Abedelnasser Abulrob1,2,3, Slavisa Corluka4, Barbara Blasiak5,6, B Gino Fallone7, Dragana Ponjevic8, John Matyas8, Boguslaw Tomanek9,10,11. 1. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. Abedelnasser.abulrob@nrc.gc.ca. 2. Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada. Abedelnasser.abulrob@nrc.gc.ca. 3. Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa, ON, K1A 0R6, Canada. Abedelnasser.abulrob@nrc.gc.ca. 4. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. 5. Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland. 6. Department of Clinical Neurosciences, University of Calgary, Calgary, Canada. 7. Department of Oncology, University of Alberta, Edmonton, Canada. 8. Department of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada. 9. Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland. tomanek@ualberta.ca. 10. Department of Clinical Neurosciences, University of Calgary, Calgary, Canada. tomanek@ualberta.ca. 11. Department of Oncology, University of Alberta, Edmonton, Canada. tomanek@ualberta.ca.
Abstract
PURPOSE: Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, or Her2/neu. Both diagnosis and treatment of TNBC remain a clinical challenge. LyP-1 is a cyclic 9 amino acid peptide that can bind to breast cancer cells. The goal of this study was to design and characterize LyP-1 conjugated to fluorescent iron oxide nanoparticles (LyP-1-Fe3O4-Cy5.5) as a contrast agent for improved and specific magnetic resonance imaging (MRI) in a preclinical model of TNBC. PROCEDURES: The binding of LyP-1-Fe3O4-Cy5.5 to MDA-MB-231 TNBC cells was evaluated and compared to scrambled peptide bio-conjugated to iron oxide nanoparticles (Ctlpep-Fe3O4-Cy5.5) as a negative control. Following the in vitro study, the MDA-MB-231 cells were injected into mammary glands of nude mice. Mice were divided into two groups: control group received Ctlpep- Fe3O4-Cy5.5 and LyP-1 group received LyP-1-Fe3O4-Cy5.5 (tail vein injection at 2 mg/kg of Fe3O4). Mice were imaged with an in vivo fluorescence imager and a 9.4 T MRI system at various time points after contrast agent injection. The T2 relaxation time was measured to observe accumulation of the contrast agent in breast tumor and muscle for both targeted and non-targeted contrast agents. RESULTS: Immunofluorescence revealed dense binding of the LyP-1-Fe3O4-Cy5.5 contrast agent to MDA-MB-231 cells; while little appreciable binding was observed to the scrambled negative control (Ctlpep-Fe3O4-Cy5.5). Optical imaging performed in tumor-bearing mice showed increased fluorescent signal in mammary gland of animals injected by LyP-1-Fe3O4-Cy5.5 but not Ctlpep- Fe3O4-Cy5.5. The results were confirmed ex vivo by the 2.6-fold increase of fluorescent signal from LyP-1-Fe3O4-Cy5.5 in extracted tumors when compared to the negative control. In MR imaging studies, there was a statistically significant (P < 0.01) difference in normalized T2 between healthy breast and tumor tissue at 1, 2, and 24 h post injection of the LyP-1-Fe3O4-Cy5.5. In animals injected with LyP-1-Fe3O4, distinct ring-like structures were observed with clear contrast between the tumor core and rim. CONCLUSION: The results demonstrate that LyP-1-Fe3O4 significantly improves MRI contrast of TNBC, hence has the potential to be exploited for the specific delivery of cancer therapeutics.
PURPOSE: Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, or Her2/neu. Both diagnosis and treatment of TNBC remain a clinical challenge. LyP-1 is a cyclic 9 amino acid peptide that can bind to breast cancer cells. The goal of this study was to design and characterize LyP-1 conjugated to fluorescent iron oxide nanoparticles (LyP-1-Fe3O4-Cy5.5) as a contrast agent for improved and specific magnetic resonance imaging (MRI) in a preclinical model of TNBC. PROCEDURES: The binding of LyP-1-Fe3O4-Cy5.5 to MDA-MB-231 TNBC cells was evaluated and compared to scrambled peptide bio-conjugated to iron oxide nanoparticles (Ctlpep-Fe3O4-Cy5.5) as a negative control. Following the in vitro study, the MDA-MB-231 cells were injected into mammary glands of nude mice. Mice were divided into two groups: control group received Ctlpep- Fe3O4-Cy5.5 and LyP-1 group received LyP-1-Fe3O4-Cy5.5 (tail vein injection at 2 mg/kg of Fe3O4). Mice were imaged with an in vivo fluorescence imager and a 9.4 T MRI system at various time points after contrast agent injection. The T2 relaxation time was measured to observe accumulation of the contrast agent in breast tumor and muscle for both targeted and non-targeted contrast agents. RESULTS: Immunofluorescence revealed dense binding of the LyP-1-Fe3O4-Cy5.5 contrast agent to MDA-MB-231 cells; while little appreciable binding was observed to the scrambled negative control (Ctlpep-Fe3O4-Cy5.5). Optical imaging performed in tumor-bearing mice showed increased fluorescent signal in mammary gland of animals injected by LyP-1-Fe3O4-Cy5.5 but not Ctlpep- Fe3O4-Cy5.5. The results were confirmed ex vivo by the 2.6-fold increase of fluorescent signal from LyP-1-Fe3O4-Cy5.5 in extracted tumors when compared to the negative control. In MR imaging studies, there was a statistically significant (P < 0.01) difference in normalized T2 between healthy breast and tumor tissue at 1, 2, and 24 h post injection of the LyP-1-Fe3O4-Cy5.5. In animals injected with LyP-1-Fe3O4, distinct ring-like structures were observed with clear contrast between the tumor core and rim. CONCLUSION: The results demonstrate that LyP-1-Fe3O4 significantly improves MRI contrast of TNBC, hence has the potential to be exploited for the specific delivery of cancer therapeutics.
Entities:
Keywords:
Breast cancer; Iron oxide nanoparticles; LYP1 peptide; MRI; Molecular imaging; Optical imaging; Triple negative
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