniodinated ionic and nonionic solutions also were tested for comparison. RESULTS: HOCM irreversibly impairs the metabolic and mechanical functions, whereas ionic and nonionic LOCM and test solutions induce transient cardiac failure but no permanent alteration of the metabolic or mechanical parameters. CONCLUSION: In this protocol, HOCM causes irreversible degradation of the biochemical status and definitive heart failure, whereas ionic and nonionic LOCM only induce transient changes of myocardial function. Treatments with the LOCM do not induce any modification of the ATP and PCr content, and, at the end of the reperfusion period, the mechanical function is equivalent to that of control hearts. Depending on the ionic content of the solutions (iodinated or not), the evolution of the ventricular developed pressure after injection differs from one group of hearts to another. From these experiments, it is concluded that ionic imbalance and viscosity of the solutions, rather than iodine content or hyperosmolality, should be considered the causes of heart failure.

Spectroscopic and metabolic effects of MnCl2 and MnDPDP on the isolated and perfused rat heart.

RATIONALE AND OBJECTIVES: Several works have shown that the hepatobiliary magnetic resonance imaging contrast agent manganese dipyridoxyl diphosphate (MnDPDP) partly releases its metallic ion and exhibits cardiovascular effects that are supposed to arise from the free manganese ions (Mn++). In the current study, the cellular internalization of Mn by the isolated rat heart is monitored through the mechanical function of the organ and the relative broadening of the P-31 nuclear magnetic resonances. METHODS: Rat hearts were perfused with manganese chloride (MnCl2; 15 and 25 microM) or MnDPDP (25 microM). Variations of the linewidths, heights, and surfaces of phosphocreatine and adenosine triphosphate peaks were monitored. Cardiac function was monitored simultaneously through heart rate, left ventricular pressure, and coronary flow. RESULTS: Influx of Mn++ induces a significant broadening of the P-31 resonances of adenosine triphosphate and phosphocreatine because of a strong scalar paramagnetic interaction between the nuclei and the ion. Compared with MnDPDP administered at the same concentration, MnCl2 induced a more pronounced and dose-dependent line broadening as well as a coronary vasodilation. Calcium channel blockers (nifedipine and verapamil) and EDTA inhibit MnCl2 influx. Similarly, verapamil, EDTA, and DPDP reduce the alterations provoked by MnDPDP. CONCLUSIONS: The effects of MnDPDP are smaller but of the same type than those induced by MnCl2. Their inhibition by calcium channel blockers (verapamil and nifedipine) and by an excess of strong chelators such as DPDP or EDTA confirms that they originate from a partial release of Mn++ by the contrast agent.

Synergistic effects of relaxation and susceptibility in differentiation between compartmentalized and noncompartmentalized tissues.

RATIONALE AND OBJECTIVES: This study illustrates the synergistic effects of relaxation- and susceptibility-based contrast enhancement. Using a combination of gadolinium (Gd) and dysprosium (Dy) complexes and a sequence capable of taking advantage of the particular relaxation behavior of this combination, the difference between compartmentalized and noncompartmentalized regions was significantly enhanced. METHODS: Magnetic resonance imaging of the rat kidney was performed before and immediately after the administration of a combination of Gd and Dy chelates (Gd-DTPA-BMA and Dy-DTPA-BMA). RESULTS: The signal intensity (SI) of the renal parenchyma was reduced by 85%, whereas the collecting tubes had a 100% increase of their SI as demonstrated by a short repetition time (600 msec), long echo time (50 msec), and spin-echo sequence. CONCLUSIONS: The high R2* effect, specific to the compartmentalized tissues, associated with the moderately high R1 and R2 developed in the remaining areas, results in an important improvement in tissue differentiation, which potentially is useful for the evaluation of pathological changes as in tubular necrosis.

Stability of MRI paramagnetic contrast media: a proton relaxometric protocol for transmetallation assessment.

RATIONALE AND OBJECTIVES: The suitability of paramagnetic complexes as magnetic resonance contrast agents depends on various factors such as their relaxivity, stability, selectivity, and the inertness toward transmetallation by endogenous ions. The transmetallation of a series of 18 gadolinium complexes by the Zn2+ ion was studied in vitro by proton relaxometry. METHODS: Transmetallation was analyzed through the evolution of the paramagnetic longitudinal relaxation rate of water protons at 37 degrees C in pH = 7 phosphate buffer solutions containing 2.5 mmol/L of the gadolinium complexes and 2.5 mmol/L zinc chloride. The measurements were performed at 0.47 T over a period of at least 3 days. RESULTS: The results confirm the high stability of macrocyclic systems and a high sensitivity of Gd-diethylenetriamine-pentaacetic acid (DTPA) derivatives to transmetallation by Zn2+ ions. The decreasing order of stability with respect to metal exchange is as follows: Gd-macrocyclics > Gd-C-functionalized DTPA > Gd-DTPA > primary and secondary Gd-DTPA bisamides. The ternary bisamide analyzed in this study [Gd-DTPA-1,11-bisbismethylamino-1,11-dioxo-3,6,9-triaza-3,6,9-tris(carboxymethyl)undecane] is more stable than the parent compound Gd-DTPA. CONCLUSIONS: A simple relaxometric protocol has been successfully developed to study the in vitro transmetallation process of gadolinium complexes. The importance of the functionalization and substitution of the DTPA-like complexes is clearly shown.

Paramagnetic liposomes as magnetic resonance imaging contrast agents. Assessment of contrast efficacy in various liver models.

RATIONALE AND OBJECTIVES: Liposomal gadolinium (Gd)-HP-DO3A has been evaluated as a contrast agent for liver magnetic resonance imaging. The influence of various liposomal physicochemical properties on the liver uptake and contrast efficacy was investigated in various ex vivo and in vivo liver models. METHODS: Liposomes of different size and membrane properties were prepared. The liposome size ranged from 74 to 304 nm. Two types of phospholipid compositions were studied; a mixture of hydrogenated phosphatidylcholine (HPC) and hydrogenated phosphatidylserine (HPS) with a phase transition temperature (Tm) of 51 degrees C and, a blend composed of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) displaying a Tm of 41 degrees C. Ex vivo tissue relaxometry and in vivo liver imaging were used to study the influence of liposome composition on the liver uptake and contrast efficacy of intravenously injected liposomes. The influence of liposome size and composition on the kinetics of liver uptake and imaging effect was assessed ex vivo in the perfused rat liver. RESULTS: The HPC/HPS preparations showed generally a higher and faster liver uptake than the DPPC/DPPG preparations due to a higher stability in blood/perfusate (high Tm) and to the HPS component. The liposome size modulated the extent and kinetics of liver uptake; the larger the size, the faster and more extensive was the liver uptake. Both types of liposome preparations were shown to be efficient liver susceptibility agents both ex vivo and in vivo due to their uptake by the Kupffer cells of liver. The lack of full correlation between the extent of liver uptake and degree of contrast enhancement might be attributed to different regimes of susceptibility-based relaxation. CONCLUSIONS: The present study has demonstrated the influence of key liposomal physicochemical properties on the liver uptake and contrast efficacy of liposome-encapsulated Gd chelates, exemplified by Gd-HP-DO3A.