Targeted Delivery of Xanthohumol via RGD-conjugated uIONPs Inhibits Growth in Multiple Myeloma Cell Lines and Induces Apoptosis

Date of Award

6-2026

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Dr. Xinyu Wang Ph.D.

Second Advisor

Yujin Kim, PharmD, Ph.D.

Third Advisor

Yuancheng Li, Ph.D.

Fourth Advisor

Francis E Jenney Jr., Ph.D.

Abstract

Multiple myeloma (MM) is a hematological malignancy characterized by the uncontrolled proliferation of monoclonal plasma cells within the bone marrow. This growth leads to severe complications, including anemia, hypercalcemia, bone lesions, and renal insufficiency. While proteasome inhibitors like Bortezomib (BTZ) are standard treatments, MM remains largely incurable due to the protective bone marrow microenvironment, which upregulates survival factors such as vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). Furthermore, the systemic toxicity of traditional chemotherapies, like BTZ, necessitates safer alternatives such as xanthohumol (XN). XN is a prenylated flavonoid from Humulus lupulus, offers potent anticancer properties, but suffers from rapid in vivo degradation. To enhance stability and delivery of XN in cells, we prepared ultrafine iron oxide nanoparticles (uIONP). RGD-conjugated uIONPs were prepared and loaded with XN for targeted MM therapy. The RGD tripeptide is used to help specific binding to overexpressed integrins on the MM cell surface. The nanoparticle delivery vehicle was characterized based on its hydrodynamic dimensions and zeta potential. We also observed the characterization of uIONP loaded with XN (nontargeted drug control) and RGD-uIONP without loaded XN (vehicle control). Having established that XN was successfully loaded into the uIONPs, we investigated its ability to inhibit MM cell growth and ability to upregulate pro-apoptotic protein expression relative to the effects observed with XN alone. Our hypothesis is that XN released from uIONP exerts inhibitory effects on MM cell growth and induces apoptosis. To address this hypothesis, we assessed cell viability using Presto Blue assays to examine the effects of XN alone on three MM cell lines (RPMI 8226, U266, and MM.1S). In addition, we measured cell viability using the Presto Blue assay with uIONP loaded with XN, RGD-uIONP without XN, and RGD-uIONP at a 40 μM XN concentration over time. Western blots were also performed on human RPMI 8226, MM.1S, and U266 cell lysates after 24 hours of XN treatment to assess the expression of apoptotic markers, cleaved-caspase 3 and cleaved PARP1. XN alone showed a time and dose-dependent decrease in cell viability over a period of time (24,48,and 72 hours) on the RPMI 8226, U266, and MM.1S cells. RGD-uIONP showed a time-dependent decrease in cell viability on the RPMI 8226 and MM.1S cells as well. The western blot results indicate that the potential mechanism of cell death at higher XN concentrations is apoptosis. However, the uIONPs did not show high expression of the apoptotic markers, which was hypothesized to be the potential mechanism of cell death. In conclusion, the results indicate that XN and RGD-uIONP/XN induce cell death in MM cell lines and XN alone induces apoptosis in the MM cells. Further experiments will be performed to evaluate the cytotoxic effects and mechanism of cell death with the RGD-uIONP/XN on other MM cells.

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