ABSTRACTGadolinium-based contrast agents have been used in hundreds of millions of patients in the past 30 years, with an exemplary safety record. However, assumptions made at their inception have ...been recently challenged, rekindling innovation efforts. This critical review outlines the motivations, technical obstacles, problems, and the most recent published progress toward the creation of alternatives to the existing gadolinium-based contrast agent.
Abstract The methodology and published work aimed at speciation of gadolinium based contrast agents in tissues is reviewed. The discussion focusses on the context of Gd deposited long term in tissue ...following administration of the contrast agents. Detection of Gd without identification of the chemical form detected is simple and straight forward using a variety of methods. Determination of the chemical form of Gd detected is far more complex and most method require inherently imperfect extraction steps that can alter the Gd chemical species detected. Control studies wherein Gd is not deposited biologically or is deposited in animal tissues are also inherently imperfect. Strengths and weaknesses of the various methods used and examples are demonstrated. It is concluded that a combination of spatially resolved mass spectral based methods, combined with extraction / HPLC analysis methods can provide sufficient sensitivity, spatial resolution and chemical species specificity to address the title question on ex vivo tissue samples.
Radiotherapeutic drugs and medical imaging agents, although used for different purposes, both benefit from precise targeting. When systemically administered, either would be most useful if designed ...to find and bind only a tumor, single type of cell, or unique molecular assembly thereon. In this Account, we examine the use of small peptides, natural and synthetic, to create biochemically specific molecular imaging agents and radiotherapeutic pharmaceuticals, discussing three distinct examples. In one project, a small natural peptide known to target members of the bombesin family of receptors was chemically attached to a strong, versatile metal chelator, DO3A, through a series of small-molecule linkers. The linkers powerfully affected not only binding strength for the bombesin receptors, tissue distribution, and tumor uptake in vivo but also receptor subtype specificity. When the assembly is combined with an active metal ion for human trials, the versatility of the DO3A (dodecanetriacetate) chelate affords choices in selecting the metal ion for different purposes: lutetium for a combination radiotherapeutic and diagnostic agent, 177Lu-AMBA, and gallium for a positron emission tomography (PET) imaging agent, 68Ga-AMBA. We also created small (∼5-kDa) bivalent peptides, each composed of different chemically linked peptides derived from phage display. The monomer peptides bound to the same target protein, VEGF-R2, a primary target of vascular endothelial growth factor (VEGF), the angiogenesis-stimulating protein. Several families of the monomer peptides did not compete with one another for the binding site on VEGF-R2. Their combination into fully synthetic hetero-bivalent molecules yielded subnanomolar K d values and greater than 100-fold improvements over homo-bivalent molecules. Biological activity was evident in the hetero-bivalents, whereas none or very little existed in homo-bivalents, monomers, and monomer mixtures. In ultrasound imaging, tiny bubbles (2 μm in diameter) filled with inert gas can be used as effective contrast agents. By coating the shell of such bubbles with the peptide TKPPR (a tuftsin antagonist), we created contrast agents that bound unexpectedly to cultured endothelial cells expressing angiogenesis targets; the binding was attributable to a previously unnoticed and powerful multivalency effect. TKPPR binds specifically to neuropilin-1 (NP-1), a VEGF co-receptor, but only when multimerized is it avid. Tuftsin, a small peptide derived from immunoglobulin G (IgG) that binds to macrophages during inflammation, has been studied for over 30 years; the receptor has never been cloned. Our results led to new conclusions about tuftsin, NP-1, and the purpose, heretofore unknown, of exon 8 in VEGF, which appears to be involved in NP-1 binding. Our disparate projects demonstrate that small-peptide targeted molecules can be very versatile in drug discovery in combination with classical medicinal chemistry. In particular, multivalent interactions can lead to unpredictable and useful biochemical information, as well as new drug candidates.
Fine-Tuning the pH Trigger of Self-Assembly Ghosh, Arijit; Haverick, Mark; Stump, Keith ...
Journal of the American Chemical Society,
02/2012, Letnik:
134, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The creation of smart, self-assembling materials that undergo morphological transitions in response to specific physiological environments can allow for the enhanced accumulation of imaging or drug ...delivery agents based on differences in diffusion kinetics. Here, we have developed a series of self-assembling peptide amphiphile molecules that transform either isolated from molecules or spherical micelles into nanofibers when the pH is slightly reduced from 7.4 to 6.6, in isotonic salt solutions that simulate the acidic extracellular microenvironment of malignant tumor tissue. This transition is rapid and reversible, indicating the system is in thermodynamic equilibrium. The self-assembly phase diagrams show a single-molecule-to-nanofiber transition with a highly concentration-dependent transition pH. However, addition of a sterically bulky Gd(DO3A) imaging tag on the exterior periphery shifts this self-assembly to more acidic pH values and also induces a spherical micellar morphology at high pH and concentration ranges. By balancing the attractive hydrophobic and hydrogen-bonding forces, and the repulsive electrostatic and steric forces, the self-assembly morphology and the pH of transition can be systematically shifted by tenths a pH unit.
Boehm-Sturm et al ( 1 ) pose a possible paradigm shift in magnetic resonance (MR) imaging: the substitution of iron chelates for gadolinium chelates as paramagnetic contrast agents. The advent of ...nephrogenic systemic fibrosis challenges the wide-spread perception that gadolinium is benign, and that all gadolinium-based contrast agents (GBCAs) are identical. Long-term gadolinium retention in patients with normal renal function is now a disturbing fact. Unlike gadolinium, iron is an endogenous metal with a tightly regulated transport and storage mechanism. The question the article raises is therefore a compelling one.
The aim of this study was to evaluate the pharmacokinetics and safety profile of MT218, a peptide-targeted gadolinium-based contrast agent, in healthy males.
This was a double-blind, randomized, ...placebo-controlled, single-ascending-dose study including 30 healthy male subjects. In each dose group (0.01, 0.02, 0.04, and 0.08 mmol/kg), 4 subjects received MT218 and 2 subjects received placebo (saline) in bolus injections. The highest dose group (0.08 mmol/kg) was assessed in 2 cohorts, 1 fasted and 1 nonfasted. Clinical laboratory tests, vital signs, and electrocardiograms were investigated. Gadolinium concentrations were measured in plasma samples collected before administration and over a 24-hour period postinjection, and in urine specimens collected until 22 days. A noncompartmental model was used for pharmacokinetic analysis. A clinical and biological safety follow-up was carried out for up to 6 months.
No clinically significant modifications in biochemistry, hematology, urinalysis, electrocardiogram parameters, or vital signs were reported at any time point for any treatment group. No serious adverse events were observed in any dose group. Transient dizziness, hyperhidrosis, and injection site coldness were the main adverse events reported in both the MT218 and placebo groups. The mean total apparent clearance decreased slightly with increasing dose, and the median plasma t 1/2 ranged from 1.7 hours in the 0.01 mmol/kg group to 2.7 hours in the 0.08 mmol/kg nonfasted group. MT218 was rapidly excreted via renal filtration with 42.9% to 52.8% of the injected dose measured in urine within the first hour after administration, and 92.5% to 117.3% in urine within 24 hours. No Gd was detected by inductively coupled plasma mass spectrometry in urine after 21 days.
Single intravenous administration of MT218 was safely tolerated in the healthy males. Its pharmacokinetic parameters and safety profile are well aligned with those of other gadolinium-based contrast agents.
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