Annexin A5–methotrexate: a novel targeted therapeutic against breast cancer and leukemia

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dc.contributor.advisorHarrison, Roger G.
dc.contributor.authorAissanou, Adam
dc.contributor.committeeMemberMcNally, Lacey R.
dc.contributor.committeeMemberSikavitsas, Vassilios I.
dc.date.accessioned2020-12-21T19:51:06Z
dc.date.available2020-12-21T19:51:06Z
dc.date.issued2020-12-18
dc.date.manuscript2020-12-15
dc.description.abstractOne of the most challenging issues of chemotherapy in cancer treatments relies on specifically targeting and carrying the drug to the tumor cells. While tumor ablation surgery can be efficient, metastatic cancers are more challenging to treat because of the spread distribution of tumor cells in the body. Methotrexate is an FDA approved antimetabolite drug for the treatment of breast cancer and acute lymphoblastic leukemia. However, despite several conjugation attempts to optimize its delivery to cancer cells, methotrexate still does not offer a reliable enough therapeutic effect in the clinic. We have investigated the conjugation of methotrexate to annexin A5, a human protein that specifically binds to the cancer cell marker phosphatidylserine. Once conjugated to annexin A5, methotrexate’s cytostatic effect would be specifically delivered to cancer cells without causing off-target damage to healthy cells. This novel drug conjugate has been designed as a response to the currently urgent clinical needs for a targeted and specific chemotherapeutic treatment for triple negative breast cancer and lymphoblastic leukemia. The successful conjugation of methotrexate to annexin A5 was confirmed by measuring the final concentration of annexin A5 and methotrexate in the conjugate. The increase in size of the conjugate was confirmed by SDS-PAGE. Cell viability assays of free and conjugated methotrexate were conducted on both tumor and non-tumor cells. The conjugate induced a toxicity that was statistically equivalent to the one delivered by the free drug on the triple negative breast cancer 4T1 and EMT6 cell lines, and on the lymphoblastic leukemia P388 cell line. However, while free methotrexate induces a cell mortality in healthy endothelial HUVEC and HAAE-1 cells, the conjugate does not cause any significant decrease of the cell viability, confirming its specificity towards tumor cells.en_US
dc.identifier.urihttps://hdl.handle.net/11244/326675
dc.languageen_USen_US
dc.subjectTargeting cancer chemotherapeutic delivery to tumor siteen_US
dc.subjectMethotrexate targeted protein conjugate against breast cancer and leukemiaen_US
dc.subjectConjugation of methotrexate to annexin A5 via EDC/NHS chemistryen_US
dc.subject4T1 EMT6 P388 HAAE-1 HUVECen_US
dc.subjectAnnexin A5 targeting carrier agent specific to externalized phosphatidylserine of cancer cellsen_US
dc.thesis.degreeMaster of Scienceen_US
dc.titleAnnexin A5–methotrexate: a novel targeted therapeutic against breast cancer and leukemiaen_US
ou.groupGallogly College of Engineering::Stephenson School of Biomedical Engineeringen_US
shareok.nativefileaccessrestricteden_US
shareok.orcidhttps://orcid.org/0000-0002-9556-7434en_US

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