Ms. Liberty N. Gendron Profile

Liberty N. Gendron

at Dartmouth College

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Publications (3)

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Proceedings Article | 14 August 2019 Presentation

Tumor targeting vitamin B12 derivatives for x-ray activated chemotherapy (Conference Presentation)

Jennifer Shell, Thomas Shell, Brian Pogue, Liberty Gendron, Colter Sheveland

Proceedings Volume 11070, 110705G (2019) https://doi.org/10.1117/12.2528263

KEYWORDS: Tumors, X-rays, Cancer, Radiotherapy, Receptors, Tissues

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X-Ray activated pharmaceutical therapy is highly sought after as it provides deep tissue, synergistic method of treating cancers in which the standard method of care involves radiotherapy. Traditional drugs utilized as neoadjuvant chemotherapy have significant side effects and a lack of selectivity, leaving a dire need for targeted drug delivery methods. We have recently developed a unique delivery platform whereby the drug is conjugated to an alkylcobalamin vitamin B12 scaffold, and these alkylcobalamins are actively transported into cells by transcobalamin receptors (TCblR). A large number of cancer types have enhanced expression of these receptors; therefore, the drug-cobalamin conjugate could be effectively ferried into the tumor selectively via the TCblR pathway. This delivery system provides light-activatable release of chemotherapeutics. Due to the drug becoming active at the specific site that it is needed, such as a tumor, the potential side effects of that drug in organs at risk are mitigated. As a proof of concept, we have found that a fluorescent cobalamin derivative localized within xenograft tumors in mice, demonstrating the effectiveness of the vitamin B12 scaffold as a theranostic targeting agent. In addition, this derivative is also activated with clinical X-ray doses from a linear accelerator. We explored the ability of a variety of cobalamin drug conjugates to be used in combination with radiotherapy to elicit an enhanced reduction in tumor margins in pancreatic adenocarcinoma models.

Proceedings Article | 4 March 2019 Presentation

Tumor targeting cetuximab conjugated europium microspheres for Cherenkov excited luminescence scanned imaging (Conference Presentation)

Jennifer Shell, Liberty Gendron, Ethan LaRochelle, Xu Cao, Brian Pogue

Proceedings Volume 10862, 1086217 (2019) https://doi.org/10.1117/12.2515383

KEYWORDS: Tumors, Luminescence, Europium, Radiotherapy, Phototherapy, In vitro testing, Microscopy, Visualization, In vivo imaging

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Cherenkov emission, which is generated during radiation therapy, can be utilized for imaging that is synergistic with radiation therapy. Cherenkov light can be utilized to excite phosphors, which then can be imaged utilizing Cherenkov excited luminescence scanned imaging (CELSI). Europium chelate microspheres, which exhibit bright luminescence with long luminescent lifetime, were appended with multiple copies of cetuximab. This will allow for selective imaging of EGFR overexpressing tumors during the course of radiation therapy via CELSI. We have characterized the functionality of the cetuximab loaded microspheres in vitro via ELISA, as well as via fluorescence microscopy in EGFR overexpressing A431 cells. These microspheres were intravenously injected into athymic nude mice bearing A431 flank tumors and allowed to incubate for a series of time points. They were then imaged first via standard fluorescence imaging to determine the ideal time point for visualizing tumors via CELSI. After demonstrating selective accumulation in tumors, imaging was then undertaken in vivo via CELSI. These antibody conjugated europium microspheres provide promise to image tumors selectively with CELSI. Future studies involve conjugating other antibodies to the europium microspheres to utilize in CELSI.

Proceedings Article | 4 March 2019 Presentation

Light-activated Vitamin B12 Derivatives as Theranostic Agents (Conference Presentation)

Jennifer Shell, Liberty Gendron, Dillon Zites, Thomas Shell, Brian Pogue

Proceedings Volume 10862, 108620M (2019) https://doi.org/10.1117/12.2515379

KEYWORDS: Tumors, Receptors, Tissues, Cancer, Natural surfaces, Windows, Tissue optics, Luminescence, Pancreatic cancer, Cell death

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The discovery of new tumor targeting agents is desirable to expand imaging and drug delivery platforms. Cobalamins, vitamin B12 derivatives, selectively accumulate in tumor versus benign tissue due to overexpression of transcobalamin receptors in a variety of cancer types. Multiple forms of this vitamin are taken into cells via transport through transcobalamin receptors on the cell surface. Alkylcobalamins are light-activatable, and we have discovered that the wavelength of this light activation is tunable via appendage of a fluorophore. We have been able to harness this cobalamin platform to release drugs with a variety of wavelengths of light, including those within the optical window of tissue. This cobalamin drug delivery platform provides selective spatiotemporal activation of drug only where needed, thereby diminishing side effects of traditional chemotherapy. A Bodipy650-cobalamin was synthesized and utilized to study the tumor targeting ability of cobalamin derivatives in athymic nude mice with subcutaneous MCF-7 and MIA PaCa-2 tumors, which have been demonstrated to overexpress transcobalamin receptors. The fluorescently labeled cobalamin was injected intravenously into the mice and allowed to incubate for a series of time points. Fluorescence imaging revealed that this cobalamin conjugate selectively accumulated in both tumor types. We utilized this cobalamin platform for tumor selective, light-activated delivery of the pancreatic cancer drugs erlotinib and SN38. We determined light-induced apoptosis in MIA PaCa-2 cells in vitro and explored the reduction of MIA PaCa-2 tumors in vivo utilizing these cobalamin drug conjugates. This cobalamin platform provides potential for development of new theranostic tools for drug delivery.

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