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AKRON, OH, United States

Sysel A.M.,Bnoat Oncology, Inc. | Valli V.E.,VDx Research Services | Nagle R.B.,Arizona Cancer Center | Bauer J.A.,Bnoat Oncology, Inc.
Anticancer Research | Year: 2013

Background/Aim: Cancer cells have an essential demand for vitamin B12 (cobalamin) to enable cellular replication. The present pilot study quantified the immunohistochemical expression of vitamin B12 transport protein (Transcobalamin II; TCII), cell surface receptor (Transcobalamin II-R; TCII-R) and proliferation protein (Ki-67) in human tumor xenografts. Materials and Methods: Tissue microarray slides containing 34 xenograft tumor tissues were immunohistochemically stained using TCN2 (anti-TCII), CD320 (anti-TCII-R) and MIB-1 (anti-Ki-67) antibodies. Representatively stained areas of all slides were digitally imaged and protein expression was quantified using ImageJ software plugins. Results: All xenograft tumor tissues stained positively for TCII, TCII-R and Ki-67 proteins; expression varied both within and between tumor types. Correlation between TCII/TCII-R and Ki-67 expression was not significant in xenograft tissues. Conclusion: Proliferating cancer cells express measurable levels of TCII and TCII-R. Immunohistochemical quantification of these markers may be useful as a tool for detection of tumors, tailored selection of anti-tumor therapies and surveillance for evidence of recurrent disease. Source

Sysel A.M.,Bnoat Oncology, Inc. | Horne W.I.,Northeast Ohio Medical University | Steiner J.M.,Texas A&M University | Suchodolski J.S.,Texas A&M University | Bauer J.A.,Bnoat Oncology, Inc.
Anticancer Research | Year: 2012

Background/Aim: Cobalamin and folate are interdependent co-factors of the methionine synthase pathway. This study evaluated the effect of intravenously-administered nitrosylcobalamin (NO-Cbl), a vitamin B12 analog, on serum folate concentrations in healthy dogs. Materials and Methods: Four dogs received a 10-mg/kg, 20-mg/kg and 40-mg/kg intravenous bolus dose of NO-Cbl, with a 14-day washout period between doses. Blood samples were collected at baseline and post-dosing, and serum cobalamin and folate concentrations were measured. Results: For each dose, serum cobalamin concentrations were inversely correlated with serum folate concentrations. Spearman rank correlation coefficient values were -0.976 (10 mg/kg, p<0.0096), and -1.0 (20 mg/kg, p<0.008; 40 mg/kg, p<0.0046). Conclusion: Cellular uptake of NO-Cbl, following intravenous administration exerted a biological effect on folate, similar to that previously described for other vitamin B12 analogs. Serum folate concentration may serve as a pharmacodynamic biomarker of intracellular nitrosylcobalamin activity following intravenous administration. Source

Sysel A.M.,Bnoat Oncology, Inc. | Horne W.I.,Northeast Ohio Medical University | Steiner J.M.,Texas A&M University | Suchodolski J.S.,Texas A&M University | Bauer J.A.,Bnoat Oncology, Inc.
Anticancer Research | Year: 2012

Background/Aim: Nitrosylcobalamin (NO-Cbl) is a cobalamin-based anti-tumor agent. This study evaluated the pharmacokinetic parameters of NO-Cbl following intravenous administration in dogs. Materials and Methods: Four dogs received 10 mg/kg, 20 mg/kg and 40 mg/kg intravenous bolus doses of NO-Cbl, with a 14-day washout period between doses. Blood samples were collected at baseline and postdosing, and noncompartmental pharmacokinetic parameters were determined. Results: Average peak serum concentrations of 2265, 5523 and 13,866 pg/mL were achieved following single-dose bolus intravenous administration of 10 mg/kg, 20 mg/kg and 40 mg/kg of NO-Cbl respectively. The average area under the curve was 12,697 h x pg/mL, 24,497 h x pg/mL and 44,976 h x pg/mL respectively, with an average elimination half-life of 16.2 h, 13.5 h and 13.1 h respectively. Conclusion: These results can be used to determine the dose and dosing intervals for clinical trials evaluating NO-Cbl in humans and companion animals. Source

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 200.00K | Year: 2010

Oncology remains a major market of unmet need. BNOAT Oncology¿s long-term objective is New Drug Approval of its lead candidate nitrosylcobalamin, a tumor-specific, apoptosis-inducing, anti-cancer drug. Research Design and Methods: Nitrosylcobalamin purification will include crystallizations, various chromatographic techniques including basic ion-exchange resins, neutral ion exchange, gel filtration chromatography, and size exclusion chromatography. Proprietary formulation design algorithms and phospholipid gel (PG) depot formulation templates will be used in the development of the intravenous-depot formulation and the oral formulation. A variety of excipients will be used to design test formulations for their ability to achieve an optimized PK profile and work independently of intrinsic factor and/or vitamin B12 levels in the gut. Anticipated Results: A PG Depot formulation with a duration of release over a time course of 3-7 days in addition to an oral delivery independent of cobalamin metabolism. Purity (98%) of nitrosylcobalamin as determined by HPLC analysis.

Dunphy M.J.,Bnoat Oncology, Inc. | Dunphy M.J.,Walsh University | Sysel A.M.,Bnoat Oncology, Inc. | Lupica J.A.,Bnoat Oncology, Inc. | And 4 more authors.
Chromatographia | Year: 2014

Nitrosylcobalamin (NO-Cbl), a novel vitamin B12 analog and anti-tumor agent, functions as a biologic 'Trojan horse', utilizing the vitamin B12 transcobalamin II transport protein and cell surface receptor to specifically target cancer cells. A stability-indicating HPLC method was developed for the detection of NO-Cbl during forced degradation studies. This method utilized an Ascentis® RP-Amide (150 mm x 4.6 mm, 5 μm) column at 35°C with a mobile phase (1.0 mL min-1) combining a gradient of methanol and an acetate buffer at pH 6.0. Detection wavelengths of 450 and 254 nm were used to detect corrin and non-corrin-based products, respectively. NO-Cbl, synthesized from hydroxocobalamin and pure nitric oxide gas, was subjected to degradative stress conditions including oxidation, hydrolysis and thermal and radiant energy challenge. The method was validated by assessing linearity, accuracy, precision, detection and quantitation limits and robustness. The method was applied successfully for purity assessment of synthesized NO-Cbl and for the determination of NO-Cbl during kinetic studies in aqueous solution and in solid-state degradation assessments. This HPLC method is suitable for the separation of cobalamins in aqueous and methanolic solutions, for routine detection of NO-Cbl and for purity assessment of synthesized NO-Cbl. Additionally, this method has potential application in identification and monitoring of diseases involving altered nitric oxide homeostasis where vitamin B12 therapy is utilized to scavenge excess nitric oxide, subsequently resulting in the in vivo production of NO-Cbl. © 2014 Springer-Verlag. Source

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