Abstract

Today, cancer is the second leading cause of death worldwide where chemotherapy is one of the common strategies to control it. Platinum-based chemotherapeutic drugs (PBDs) are a mainstay in chemotherapy due to their high effectiveness in a wide spectrum of cancer types. Severe toxicity and innate or acquired drug resistance are the two main problems limiting PBD clinical use. One approach to overcome both problems is by employing cancer-targeting drug delivery systems where liposomes, in particular, are gaining much attention in oncology application and have established superior potency compared to the corresponding free drugs in clinical application already. This study aims to evaluate the cytotoxicity of liposome-encapsulated nedaplatin, a second generation platinum-based anticancer drug which is clinically available and heavily used in Japan only thus far, in comparison to its non-encapsulated free form in three cancer cell lines; non-small cell lung cancer A549, breast cancer MCF7 and osteosarcoma U2OS. The novel liposome was designed and produced in the Chemistry department at The American University in Cairo and showed promising physicochemical properties which were found to be reflected biologically. We evaluated cytotoxicity using different approaches including MTT, live cell counting, clonogenic survival assay and Cytokinesis Block Proliferation Index (CBPI) assay, all showing statistically significant superior anti-proliferative effects for liposomal nedaplatin. Genotoxicity in terms of chromosomal damage assessed through micronucleus formation fold changes and DNA damage in the form of DNA double-strand breaks (DSBs), the most deleterious type of DNA damage and one known to be induced by PBD-DNA interstrand crosslinking, supported superior activity of liposomal nedaplatin from which it was inferred that the liposomal formulation demonstrated successful drug delivery to the molecular target, DNA, achieving good drug release and expected cellular distribution. Nedaplatin was shown to induce cell death through apoptosis in the 3 cell lines as demonstrated in nuclear morphological changes and pre-apoptotic marker signals identified by immunofluorescent staining for gH2AX.

Department

Biotechnology Program

Degree Name

MS in Biotechnology

Graduation Date

6-1-2018

Submission Date

February 2018

First Advisor

Kakarougkas, Andreas

Committee Member 1

Gad, Mohamed

Committee Member 2

Amleh, Asma

Extent

88 p.

Document Type

Master's Thesis

Rights

The author retains all rights with regard to copyright. The author certifies that written permission from the owner(s) of third-party copyrighted matter included in the thesis, dissertation, paper, or record of study has been obtained. The author further certifies that IRB approval has been obtained for this thesis, or that IRB approval is not necessary for this thesis. Insofar as this thesis, dissertation, paper, or record of study is an educational record as defined in the Family Educational Rights and Privacy Act (FERPA) (20 USC 1232g), the author has granted consent to disclosure of it to anyone who requests a copy.

Institutional Review Board (IRB) Approval

Not necessary for this item

Comments

AUCstudent research grant

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