Paramagnetic Liposomes Research Articles

Synthetic and Nanotechnological Approaches for a Diagnostic Use of Manganese.

The development of multimodal imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) allows the contemporary obtaining of metabolic and morphological information. To fully exploit the complementarity of the two imaging modalities, the design of probes displaying radioactive and magnetic properties at the same time could be very beneficial. In this regard, transition metals offer appealing options, with manganese representing an ideal candidate. As nanosized imaging probes have demonstrated great value for designing advanced diagnostic/theranostic procedures, this work focuses on the potential of liposomal formulations loaded with a new synthesized paramagnetic Mn(II) chelates. Negatively charged liposomes were produced by thin-layer hydration method and extrusion. The obtained formulations were characterized in terms of size, surface charge, efficiency of encapsulation, stability over time, relaxivity, effective magnetic moment, and in vitro antiproliferative effect on human cells by means of the MTT assay. The negatively charged paramagnetic liposomes were monodisperse, with an average hydrodynamic diameter not exceeding 200 nm, and they displayed good stability and no cytotoxicity. As determined by optical emission spectroscopy, manganese complexes are loaded almost completely on liposomes maintaining their paramagnetic properties.

Liposomal Fe(III) Macrocyclic Complexes with Hydroxypropyl Pendants as MRI Probes.

Paramagnetic liposomes containing Fe(III) complexes were prepared by incorporation of mononuclear (Fe(L1) or Fe(L3)) or dinuclear (Fe2(L2)) coordination complexes of 1,4,7-triazacyclononane macrocycles containing 2-hydroxypropyl pendant groups. Two different types of paramagnetic liposomes were prepared. The first type, LipoA, has the mononuclear Fe(L1) complex loaded into the internal aqueous core. The second type, LipoB, has the amphiphilic Fe(L3) complex inserted into the liposomal bilayer and the internal aqueous core loaded with either Fe(L1) (LipoB1) or Fe2(L2) (LipoB2). LipoA enhances both T1 and T2 water proton relaxation rates. Treatment of LipoA with osmotic gradients to produce a nonspherical liposome produces a liposome with a chemical exchange saturation transfer effect as shown by an asymmetry analysis but only at high osmolarity. LipoB1, which contains an amphiphilic complex in the liposomal bilayer, produced a broadened Z-spectrum upon treatment of the liposome with osmotic gradients. The r1 relaxivity of LipoB1 and LipoB2 were higher than the r1 relaxivity of LipoA on a per Fe basis, suggesting an important contribution from the amphiphilic Fe(III) center. The r1 relaxivities of paramagnetic liposomes are relatively constant over a range of magnetic field strengths (1.4-9.4 T), with the ratio of r2/r1 substantially increasing at high field strengths. MRI studies of LipoB1 in mice showed prolonged contrast enhancement in blood compared to the clinically employed Gd(DOTA), which was injected at a 2-fold higher dose per metal than the Fe(III)-loaded liposomes.

The Positive Influence of Therapeutic Agent on Relaxivities of Gadolinium-Loaded Liposomal Theranostics

This study investigates changes in the MRI contrast properties of Gd(III)-containing paramagnetic liposomes following the incorporation of photosensitizing agent (ZnPc—zinc phthalocyanine). It provides identification of mechanisms responsible for enhancement of proton relaxation rate and hence, the increased both r1 and r2 relaxivities. Five liposomal formulations, containing fatty acids derivatives of Gd(III) salt and hydrophobic ZnPc, were synthesized. NMRD profiles of liposomal solutions (magnetic field range from 0.0002 to 9.4 T) were obtained and Modified Florence model was applied. The contrast properties of the model drug itself was separated from the lipid bilayer deformation influence, caused by its incorporation. The latter resulted, among other, in optimization of an apparent water exchange correlation time. As Gd(III) is located in the outer and inner lipid layers, some of the Gd(III) chelates are localized in aqueous interior of the liposomes, thus their contrasting efficiency depends on the water exchange rate through the membrane. The proposed approach raises the possibility of reducing the amount of potentially harmful contrast media based on gadolinium, by taking into account the increase of the relaxation effect caused by other components of the system.

Amphiphilic Ditopic Bis-Aqua Gd-AAZTA-like Complexes Enhance Relaxivity of Lipidic MRI Nanoprobes.

Two amphiphilic mono- and dimeric GdAAZTA-like chelates composed of stable bis-aquo Gd(III) complexes (q=2) linked to one (for the monomer) or two dodecyl aliphatic chains (for the dimer) were synthesized. Both chelates showed high relaxivity when incorporated into the lipid bilayer of liposomes or after interaction with human serum albumin (HSA). The ditopic complex shows a significantly decreased internal motion relative to the monomeric complex, associated with an enhanced relaxivity (r1 ≈60 mm(-1) s(-1) , at 30 MHz and 310 K). The presence of two metal-bound water molecules in fast exchange and the restricted rotational freedom make the relaxivity of this system the highest measured for paramagnetic liposomes.

Innovative Design of Ca-Sensitive Paramagnetic Liposomes Results in an Unprecedented Increase in Longitudinal Relaxivity.

Bioresponsive MRI contrast agents sensitive to Ca(II) fluctuations may play a critical role in the development of functional molecular imaging methods to study brain physiology or abnormalities in muscle contraction. A great challenge in their chemistry is the preparation of probes capable of inducing a strong signal variation that could be detected in a robust way. To this end, the incorporation of small molecular weight bioresponsive agents into nanocarriers can improve the overall properties in a few ways: (i) the agent can be delivered into the tissue of interest, increasing the local concentration; (ii) its biokinetic properties and retention time will improve; (iii) the high molecular weight and size of the nanocarrier may cause additional changes in the MRI signal and raise the chances for their detection in functional experiments. In this work, we report the preparation of the new class of liposome-based, Ca-sensitive MRI agents. We synthesized a novel amphiphilic ligand which was incorporated into the liposome bilayer. A remarkable increase of ∼420% in longitudinal relaxivity r1, from 7.3 mM(-1) s(-1) to 38.1 mM(-1) s(-1) at 25 °C and 21.5 MHz in the absence and presence of Ca(II), respectively, was achieved by the most active liposomal formulation. To the best of our knowledge, this is the highest change in r1 observed for Ca-sensitive agents at physiological pH and can be explained by simultaneous Ca-triggered increase in hydration and reduction of local motion of Gd(III) complex, which can be followed at low magnetic fields.

Gd-DTPA-Dopamine-Bisphytanyl Amphiphile: Synthesis, Characterisation and Relaxation Parameters of the Nanoassemblies and Their Potential as MRI Contrast Agents.

Here, a new amphiphilic magnetic resonance imaging (MRI) contrast agent, a Gd(III)-chelated diethylenetriaminepentaacetic acid conjugated to two branched alkyl chains via a dopamine spacer, Gd-DTPA-dopamine-bisphytanyl (Gd-DTPA-Dop-Phy), which is readily capable of self-assembling into liposomal nanoassemblies upon dispersion in an aqueous solution, is reported. In vitro relaxivities of the dispersions were found to be much higher than Magnevist, a commercially available contrast agent, at 0.47 T but comparable at 9.40 T. Analysis of variable temperature (17)O NMR transverse relaxation measurements revealed the water exchange of the nanoassemblies to be faster than that previously reported for paramagnetic liposomes. Molecular reorientation dynamics were probed by (1)H NMRD profiles using a classical inner and outer sphere relaxation model and a Lipari-Szabo "model-free" approach. High payloads of Gd(III) ions in the liposomal nanoassemblies made solely from the Gd-DTPA-Dop-Phy amphiphiles, in combination with slow molecular reorientation and fast water exchange makes this novel amphiphile a suitable candidate to be investigated as an advanced MRI contrast agent.

P8.06 - Liposomal drug delivery with anti-cancer flutamide-related radical pair system under exposure to pulsating electromagnetic fields

ABSTRACT Background: The process of liposomal drug delivery is generally understood based on the destabilization of liposomal membranes in the target tissue. On the other hand, the membrane structure must be stable enough in the bloodstream for the reduction of side effects. Previously, we demonstrated the design of paramagnetic liposomes modified with 2, 2'-azobis(2, 4-dimethylvaleronitrile) (AMVN) to show the broad potential opportunities in drug delivery systems [ 1 ]. This finding can be expected to reveal new knowledge for resolving important clinical problems. In our present research, we considered examining electromagnetic effects of combined AC/DC fields to measure the physicochemical changes of flutamide-entrapped liposomal membranes modified with reactive oxygen species. Materials & methods: For the preparation of multilamellar vesicles (MLVs), each dry film composed of various molar ratios of phospholipids, photosensitizers and anti-cancer flutamide was hydrated by vortexing them with some appropriate buffer solutions. Each of the MLV dispersions was transferred to a Mini-Extrudor (Avanti Polar Lipids, Inc.) to produce small unilamellar vesicles (SUVs). Under exposure to electromagnetic fields, the photosensitizers and flutamide in the liposomal membrane were excited by a laser emission wavelength of 335 nm. In order to compare the effects of the pulsating electromagnetic fields on the behaviour of the model membranes, we measured the spectral changes as well as the delayed fluorescence with absorbance at 380 and 290 nm after the emission. Results: In the results of our measurements, we found the possibility that a high frequency of up to 2 MHz affects the radical pair mechanisms in the process of membrane modifications induced by excited singlet oxygen. In addition, the electromagnetic effects may make a lot of advantageous pores in the modified membrane to release the flutamide-related cage products. Conclusions: We strongly propose a new drug release technology using these liposomes equipped with electromagnetic controls. acknowledgement: A Grant-in-Aid for Encouragement of Scientists (No.26930033) from the Japan Society for the Promotion of Science (JSPS).

Frequency-encoded MRI-CEST agents based on paramagnetic liposomes/RBC aggregates.

Paramagnetic liposomes containing Dy-HPDO3A in their inner water compartment and carrying a residual positive charge on their outer surface have been electrostatically bound to the membrane of red blood cells (RBCs). These aggregates yield two chemical exchange saturation transfer (CEST) pools represented by liposomal water protons (LipoCEST) and cytoplasmatic water protons (ErythroCEST), respectively. The absorption frequencies of the two pools fall at the negative and positive side of the solvent water resonance as expected from the dipolar (LipoCEST) and BMS (bulk magnetic susceptibility) (ErythroCEST) origin of the paramagnetic induced shift of their water protons resonances, respectively. In vivo magnetic resonance imaging (MRI) shows that the liposomes/RBC aggregates report about the vascular volume whereas the residual LipoCEST effect informs about the presence of released liposomes in the region of interest (ROI). Besides being an innovative blood cell labeling for MRI, the LipoCEST/RBC aggregates provide a route to improve the circulation lifetime of the liposomes and the CEST procedure allows assessing the deassembly of the aggregates and accumulation of the liposomes in the ROI.

Insights on the relaxation of liposomes encapsulating paramagnetic Ln-based complexes.

To describe and quantify the different relaxation mechanisms operating in suspensions of liposomes that encapsulate paramagnetic lanthanide(III) complexes. The transverse relaxation rate of lanthanide-loaded liposomes receives contribution from the exchange between intraliposomal and bulk water protons, and from magnetic susceptibility effects. Phospholipids vesicles encapsulating different Ln(III)-HPDO3A complexes (Ln = Eu, Gd, or Dy) were prepared using the conventional thin film rehydration method. Relaxation times (T1 , T2 , and T2*) were measured at 14 Tesla (T) and 25 °C. The effect of compartmentalization of the paramagnetic agent inside the liposomal cavity was evaluated by means of an IRON-modified MRI sequence. NMR measurements demonstrated that Curie spin relaxation is the dominant contribution (> 90%) to the observed transverse relaxation rate of paramagnetic liposomes. This was further confirmed by MRI that showed the ability of the liposome entrapped lanthanide complexes to generate IRON-MRI positive contrast in a size dependent manner. The Curie spin relaxation mechanism is by far the principal mechanism involved in the T2 shortening of the water protons in suspension of paramagnetic liposomes at 14T. The access to IRON contrast extends the potential of such nanosystems as MRI contrast agents.

Molecular imaging of angiogenesis to delineate the tumor margins in glioma rat model with endoglin‐targeted paramagnetic liposomes using 3T MRI

To evaluate the use of endoglin-targeted paramagnetic liposomes in delineating the glioma margins using magnetic resonance (MR) angiogenesis imaging in a rat model. Four liposome preparations, including nontargeted paramagnetic liposomes (Gd-SLs), isotype control IgG-coupled paramagnetic liposomes (IgG-Gd-SLs), endoglin monoclonal antibody coupled paramagnetic liposomes (MAb-Gd-SLs), and biotinylated antibodies (Bio-MAb)/streptavidin-coupled paramagnetic liposomes (SAv-Gd-SLs) for two-step pretargeting imaging, were formulated. All animal experiments were carried out with the approval of the Shanghai Animal Care. C6 glioma-bearing Sprague-Dawley rats were intravenously injected with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) or the previously mentioned liposomes (n = 5) and imaged with MR. T1 -weighted MRI was performed before and dynamically repeated after different contrast agents were injected. The enhancement features of the tumors were compared. The signal enhancement of the tumor in the two-step pretargeting group increased by 117.9 ± 5.3% at the periphery and 109.2 ± 3.5% in the center (P = 0.032) at the 8-hour timepoint after SAv-Gd-SLs injection. Ring-like enhancement margins were demonstrated at the periphery of the tumor in the two-step targeted group. The specificity of the targeted liposomes was supported by the competitive study. The signal of peak enhancement using MAb-Gd-SLs was 59% less than that of the two-step group and only slightly higher than the non-targeted groups. The two-step endoglin-targeted imaging using biotin-streptavidin interaction was demonstrated to induce intense enhancement of the tumor periphery, which implies that this advanced MR molecular contrast agent may be suitable for accurately delineating glioma tumor margins. J. Magn. Reson. Imaging 2015;41:1056-1064. © 2014 Wiley Periodicals, Inc.

In vivo MRI visualization of release from liposomes triggered by local application of pulsed low-intensity non-focused ultrasound

The work aimed at developing a MRI-guided protocol for the visualization of the release of material entrapped in liposomes stimulated by the local application of pulsed low-intensity non-focused ultrasound (pLINFU). The task was achieved by formulating liposomes filled up with the clinically approved paramagnetic agent gadoteridol, because the release of the agent from the nanovesicles is accompanied by a significant MRI signal enhancement. The protocol was validated in vivo on mice-bearing subcutaneous syngeneic B16 melanoma and i.v. injected with the paramagnetic liposomes. Upon exposing tumor to pLINFU (3MHz, insonation time 2min, duty cycle 50%) few minutes after liposomes injection, a signal enhancement of ca. 35% was detected. The effective release of the agent was confirmed by the strong enhancement measured in kidneys calyx and bladder due to the rapid renal excretion of the agent released in the tumor. From the Clinical EditorIn this paper, a pulsed low-intensity non-focused ultrasound-based technique was used to release a paramagnetic MRI contrast agent from liposomes, demonstrating the feasibility of this triggered release system in a mouse melanoma model for future research applications.

Research Spotlight: Multifunctional Liposomes for MRI and image-guided Drug Delivery

Liposomes are a class of nanovesicles that have been explored extensively in the biomedical arena for early diagnosis and treatment of disease. In recent years, several liposomal drug formulations have been clinically approved in oncology. In a modular approach, the properties of liposomes can be tailored for combined molecular MRI, therapy and image-guided delivery of therapeutic drugs. Over the last year, extensive research has been performed in the authors laboratory on paramagnetic liposomes as innovative imaging probes for the detection of specific molecular or cellular targets and image-guided drug delivery using multifunctional, temperature-sensitive liposomes. A number of key achievements by the authors group will be highlighted in this research spotlight.

Paramagnetic liposomes for molecular MRI and MRI‐guided drug delivery

Paramagnetic liposomes for molecular MRI and MRI‐guided drug delivery

Development of a novel lipidic nanoparticle probe using liposomal encapsulated Gd2O3–DEG for molecular MRI

Recently, it has been showed that gadolinium oxide nanoparticles can provide high-contrast enhancement in magnetic resonance imaging (MRI). Moreover, liposomes due to high biocompatibility have shown unique model systems, with the most successful application being the drug delivery system. As a suitable cell-tracking contrast agent (CA) in molecular MRI (mMRI), the synthesis and optimisation characteristic of a novel paramagnetic liposomes (PMLs) based on gadolinium nanoparticles, essentially composed of a new complex of gadolinium oxide–diethylene glycol (Gd2O3–DEG) loaded in liposomes have been determined in this research. Gd2O3–DEG was prepared by a new supervised polyol method and was encapsulated with liposome by the film hydration method. The paramagnetic liposome nanoparticle (PMLN) sizes ranged from 65 to 170 nm. The r1 of PMLNs and Gd2O3–DEG were much higher than that of Gd-diethylenetriamine penta-acetic acid (Gd-DTPA). In MC/9 cell lines, the experiments showed similar results as in water. PMLNs with lower T1 than Gd-DTPA are sensitive, positive MRI CA that could be attractive candidates for cellular and molecular lipid content targets such as diagnostic applications.

The magnetic susceptibility effect of gadolinium-based contrast agents on PRFS-based MR thermometry during thermal interventions.

BackgroundProton resonance frequency shift (PRFS) magnetic resonance (MR) thermometry exploits the local magnetic field changes induced by the temperature dependence of the electron screening constant of water protons. Any other local magnetic field changes will therefore translate into incorrect temperature readings and need to be considered accordingly. Here, we investigated the susceptibility changes induced by the inflow and presence of a paramagnetic MR contrast agent and their implications on PRFS thermometry.MethodsPhantom measurements were performed to demonstrate the effect of sudden gadopentetate dimeglumine (Gd-DTPA) inflow on the phase shift measured using a PRFS thermometry sequence on a clinical 3 T magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) system. By proton nuclear magnetic resonance spectroscopy, the temperature dependence of the Gd-DTPA susceptibility was measured, as well as the effect of liposomal encapsulation and release on the bulk magnetic susceptibility of Gd-DTPA. In vivo studies were carried out to measure the temperature error induced in a rat hind leg muscle upon intravenous Gd-DTPA injection.ResultsThe phantom study showed a significant phase shift inside the phantom of 0.6 ± 0.2 radians (mean ± standard deviation) upon Gd-DTPA injection (1.0 mM, clinically relevant amount). A Gd-DTPA-induced magnetic susceptibility shift of ΔχGd-DTPA = 0.109 ppm/mM was measured in a cylinder parallel to the main magnetic field at 37°C. The temperature dependence of the susceptibility shift showed dΔχGd-DTPA/dT = -0.00038 ± 0.00008 ppm/mM/°C. No additional susceptibility effect was measured upon Gd release from paramagnetic liposomes. In vivo, intravenous Gd-DTPA injection resulted in a perceived temperature change of 2.0°C ± 0.1°C at the center of the hind leg muscle.ConclusionsThe use of a paramagnetic MR contrast agent prior to MR-HIFU treatment may influence the accuracy of the PRFS MR thermometry. Depending on the treatment workflow, Gd-induced temperature errors ranging between -4°C and +3°C can be expected. Longer waiting time between contrast agent injection and treatment, as well as shortening the ablation duration by increasing the sonication power, will minimize the Gd influence. Compensation for the phase changes induced by the changing Gd presence is difficult as the magnetic field changes are arising nonlocally in the surroundings of the susceptibility change.

In Vivo Magnetic Resonance Imaging Detection of Paramagnetic Liposomes Loaded with Amphiphilic Gadolinium(III) Complexes: Impact of Molecular Structure on Relaxivity and Excretion Efficiency.

The magnetic resonance imaging (MRI) performance of two liposome formulations incorporating amphiphilic 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-like GdIII complexes has been investigated both in vitro and in vivo. The complexes differ in one donor group of the coordination cage (carboxylate versus carboxoamide), and in the length (C12 versus C18 ) and the point of attachment of the aliphatic chains to the chelators. The in vitro 1 H relaxometric characterisation of the systems, performed with a newly developed relaxation model that takes into account the contributions of the GdIII chelates pointing in- and outwards of the liposome, indicates that their efficacy is optimal in the range 0.5-1.5 T. The tetracarboxylic C12 -containing liposomes (LIPO-GdDOTA(GAC12 )2 ; GA=glutaric acid) are four-fold more efficient than the monoamide C18 -based analogue (LIPO-GdDOTAMA(C18 )2 ). Such a difference is also found in vivo at 1 T in a melanoma tumour model on mice. A few hours after intravenous injection, the T1 contrast enhancement in the organs where the nanovesicles typically distribute (liver, spleen, kidneys and tumour) is much higher for LIPO-GdDOTA(GAC12 )2 . Interestingly, after about 7 h post-injection the contrast enhancement observed for the more efficient liposomes decreases rapidly and becomes lower than for LIPO-GdDOTAMA(C18 )2 . The relaxometric data and the quantification of the GdIII complexes in the organs, determined ex vivo by inductively coupled plasma mass spectrometry, indicate that: 1) the differences in the contrast enhancement can be attributed to the different rate of water exchange and rotational dynamics of the Gd complexes, and 2) the rapid contrast decrease is caused by a faster clearance of GdDOTA(GAC12 )2 from the organs. This is also confirmed by using a newly synthesised amphiphilic cyanine-based fluorescent probe (Cy5-(C16 )2 ). As one of the main limitations for the clinical translation of liposomes incorporating amphiphilic imaging agents is related to their very long persistence in the body, the results reported herein suggest that the clearance of the probes can be accelerated, without compromising their role, by a proper selection of the lipophilic portion of the incorporated compound as well as of the ligand site at which the aliphatic tails are linked. Then, GdDOTA(GAC12 )2 complex may represent a good candidate for the development of improved MRI protocols based on paramagnetically labelled lipidic nanoparticles.

Paramagnetic liposomes for molecular MRI and MRI‐guided drug delivery

Liposomes are a versatile class of nanoparticles with tunable properties, and multiple liposomal drug formulations have been clinically approved for cancer treatment. In recent years, an extensive library of gadolinium (Gd)-containing liposomal MRI contrast agents has been developed for molecular and cellular imaging of disease-specific markers and for image-guided drug delivery. This review discusses the advances in the development and novel applications of paramagnetic liposomes in molecular and cellular imaging, and in image-guided drug delivery. A high targeting specificity has been achieved in vitro using ligand-conjugated paramagnetic liposomes. On targeting of internalizing cell receptors, the effective longitudinal relaxivity r1 of paramagnetic liposomes is modulated by compartmentalization effects. This provides unique opportunities to monitor the biological fate of liposomes. In vivo contrast-enhanced MRI studies with nontargeted liposomes have shown the extravasation of liposomes in diseases associated with endothelial dysfunction, such as tumors and myocardial infarction. The in vivo use of targeted paramagnetic liposomes has facilitated the specific imaging of pathophysiological processes, such as angiogenesis and inflammation. Paramagnetic liposomes loaded with drugs have been utilized for therapeutic interventions. MR image-guided drug delivery using such liposomes allows the visualization and quantification of local drug delivery.

Dual Functional Gd(III)-DOTA Liposomes for Cancer Therapy and Diagnosis as a Theragnostic Carrier

Development of dual functional liposome has been studied for cancer theragnostics. Therefore, we focused on ultrasound-sensitive liposomes with doxorubicin (DOX) and gadolinium (Gd) as a theragnostic carrier having a potential for cancer therapy and diagnosis. In this study, Gd(III)-DOTA-modified sonosensitive liposomes (GL) was developed using chemically synthesized Gd(III)-DOTA-DPPE lipid. Sonosensitivity of GL to 1 MHz ultrasound induced 25% of DOX release. The relaxivities () of GL were , which was higher than that of MR-bester. Intracellular delivery of DOX from GL by ultrasound irradiation was evaluated according to ultrasound intensity, resulting in increase of uptake of DOX released from ultrasound-triggered GLs compared to GL3 or Doxil without ultrasound. Taken together, this study shows that the paramagnetic and sonosensitive liposomes, GL, is a novel and highly effective delivery system for drug with the potential for broad applications in human disease.

A concise review of magnetic resonance molecular imaging of tumor angiogenesis by targeting integrin αvβ3 with magnetic probes

Angiogenesis is an essential step for the growth and spread of malignant tumors. Accurate detection and quantification of tumor angiogenesis is important for early diagnosis of cancers as well as post therapy assessment of antiangiogenic drugs. The cell adhesion molecule integrin αvβ3 is a specific marker of angiogenesis, which is highly expressed on activated and proliferating endothelial cells, but generally not on quiescent endothelial cells. Therefore, in recent years, many different approaches have been developed for imaging αvβ3 expression, for the detection and characterization of tumor angiogenesis. The present review provides an overview of the current status of magnetic resonance molecular imaging of integrin αvβ3, including the new development of high sensitive contrast agents and strategies for improving the specificity of targeting probes and the biological effects of imaging probes on αvβ3 positive cells.

CEST: From basic principles to applications, challenges and opportunities

Chemical Exchange Saturation Transfer (CEST) offers a new type of contrast for MRI that is molecule specific. In this approach, a slowly exchanging NMR active nucleus, typically a proton, possessing a chemical shift distinct from water is selectively saturated and the saturated spin is transferred to the bulk water via chemical exchange. Many molecules can act as CEST agents, both naturally occurring endogenous molecules and new types of exogenous agents. A large variety of molecules have been demonstrated as potential agents, including small diamagnetic molecules, complexes of paramagnetic ions, endogenous macromolecules, dendrimers and liposomes. In this review we described the basic principles of the CEST experiment, with emphasis on the similarity to earlier saturation transfer experiments described in the literature. Interest in quantitative CEST has also resulted in the development of new exchange-sensitive detection schemes. Some emerging clinical applications of CEST are described and the challenges and opportunities associated with translation of these methods to the clinical environment are discussed.