Targeting Dendrimer-Chelates to Tumors and Tumor Cells Expressing the High-Affinity Folate Receptor

Wiener, Erik C.; Konda, Sreenivas; Shadron, Amber; Brechbiel, Martin W.; Gansow, Otto A.

doi:10.1097/00004424-199712000-00005

Cited by 204 publications

(138 citation statements)

References 9 publications

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“…The first example dealt with the targeting of tumor cells overexpressing high affinity folate receptor (hRF). Wiener et al (24) showed that the uptake of a folate-conjugated dendrimer into cells occurs with a sigmoidal dose-responsive curve, as expected for a specific uptake. The folate receptor positive cell line (8.2 ϫ 10 8 cells) was treated with 28 nM folate-conjugated PAMAM-TU-DTPAGd(III) and incubated at 37°C for 40 minutes.…”

Section: Routes For Efficient Cellular Uptake Of Gd(iii) Complexesmentioning

confidence: 78%

Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations

Aime

Cabella

Colombatto³

et al. 2002

Magnetic Resonance Imaging

328

275

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Can gadolinium III [Gd(III)] complexes be considered good candidates for magnetic resonance (MR)-molecular imaging studies? In this review article, we examine the principal issues that are the basis of successful use of Gd-based protocols in molecular imaging applications. High relaxivity is the primary requisite. Therefore, the design of such paramagnetic probes has to be pursued keeping in mind the relationships between structure, dynamics, and the relevant parameters involved in paramagnetic relaxation processes. Moreover, the limited number of target molecules on cellular membranes makes it necessary to define strategies aimed at delivering many Gd-containing moieties to the sites of interest. Examples are reported for the attainment of very high relaxivities for the design of new routes for pursuing the accumulation of small sized Gd(III) complexes at the targeting sites. An efficient cellular uptake of Gd-containing probes is the key step for attaining the visualization of targeted cells by MR imaging, and selected examples are reported. In this context, the problem of the assessment of the minimum amount of Gd(III) complexes necessary for the MR imaging-visualization of cells has been addressed by reporting the authors' observations on the cell-internalization of Gd(III) complexes. A particularly efficient delivery system is represented by Gd-loaded apoferritin, which allows the MR visualization of hepatocytes when the number of Gd-complexes per cell is 4 Ϯ 1 ϫ 10 7 . Finally, the potential of responsive systems is considered by outlining the exploitation of the amplification effect brought about by the action of a specific enzymatic activity on the relaxivity of a suitably functionalized Gd(III) complex. IT IS NOW WELL ESTABLISHED that magnetic resonance imaging (MRI) is the pre-eminent methodology among the various diagnostic modalities currently available, as it offers a powerful way to map structure and function in soft tissues by sampling the amount, flow, and environment of water protons in vivo. The intrinsic contrast can be augmented by the use of contrast agents (CA) in both clinical and experimental settings. Thus, the use of CA adds highly relevant physiological information to the superb anatomical resolution obtained in MR images. Most of the work with CAs has dealt with the use of gadolinium (III) [Gd(III)] complexes, because this metal ion couples a large magnetic moment with a long electron spin relaxation time.The new scenery of molecular imaging applications requires the development of a novel class of CAs characterized by a higher contrasting ability and improved targeting capabilities (1). In this survey, we intend to tackle some basic issues that are of fundamental importance for the use of Gd(III)-based systems in molecular imaging applications, namely: 1) actual understanding of the determinants of T 1 -relaxivity of Gd(III) complexes, and how to proceed to attain very high relaxivities; 2) how one may envisage efficient routes for the delivery of a high number of Gd(III) complexes a...

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Section: Routes For Efficient Cellular Uptake Of Gd(iii) Complexesmentioning

confidence: 78%

Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations

Aime

Cabella

Colombatto³

et al. 2002

Magnetic Resonance Imaging

328

275

View full text Add to dashboard Cite

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“…(52)(53)(54)(55)(56) There are number of examples in the literature of efficient cellular uptake of Gd(III) complexes using Gd-DOTA derived molecules (57)(58)(59)(60). More recent efforts have sought to maximize the load of Gd delivered per receptor by tethering carrier molecules to dendridic polymers containing high numbers of Gd(III)(61), uptake through the folate receptor has been demonstrated by this means as has avidin-biotin antibody-based targeting (59,62,63). Again, definitive measurement of the amount of Gd required to produce contrast depends upon the imaging parameters employed and these must also be evaluated when testing the new contrast agents.…”

Section: Resultsmentioning

confidence: 99%

Development of Contrast Agents Targeted to Macrophage Scavenger Receptors for MRI of Vascular Inflammation

2006

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Atherosclerosis is a leading cause of death in the U.S. Because there is a potential to prevent coronary and arterial diseases through early diagnosis, there is a need for methods to image arteries in the subclinical stage as well as clinical stage using various non-invasive techniques, including Magnetic Resonance Imaging (MRI). We describe a development of a novel MRI contrast agent targeted to plaques that will allow imaging of lesion formation. The contrast agent is directed to macrophages, one of the earliest components of developing plaques. Macrophages are labeled through the macrophage scavenger receptor A, a macrophage specific cell surface protein, using an MRI contrast agent derived from scavenger receptor ligands. We have synthesized and characterized these contrast agents with a range of relaxivities. In vitro studies show that the targeted contrast agent accumulates in macrophages and solution studies indicate that micromolar concentrations are sufficient to produce contrast in an MR image. Cell toxicity and initial biodistribution studies indicate low toxicity, no detectable retention in normal blood vessels, and rapid clearance from blood. The promising performance of this contrast agent targeted towards vascular inflammation opens doors to tracking of other inflammatory diseases such as tumor immunotherapy and transplant acceptance using MRI.

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“…The interstitial residence time of the targeted agent may increase with its specific binding to the soluble form of the receptor. Ideally, the results may also be the result of specific binding of the agent to the cell surface receptor, coupled with intracellular accumulation caused by receptor recycling (28) without soluble receptor binding. Finally, a combination of binding to the cell surface receptor and the soluble receptor may also occur.…”

Section: Discussionmentioning

confidence: 99%

Folate receptor-mediated targeted polymeric gadolinium complexes for magnetic resonance imaging in pulmonary tumor xenografts

Zheng

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. Targeted delivery is a highly desirable strategy for diagnostic imaging due to enhanced efficacy and reduced dosage/toxicity. The need to develop target-specific magnetic resonance imaging (MRI) contrast agents to aid in disease characterization is highly essential. In this study, a specific contrast agent, Gd-DTPA-poly-L-lysine (PL-Gd-DTPA)-folate, was synthesized and evaluated for its efficacy as a targeted agent for the imaging of tumors that overexpress the folate receptor. Folic acid was conjugated to PL-Gd-DTPA via the ε-amino groups. The receptor binding properties of folate-PL-Gd-DTPA were studied in cultured tumor cells that overexpressed the folate receptor. The tumor-selecting properties of folate-PL-Gd-DTPA were then evaluated in BALB/c mice bearing subcutaneously implanted folate receptor-positive tumors. Tissue MR signal intensities were measured at six different time-points. In the in vitro study, the folate-PL-Gd-DTPA was able to bind to these cells, which overexpressed the folate receptor, as with free folic acid. Excellent tumor selectivity was also shown in the animal model; after the success of injection of folate-PL-Gd-DTPA, a maximum intensity increase of 125.4% was observed from pre-injection compared to post-injection images of the tumor at the 48 h time-point. The liver enhancement was non-specific and the muscle signal intensity at any time-point after injection showed no statistical difference with that observed before injection. Folate-PL-Gd-DTPA is a promising, novel receptorspecific MRI contrast agent with potential applications in the imaging of human folate receptor-positive tumors.

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Targeting Dendrimer-Chelates to Tumors and Tumor Cells Expressing the High-Affinity Folate Receptor

Abstract: These data demonstrate that folate-conjugated magnetic resonance imaging contrast agents represent a promising new approach to tumor targeting.

Cited by 204 publications

References 9 publications

Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations

Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations

Development of Contrast Agents Targeted to Macrophage Scavenger Receptors for MRI of Vascular Inflammation

Folate receptor-mediated targeted polymeric gadolinium complexes for magnetic resonance imaging in pulmonary tumor xenografts

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