Date on Master's Thesis/Doctoral Dissertation

12-2022

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

O'Toole, Martin

Committee Co-Chair (if applicable)

Bates, Paula

Committee Member

Bates, Paula

Committee Member

Clark, Geoffrey

Committee Member

Frieboes, Hermann

Committee Member

Steinbach-Rankins, Jill

Author's Keywords

Gold nanoparticle; gadolinium; AS1411; polyethylene glycol; cancer targeting

Abstract

Gold nanoparticles (GNPs) have become a pivotal platform for the delivery of pharmaceutical and diagnostic agents as well as for general therapeutic purposes. Despite their potential for use in biomedicine, their interaction with serum proteins is crucial as it could change their biological profile due to the formation of a protein corona, which can affect their delivery to target tissues in the body. Grafting the GNPs with polyethylene glycol (PEG) is widely used in research to decrease opsonization of the particles by serum proteins and decrease the uptake by the reticuloendothelial system. Here in this dissertation, we have developed a library of 4 and 10 nm GNPs conjugated with a gadolinium chelate as MRI contrast agent, cancer-targeting aptamer AS1411 (CRO aptamer was used as control), and with or without polyethylene glycol (PEG) of different molecular weights (Mw: 1, 2, and 5 kDa). We have quantified the amount of proteins that adsorbed on the surface of PEGylated and non-PEGylated GNPs after incubation in human serum proteins. Additionally, we have quantified the uptake of nanoparticles with and without protein corona by the human breast cancer cell line MDA-MB-231 and the murine monocyte/macrophage cell line RAW 264.7. Furthermore, we have investigated the in vivo biodistribution of GNPs using the murine model of 4T1 mammary carcinoma in BALB/c female mice. The in vitro results showed that PEG failed to decrease protein adsorption and the cellular uptake by macrophage cells was contingent on the different configurations of the aptamers and the length of PEG chain. While in vivo biodistribution showed that PEG increased the uptake by tumor cells for some GNPs, it did not decrease the uptake of GNPs by macrophage-rich organs.

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