37 research outputs found
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Conjugation to Biocompatible Dendrimers Increases Lanthanide T2 Relaxivity of Hydroxypyridinone (HOPO) Complexes for Magnetic Resonance Imaging (MRI)
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Next Generation Magnetic Resonance Imaging Contrast Agents
Magnetic resonance imaging (MRI) is one of the most powerful diagnostic techniques at the disposal of the medical community. Its success in the clinic, with 75 to 90 million scans performed worldwide annually, can be attributed in part to the use of injectable contrast agents to improve signal differentiation between healthy and pathological tissue. These contrast agents primarily use Gd(III) as the paramagnetic metal ion to induce contrast. With seven unpaired electrons, Gd(III) has the most paramagnetic character of any nonradioactive element. Aqueous Gd(III), however, is highly toxic; hence contrast agents use chelators to encapsulate the Gd(III) ion, which protects the patient from from the Gd(III) ion. While these chelators are necessary, they greatly decrease the relaxivity of the current commercial contrast agents. Commercial contrast agents are similar in that they are heteroatom chelators (N, O) and octadentate coordination, leaving only one open site for water coordination. Additionally, given their steric bulk, the water exchange mechanism with bulk solvent is a laboriously hindered dissociative mechanism. These factors contribute to the low efficiency of these Gd(III) complexes, as measured in relaxivity. Diagnostic scans typically inject 8-10 g of these complexes to achieve sufficient signal. Hydroxypyridinone (HOPO) chelators have emerged as a superior alternative to current commercial compounds. Using a tris(2-aminoethyl)amine (TREN) capping moiety, three bidentate HOPO chelators form a hexadentate ligand. These TREN-tris-HOPO ligands leave multiple open sites for water coordination and exhibit rapid water exchange with bulk solvent, due to their reduced steric bulk and associative exchange mechanism. These ligands use all-oxygen-donor chelators, capitalizing on the oxophilicity of Gd(III) to form highly stable complexes. From this superior family of chelators, a variety of approaches can be used to develop the next generation of MRI contrast agents. Increasing molecular weight and tumbling time has been a strategy for increasing relaxivity and efficiency of MRI contrast agents. Through macromolecular conjugation, relaxivity is readily increased; simultaneously, these macromolecules provide the potential for building multimodal and multifunctional diagnostic and therapeutic agents. The potential applications for this class of materials are further increased with the addition of targeting functionality. These agents must have the ability to be fully and rapidly excreted and have facile and uniform large-scale syntheses to be candidates for the clinic. The esteramide (EA) dendrimer is one such macromolecular platform. With eight sites for contrast agent conjugation, the esteramide dendrimer readily loads many distinct HOPO ligands with multiple lanthanides for multimodal imaging. With close to 40 kDa of polyethylene glycol units, the Gd-HOPO-EA macromolecular architecture is highly soluble and biocompatible. Furthermore, the ester core of the dendrimer is degradable under in vivo conditions, easing renal clearance with four smaller moieties. The superior properties of this system inspired investigation into a variety of other macromolecular systems. Porous silica mesoparticles provide a rigid architecture that is much larger than other macromolecules evaluated and can hold greater than 108 small molecule MRI contrast complexes. The surfaces of these particles are readily functionalized and suitable for conjugation with most small molecule MRI contrast agents. These structures use a nontoxic silica infrastructure and are excreted renally despite their large size, making them viable candidates for further in vitro and in vivo study. Gold nanoparticles (AuNP) as a solid-support system have the most potential for use as multifunctional diagnostic and therapeutic compounds. AuNP have been long used for enhancing computed tomography (CT) imaging and have recently emerged as a cancer therapeutic when their structure is irradiated. These compounds are readily synthesized in large scales and have loading sites that are close together to hold multi-tethered Gadolinium-HOPO systems for multifunctional imaging. Using a variety of macromolecules to capitalize on the structural relationship between relaxivity and size, per-Gd and per-macromolecule-Gd relaxivity have been increased dramatically at clinically and physiologically relevant conditions. These improvements show that the combination of carefully designed macromolecules with excellent HOPO chelators produces an ideal MRI contrast agent for the clinic of the future
Silica Microparticles as a Solid Support for Gadolinium Phosphonate Magnetic Resonance Imaging Contrast Agents
Particle-based magnetic resonance imaging (MRI) contrast
agents
have been the focus of recent studies, primarily due to the possibility
of preparing multimodal particles capable of simultaneously targeting,
imaging, and treating specific biological tissues <i>in vivo</i>. In addition, particle-based
MRI contrast agents often have greater sensitivity than commercially
available, soluble agents due to decreased molecular tumbling rates
following surface immobilization, leading to increased relaxivities.
Mesoporous silica particles are particularly attractive substrates
due to their large internal surface areas. In this study, we immobilized
a unique phosphonate-containing ligand onto mesoporous silica particles
with a range of pore diameters, pore volumes, and surface areas, and
GdĀ(III) ions were then chelated to the particles. Per-GdĀ(III) ionic
relaxivities ranged from ā¼2 to 10 mM<sup>ā1</sup> s<sup>ā1</sup> (37 Ā°C, 60 MHz), compared to 3.0ā3.5
mM<sup>ā1</sup> s<sup>ā1</sup> for commercial agents.
The large surface areas allowed many GdĀ(III) ions to be chelated,
leading to per-particle relaxivities of 3.3 Ć 10<sup>7</sup> mM<sup>ā1</sup> s<sup>ā1</sup>, which is the largest value
measured for a biologically suitable particle
Analysis of Lanthanide Complex Dendrimer Conjugates for Bimodal NIR and MRI Imaging
Advances in clinical diagnostic instrumentation have
enabled some
imaging modalities to be run concurrently. For diagnostic purposes,
multimodal imaging can allow for rapid location and accurate identification
of a patientās illness. The paramagnetic and near-infrared
(NIR) properties of DyĀ(III) and YbĀ(III) are interesting candidates
for the development of bimodal NIR and magnetic resonance imaging
(MRI) contrast agents. To enhance their intrinsic bimodal properties,
these lanthanides were chelated using the hexadentate-all-oxygen-donor-ligand
TREN-bisĀ(1-Me)-3,2-HOPO-TAM-NX (NX, where X = 1, 2, or 3) and subsequently
conjugated to the esteramide dendrimer (EA) to improve bioavailability,
solubility, and relaxivity. Of these new complexes synthesized and
evaluated, DyN1-EA had the largest ionic <i>T</i><sub>1</sub> relaxivity, 7.60 mM<sup>ā1</sup> s<sup>ā1</sup>, while
YbN3-EA had the largest ionic <i>T</i><sub>2</sub> relaxivity
with a NIR quantum yield of 0.17% when evaluated in mouse serum. This
is the first YbĀ(III) bimodal NIR/<i>T</i><sub>2</sub> MRI
contrast agent of its kind evaluated
Porphyrin-Substituted HāNOX Proteins as High-Relaxivity MRI Contrast Agents
Heme proteins are exquisitely tuned to carry out diverse
biological functions while employing identical heme cofactors. Although
heme protein properties are often altered through modification of
the protein scaffold, protein function can be greatly expanded and
diversified through replacement of the native heme with an unnatural
porphyrin of interest. Thus, porphyrin substitution in proteins affords
new opportunities to rationally tailor heme protein chemical properties
for new biological applications. Here, a highly thermally stable Heme
Nitric oxide/OXygen binding (H-NOX) protein is evaluated as a magnetic
resonance imaging (MRI) contrast agent. <i>T</i><sub>1</sub> and <i>T</i><sub>2</sub> relaxivities measured for the
H-NOX protein containing its native heme are compared to the protein
substituted with unnatural manganeseĀ(II/III) and gadoliniumĀ(III) porphyrins.
H-NOX proteins are found to provide unique porphyrin coordination
environments and have enhanced relaxivities compared to commercial
small-molecule agents. Porphyrin substitution is a promising strategy
to encapsulate MRI-active metals in heme protein scaffolds for future
imaging applications
Armādomain interactions can provide high binding cooperativity
Peptidyl arms extending from one protein domain to another protein domain mediate many important interactions in biology. A well-studied example of this type of proteināprotein interaction occurs between the yeast homeodomain proteins, MAT Ī±2 and MAT a1, which form a high-affinity heterodimer on DNA. The carboxyl-terminal arm extending from MAT Ī±2 to MAT a1 has been proposed to produce an allosteric conformational change in the a1 protein that generates a very large increase in the DNA binding affinity of a1. Although early studies lent some support to this model, a more recent crystal structure determination of the free a1 protein argues against any allosteric change. This note presents a thermodynamic argument that accounts for the proteinsā binding behavior, so that allosteric conformational changes are not required to explain the large affinity increase. The analysis presented here should be useful in analyzing binding behavior in other systems involving arm interactions