Development of a Tumor-Targeting MR Contrast Agent Using the High-Affinity Folate Receptor

Konda, Sreenivas; Aref, Michael; Brechbiel, Martin W.; Wiener, Erik C.

doi:10.1097/00004424-200001000-00006

Cited by 115 publications

(88 citation statements)

References 31 publications

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“…98 An alternative to polylysine vectors are nonlinear polycationic cascade polymers. 102 Also known as dendrimers, these polycations are spheroidal, can amplify the amount of therapeutic or diagnostic agent reaching the tumor cells, 103 and mediate higher transfection efficiency of therapeutic agents into cells than their linear counterparts. 102 Immune-mediated targeting of FRa-positive tumors, founded on the historical observation that antibodies are raised against FRa, 104 offer sophisticated strategies to deliver cytotoxic agents via bispecific antibody targeted T cell therapy (characterized by cytotoxic T lymphocyte-mediated tumor cell lysis), adoptive transfer of tumor-specific T lymphocytes (characterized by T cell activation and cytokine release), and immunocytokines (e.g., targeting IL-2/MOv19 fusion protein to FRa-expressing cells to activate migrating T cells).…”

Section: Exploitation Of Fra For Therapeutic and Diagnostic Potentialmentioning

confidence: 99%

“…107 Magnetic resonance (MR) imaging contrast agents based on dendrimers conjugated to folic acid and targeted to FRa-positive tumor cells have also shown improved enhancement of MR images in mice. 103 These newer conjugates are capable of concentrating at pathologic sites as non-invasive probes for diagnostic imaging and do not suffer from problems associated with ligands such as antibodies, which among other factors, can be immunogenic and expensive to produce. 98 Finally, the sensitivity of GPI links to specific phospholipases, such as phospholipase C and D, which are abundant in plasma, may also provide a means to control FRa level at the cell surface 64 or to develop sensitive biomarker assays of the soluble protein for early detection, 66,108 as has recently been described for 2 folate-related disorders.…”

Section: Exploitation Of Fra For Therapeutic and Diagnostic Potentialmentioning

confidence: 99%

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The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

Kelemen

2006

Intl Journal of Cancer

436

340

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Folate receptor a (FRa) is a membrane-bound protein with high affinity for binding and transporting physiologic levels of folate into cells. Folate is a basic component of cell metabolism and DNA synthesis and repair, and rapidly dividing cancer cells have an increased requirement for folate to maintain DNA synthesis, an observation supported by the widespread use of antifolates in cancer chemotherapy. FRa levels are high in specific malignant tumors of epithelial origin compared to normal cells, and are positively associated with tumor stage and grade, raising questions of its role in tumor etiology and progression. It has been suggested that FRa might confer a growth advantage to the tumor by modulating folate uptake from serum or by generating regulatory signals. Indeed, cell culture studies show that expression of the FRa gene, FOLR1, is regulated by extracellular folate depletion, increased homocysteine accumulation, steroid hormone concentrations, interaction with specific transcription factors and cytosolic proteins, and possibly genetic mutations. Whether FRa in tumors decreases in vivo among individuals who are folate sufficient, or whether the tumor's machinery sustains FRa levels to meet the increased folate demands of the tumor, has not been studied. Consequently, the significance of carrying a FRa-positive tumor in the era of folic acid fortification and widespread vitamin supplement use in countries such as Canada and the United States is unknown. Epidemiologic and clinical studies using human tumor specimens are lacking and increasingly needed to understand the role of environmental and genetic influences on FOLR1 expression in tumor etiology and progression. This review summarizes the literature on the complex nature of FOLR1 gene regulation and expression, and suggests future research directions. ' 2006 Wiley-Liss, Inc.

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Section: Exploitation Of Fra For Therapeutic and Diagnostic Potentialmentioning

confidence: 99%

Section: Exploitation Of Fra For Therapeutic and Diagnostic Potentialmentioning

confidence: 99%

The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

Kelemen

2006

Intl Journal of Cancer

436

340

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“…Indeed, Wiener and co-workers used Gd(DTPA) (diethylenetriamine-N,N,N',N'',N''-pentaacetic acid) dendrimers conjugated with folic acid for visualizing the folate receptor, which is overexpressed in many tumors. [9] The complex [Fe{Gd 2 L(H 2 O) 4 } 3 ] 4À contains six Gd III ions, each exhibiting high relaxivity, for a molecular mass of 3744 g mol À1 . Consequently, its efficiency by a unity mass is particularly high.…”

Section: Angewandte Chemiementioning

confidence: 99%

High Relaxivity Confined to a Small Molecular Space: A Metallostar‐Based, Potential MRI Contrast Agent

et al. 2005

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“…There is a great deal of interest in enhancing the utility of these tools in medicine and research through the development of molecularly-targeted MRI contrast agents. One example might be a chimeric molecule comprised of a contrast agent tethered to a molecule capable of binding to a specific protein or other biomolecular target with high affinity and specificity [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. For example, we previously reported that a peptide selected from a phage display library to bind the yeast Gal80 protein can be linked to GdDOTA to create a reagent capable of imaging Gal80 protein in vitro [18,19].…”

Section: Introductionmentioning

confidence: 99%

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

Hanaoka

Lubag

Castillo-Muzquiz³

et al. 2008

Magnetic Resonance Imaging

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Simple low MW chelates of Gd 3+ such as those currently used in clinical MR imaging are considered too insensitive for most molecular imaging applications. Here, we evaluated the detection limit of a molecularly targeted, low MW Gd 3+ -based, T 1 agent in a model where the receptor concentration was precisely known. The data demonstrate that receptors clustered together to form a microdomain of high local concentration can be imaged successfully even when the bulk concentration of the receptor is quite low. A GdDO3A-peptide identified by phage display to target the anti-FLAG antibody was synthesized, purified and characterized. T 1 weighted MR images were compared with the agent bound to antibody in bulk solution and with the agent bound to the antibody localized on agarose beads. Fluorescence competition binding assays show that the agent has a high binding affinity (K D = 150 nM) for the antibody while the fully bound relaxivity of the GdDO3A-peptide:anti-FLAG antibody in solution was a relatively modest 17 mM −1 s −1 . The agent:antibody complex was MR silent at concentrations below ~9 µM but was detectable down to 4 µM bulk concentrations when presented to antibody clustered together on the surface of agarose beads. These results provided an estimate of the detection limits for other T 1 -based agents with higher fully bound relaxivities or multimeric structures bound to clustered receptor molecules. The results demonstrate that the sensitivity of molecularly-targeted contrast agents depends on the local microdomain concentration of the target protein and the molecular relaxivity of the bound complex. A model is presented which predicts that for a molecularly targeted agent consisting of a single Gd 3+ complex with bound relaxivity of 100 mM −1 s −1 or, more reasonably, four tethered Gd 3+ complexes each having a bound relaxivity of 25 mM −1 s −1 , the detection limit of a protein microdomain is ~690 nM at 9.4T. These experimental and extrapolated detection limits are both well below current literature estimates and suggests that detection of low MW molecularly targeted T 1 agents is not an unrealistic goal.

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Development of a Tumor-Targeting MR Contrast Agent Using the High-Affinity Folate Receptor

Abstract: This new agent accumulates in tumors expressing hFR. These results do not differentiate between active and passive targeting mechanisms. Receptor-negative tumors suggest a mechanism other than a nonspecific blood pool effect.

Cited by 115 publications

References 31 publications

The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

High Relaxivity Confined to a Small Molecular Space: A Metallostar‐Based, Potential MRI Contrast Agent

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

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