Imaging Tumor Folate Receptors using ¹¹¹IN-DTPA-Methotrexate

Abstract

It is known that membrane folic acid receptors are responsible for cellular accumulation of folate and folate analogs, such as methotrexate, and overexpressed on various tumor cells. This study was aimed to develop an 111In labelled DTPA-methotrexate (DTPA-MTX) to image tumor folate receptors in vivo. DTPA-MTX was synthesized by reacting ethylenediamine with MTX. The resulting amino analogue of MTX was reacted with DTPA dianhydride in basic aqueous solution followed by dialysis. Tissue distribution was determined in breast tumor-bearing rats at 0.5, 2, 24, and 48 h (n = 3/time interval). To determine receptor-mediated process 111In-DTPA-MTX was co-administrated with varying blocking doses of cold folate to tumor-bearing rats. Planar imaging and whole-body autoradiograms were performed. The data was compared to that using 111In-DTPA. In animal studies, tumor/blood count density ratios at 0.5-48 h gradually increased from 0.8 +/- 0.32 to 2.2 +/- 0.41 with 111In-DTPA-MTX. Conversely, these values showed time-dependent decrease from 1.19 +/- 0.69 to 0.56 +/- 0.10 with 111In-DTPA in the same time period. Tumor/muscle and tumor/blood count density ratios significantly decreased with high doses of folic acid co-administration. Planar images and autoradiograms confirmed that the tumors could be visualized acceptably with 111In-DTPA-MTX. The results indicate the feasibility of using 111In-DTPA-MTX to image tumors through a folate receptor-mediated process.

Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumours

“…SPECT (single photon-emission computerized tomography) images obtained with this substance demonstrated that the complex accumulated in the kidney and liver as well as in malignant, but not benign ovarian cancers [37,39]. These studies have been extended by Leamon and Low amongst others [39] to the production of 99m Tc-folate conjugates with the hope of reducing the cost and half-life of the imaging agent with substantially reduced exposure of vital organs to the nuclide [40][41][42][43]. Furthermore, the 140 keV c-radiation emitted by 99m Tc is optimal for standard imaging equipment.…”

In Vivo and In Vitro Measurement of Apoptosis in Breast Cancer Cells Using99mTc-EC-Annexin V

“…9 Molecular targets (e.g., estrogen, progestin, folate, retinoic acid receptors, BRCA-1, HER-2/neu, p53, cyclin D1) provide more accurate functional information for breast cancer diagnosis and treatment. [10][11][12][13][14][15][16][17] Tagging molecular targets with radionuclides can increase our understanding of pharmacokinetic, pharmacodynamic and metabolic imaging patterns of the agent, thereby providing information useful for characterizing tumors.…”

Perspectives of Methotrexate-Based Radioagents for Application in Nuclear Medicine

“…Above reports − provided limited uptake of MTX radioagents by FR-positive cancer cell lines especially in comparison to folate-based radioagents. However, results of in vivo or ex vivo biodistribution showed detectable MTX radioagents uptake at tumor sites, but also substantial uptake in spleen.…”

“…113,114 Other investigated radioligands based on MTX vector also showed unsatisfactory traceability of FR-expressing tumors in rodent models. γ-Emitting [ 111 In]In-DTPA-ethylenediamine-MTX 115 showed very low uptake in breast tumor, but still superior than [ 111 In]In-DTPA complex and sensitive to FA blockage. [ 68 Ga]Ga-or [ 99m Tc]Tc-chitosan-polyglutamate-MTX complexes, 116 both obtained in direct labeling, showed negligible human breast tumor targetability (tumor-to-blood ratios below 1) throughout in vivo biodistribution.…”