Folate-receptor-targeted radionuclide imaging agents

Ke, Chun Yen; Mathias, Carla J.; Green, Mark

doi:10.1016/j.addr.2004.01.004

Cited by 115 publications

(130 citation statements)

References 47 publications

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“…Because of elevated expression of FR on various types of tumor cells and activated macrophages, folic acid has been exploited extensively as a drug delivery vehicle for cancer and inflammatory diseases (25)(26)(27)(28)(29). Because higher potencies are achieved generally when the drug is released from its attached targeting ligand (i.e., folic acid) in an unaltered form (30)(31)(32)(33), the data presented here suggest that disulfide bridges between folate and its therapeutic payload might constitute suitable linkers for site-specific drug release.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging

Yang¹,

Chen

Vlahov

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

290

244

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Despite functional evidence for disulfide bond-reducing activity in endosomal compartments, the mechanistic details pertaining to such process (e.g., kinetics and sites of disulfide reduction) remain largely controversial. To address these questions directly, we have synthesized a previously uncharacterized fluorescent folate conjugate, folate-(BODIPY FL)-SS-rhodamine (folate-FRET), that changes fluorescence from red to green upon disulfide bond reduction. Using this construct, we have observed that disulfide reduction: (i) occurs with a half-time of 6 h after folate-FRET endocytosis, (ii) begins in endosomes and does not depend significantly on redox machinery located on the cell surface or within the lysosome or the Golgi apparatus, (iii) occurs independently of endocytic vesicle trafficking along microtubules, and (iv) yields products that are subsequently sorted into distinct endosomes and trafficked in different directions. Finally, colocalization of folate and transferrin receptors suggest that conclusions derived from this study may apply to other endocytic pathways.disulfide bond reduction ͉ endosome ͉ folate receptor ͉ drug targeting

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Section: Discussionmentioning

confidence: 99%

Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging

Yang¹,

Chen

Vlahov

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

290

244

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“…105 The exploitation of FRa-mediated binding of folic acid-conjugated imaging agents to tumor cells is also a rapidly advancing area of cancer diagnostics. 106 For example, folic acid conjugated to various radiopharmaceutical agents such as 99m Technetium ( 99m Tc) showed promising in vivo tumor uptake qualities. 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.…”

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

439

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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“…Over the past 2 decades, the utility of folic acid for targeting the a-folate receptor on epithelial cancer cells has been demonstrated using folate-conjugated chemotherapeutics and imaging agents (7)(8)(9). Several folate-conjugated radiopharmaceuticals have been synthesized and evaluated successfully using imaging modalities such as SPECT and PET (9).…”

mentioning

confidence: 99%

A New ¹⁸F-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor–Positive Tumors

Roß¹,

Honer²,

Müller³

et al. 2010

J Nucl Med

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The folate receptor is a proven target for folate-based diagnosis and treatment of cancer. Several folic acid conjugates have been developed as radiopharmaceuticals, but a suitable 18 Flabeled folic acid derivative for routine clinical use is still lacking. The purpose of this study was to investigate the potential of 29-18 F-fluorofolic acid as a PET agent for folate receptor-positive tumors. Methods: The binding affinity of the cold reference compound 29-fluorofolic acid was determined by in vitro displacement assays using human folate receptor-positive KB cells and 3 H-folic acid. 18 F labeling of 29-fluorofolic acid was accomplished via a direct nucleophilic aromatic substitution of N 2 -(N,N-dimethylamino-methylene)-29-nitrofolic acid di-tertbutylester followed by acidic cleavage of the amino and carboxylic protecting groups. The new radiofolate was evaluated in nude mice bearing KB tumor xenografts under control and blocking conditions. Animals were either scanned from 75 to 105 min after injection of the radiotracer or sacrificed 75 min after injection for ex vivo biodistribution studies. Results: 29-fluorofolic acid showed a high binding affinity (inhibition constant, 1.8 6 0.1 nM) for the folate receptor. Direct aromatic 18 F labeling of 29-fluorofolic acid was achieved within 80 min via a convenient 2-step procedure in satisfactory radiochemical yields. The new radiotracer exhibited excellent pharmacokinetics with fast renal clearance and only moderate hepatobiliary elimination. Uptake of 29-18 F-fluorofolic acid in folate receptorpositive KB tumors was high and specific, allowing a clearcut visualization by PET. Conclusion: 29-18 F-fluorofolic acid, obtained via an integrated approach, is a promising PET agent for folate receptor-positive tumors and outperforms previously reported 18 F-labeled folates.

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Folate-receptor-targeted radionuclide imaging agents

Cited by 115 publications

References 47 publications

Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging

Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging

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

A New ¹⁸F-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor–Positive Tumors

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Folate-receptor-targeted radionuclide imaging agents

Cited by 115 publications

References 47 publications

Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging

Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging

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

A New 18F-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor–Positive Tumors

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A New ¹⁸F-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor–Positive Tumors