Preparation of xanthohumol (XN)-incorporated sub-5 ultrafine iron oxide nanoparticles: Investigation of their effects on multiple myeloma cell growth

Date of Award

6-2025

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Xinyu Wang, PhD

Second Advisor

Yuancheng Li, PhD

Third Advisor

Shu Zhu, MD, PhD

Fourth Advisor

Yujin Kim, PharmD, PhD

Fifth Advisor

Bonnie Buxton, PhD

Abstract

Multiple myeloma (MM) is a hematological cancer that affects B lymphocytes. MM cells can undergo a homing process within the bone marrow microenvironment (BMM). The BMM helps MM cells undergo proliferation through interactions with bone marrow stromal cells. The proliferation aids in MM's continued growth and spread throughout the BMM and into neighboring organs by releasing interleukin-6 and vascular endothelial growth factor (VEGF). Xanthohumol (XN) is categorized as a prenylated flavonoid and has exhibited anticancer effects in an in vitro model. It has downregulated the NF-kappa B signaling pathway, which is activated by interleukin-6 and aids in MM cell proliferation. Results indicated that XN induced a dose- and time-dependent decrease in cellular viability of RPMI 8226 cells. Furthermore, western blot analysis was used to evaluate the expression of apoptotic-related markers, showing upregulation of cleaved-caspase 3. Major challenges limiting the use of XN as an anti-cancer drug include poor aqueous solubility and a lack of capability for targeting cancerous cells. To address this, we formulated an anti-biofouling polyethylene glycol-block-allyl glycidyl ether (PEG-b-AGE) polymer-coated ultrafine iron oxide nanoparticles (uIONPs) loaded with XN (uIONP/XN) to improve the delivery efficiency to MM cells. XN is encapsulated in the hydrophobic layer of the amphiphilic coating polymer with a loading efficiency of ~66% (mg/mg Fe). Upon a short-wave radio frequency (RF) stimulation for 15 minutes, > 30% of XN was released. An RGD motif was conjugated to the uIONP as the targeting ligands for the αvβ3 integrin overexpressed on MM cells. This study compared RGD-uIONP/XN, RGD-uIONP (vehicle control), and uIONP/XN (non-targeted control) for cytotoxic effects. Results indicated that the RGD/uIONP-XN induced the greatest cytotoxic effects on the MM cells out of the uIONPs used. Understanding the mechanism of action behind the uIONPs ability to induce cell death was analyzed. Results indicated that while reactive oxidative species are produced, further studies need to be conducted to analyze ferroptosis and apoptotic markers in uIONPs.

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