Materials Science and Engineering PhD Thesis Defense by Özlem Ünal

******************************************************************

KOÇ UNIVERSITY

GRADUATE SCHOOL OF SCIENCES & ENGINEERING

MATERIALS SCIENCE AND ENGINEERING

PhD THESIS DEFENSE BY ÖZLEM ÜNAL

******************************************************************

Title: Development of Superparamagnetic Iron Oxide Based Nanotheranostics

Speaker: Özlem Ünal

Time: September 21, 2017, 11:00

Place: ENG 208

Koç University

Rumeli Feneri Yolu

Sariyer, Istanbul

Thesis Committee Members:

Assoc. Prof. Havva Yağcı Acar (Advisor, Koç University )

Prof. Dr. Levent Demirel, (Koç University)

Prof. Dr. Duygu Avcı Semiz (Boğaziçi University)

Assoc. Prof. Devrim Gözüaçık (Sabancı University)

Assoc. Prof. Uğur Ünal (Koç Üniversity)

Abstract:

Superparamagnetic iron oxide nanoparticles (SPIONs) constitute a popular nano-platform in the continuously improving field of nanomedicine. Its biocompatable nature, possibility of achieving functional surfaces with various Chemistry, response to magnetic field provide a tremendous opportunity for theranostic applications of SPIONs.

First part of this thesis, summarizes the discovery of instrinsicly luminescent polyethyleneimine (PEI) coated SPIONs which provides gene-delivery combined with bimodal imaging modality. It will be shown that  there is a tremendous and method dependent improvement in the poor blue luminescence of branched polyethyleneimine (bPEI) when coated on the surface of SPIONs. Carefully conducted spectroscopic and theoretical studies in this thesis tried to uncover the origin of such enhancement and provide an important contribution to the literature of luminescent polyamines.  Ultimately, combination of amine oxidation, surface adsorption of bPEI restricting the mobility coupled with final acidification is the major factor behind such strong emission observed from bPEI-SPION. Besides, transfection of cervical cancer cell line HeLa with therapeutic oligonucleotide, poly I:C, were demonstrated to emphesize its therapeutic potential. In short, this crucial  finding, which is about the widely used bPEI coated SPIONs in the nanomedicine, both serves as a conceptual improvement in the literature of the fluorescent polyamines and enhances the scope of bPEI/SPIONs by showing their new diagnostic capability.

Second part of this thesis is devoted to an effort to develop non-toxic, non-cationic, protein based transfection agents containing SPIONs as the signaling moiety. One of the most significant obstacles in the field of nanomedicine is the restriction of the gene carrier nanoparticles to the toxic poly-cationic compositions in order to improve their gene loading efficiency. This is a major drawback which particularly frustrates the notable biocompatibility of SPIONs. Therefore, safer and highly functional SPION based gene carrier designs need to be developed by excluding polycations to take advantage of the biocompatibility of iron oxide core to the full extend. This thesis will demonstrate the development of a novel, non-toxic multifunctional SPION based miRNA delivery agent for the first time in literature. The ultimate nanoparticle was designed as GCP conjugated SPIONs tagged with an affinity tag (antiHer2 protein) and a far red emissive fluorescent tag (Cy5) to achieve a selective and image guided delivery of autophagy related miR376 therapeutics to the breast cancer models. These nanooparticles show an excellent in vitro and in vivo biocompatibility and targeted delivery to the MDA-MB-453 and SKBR3 breast cancer cell lines, in vitro and in vivo.

Third part of this thesis work focuses on delivery of SPION-based therapeutic agents to tumor tissue with a consideration of intra-tumor heterogeneity. In order to enhance the targeting efficiency to such heterogenous tumors, SPION immuno-conjugates which combine the antibodies recognizing the overexpressed Her2 and EGFR signaling receptors on the surface of the breast cancer cells were developed in this thesis. Bispecific SPION immuno-conjugates are anionic, colloidally stable and small enough to circulate in the body. Targeting different breast tumor cell lines with such SPIONs are demonstrated in vitro. Such an approach contributes to a newly developing area of targeting nanoparticles to tumor heterogeneity.

In a conclusion, this thesis aimed to contribute to the literature of SPION based theranostics by providing new diagnostic capabilities, improving the biocompatibility and strengthening the molecular targeting issues.