Tumor Imaging in Patients with Advanced Tumors Using a New ^99mTc-Radiolabeled Vitamin B12 Derivative

Abstract

Targeting cancer cells with vitamin B12 (cobalamin) is hampered by unwanted physiologic tissue uptake mediated by transcobalamin. Adhering to good manufacturing practice, we have developed a new 99m Tc-cobalamin derivative ( 99m Tc(CO) 3 -[(4-amido-butyl)-pyridin-2-yl-methyl-amino-acetato] cobalamin, 99m Tc-PAMAcobalamin). The derivative shows no binding to transcobalamin but is recognized by haptocorrin, a protein present in the circulation and notably expressed in many tumor cells. In this prospective study, we investigated cancer-specific uptake of 99m Tc-PAMAcobalamin in 10 patients with various metastatic tumors. Methods: Ten patients with biopsy-proven metastatic cancer were included. Dynamic imaging was started immediately after injection of 300-500 MBq of 99m Tc-PAMA-cobalamin, and whole-body scintigrams were obtained at 10, 30, 60, 120, and 240 min and after 24 h. The relative tumor activity using SPECT/CT over the tumor region after 4 h was measured in comparison to disease-free lung parenchyma. Patients 3-10 received between 20 and 1,000 mg of cobalamin intravenously before injection of 99m Tc-PAMA-cobalamin. The study population comprised 4 patients with adenocarcinomas of the lung, 3 with squamous cell carcinomas of the hypopharyngeal region, 1 with prostate adenocarcinoma, 1 with breast, and 1 with colon adenocarcinoma. Results: The median age of the study group was 61 6 11 y. Six of 10 patients showed positive tumor uptake on 99m Tc-PAMA-cobalamin whole-body scintigraphy. The scan was positive in 1 patient with colon adenocarcinoma, in 3 of 4 lung adenocarcinomas, in 1 of 3 hypopharyngeal squamous cell carcinomas, and in 1 breast adenocarcinoma. Renal uptake was between 1% and 3% for the left kidney. Predosing with cobalamin increased the tumor uptake and improved blood-pool clearance. The best image quality was achieved with a predose of 20-100 ug of cold cobalamin. The mean patient dose was 2.7 6 0.9 mSv/patient. Conclusion: To our knowledge, we report for the first time on 99m Tc-PAMA-cobalamin imaging in patients with metastatic cancer disease and show that tumor targeting is feasible.

Imaging Cobalamin Uptake within Malignant Breast Tumors In Vivo

“…To determine if the HC:ASGP-R pathway was more effective than the TC:TC-R pathway in imaging Cbl uptake in malignancies, Waibel et [40]. In the only breast cancer patient studied, the primary breast tumor had been resected prior to …”

Recent trends in the development of vitamin B12derivatives for medicinal applications

“…Interestingly, these particular points of modifications have already been earlier suggested when analysing the binding of biotin modified Cbls to TCII 123. In the meantime these important developments have led to the design of an exciting variety of modified B 12 derivatives for the delivery of organic and inorganic drugs,54,118,[124][125][126][127][128][129] radiopharmaceuticals and diagnostic agents,[130][131][132][133][134][135][136][137][138] peptides and hormones[139][140][141][142][143] and fluorescence markers. 54, 144-149 Principles, strategies and progress in this area have been comprehensively summarized in 2012.…”

Does a Conjugation Site Affect Transport of Vitamin B12–Peptide Nucleic Acid Conjugates into Bacterial Cells?

“…As an endogenous compound, it reaches mammalian cells by a unique dietary pathway that can be used for the delivery of cargoes of interest into cells . Examples of this approach encompass vitamin B 12 conjugates with therapeutics (including proteins and anticancer drugs), as well as fluorescent and radioisotope labels . Certain microorganisms exhibit diversified requirements for this nutrient; some are capable of synthesizing this molecule (either de novo or from its precursors; in this regard, they are a source of Cbl for certain eukaryotes), whereas others do not need it .…”

“…[4,5] Exampleso ft his approach encompass vitamin B 12 conjugates with therapeutics (including proteins [6,7] and anticancer drugs), [8,9] as well as fluorescent [10][11][12] and radioisotope labels. [13,14] Certain microorganisms exhibit diversified requirements for this nutrient;s ome are capable of synthesizing this molecule (either de novo or from itsp recursors;i nt his regard, they are as ource of Cbl for certaine ukaryotes), [15] whereas others do not need it. [16] There are also microorganisms (Escherichia coli, Mycobacterium tuberculosis, Salmonella Typhimurium) Figure 1.…”