Graduation Year

2024

Document Type

Thesis

Degree

M.S.B.E.

Degree Name

MS in Biomedical Engineering (M.S.B.E.)

Degree Granting Department

Engineering

Major Professor

Michael Dunne, Ph.D.

Co-Major Professor

Neda Latifi, Ph.D.

Committee Member

Robert Frisina, Ph.D.

Keywords

Cancer immunotherapy, cell trafficking, melanoma, nanoscale drug delivery, tumor spheroid model

Abstract

Melanoma, the deadliest form of skin cancer, is notorious for its rapid mutation rate and high potential for metastasis, making effective treatment particularly challenging. Immunotherapy has emerged as a significant advancement in melanoma therapy, leveraging the immune system to target and eliminate cancer cells. These achievements have motivated further investigation into immune system-based strategies for this aggressive cancer. Cell-based drug delivery has been primarily achieved by either using immune cells as direct carriers for therapeutics or by employing active molecules through drug delivery systems, most often nanoparticles. While immune cells exhibit innate tumor-homing abilities, they face challenges such as limited drug loading and loss of membrane stability. Conversely, nanocarriers enhance drug encapsulation and enable controlled release but often struggle to reach the tumor site and are frequently recognized as foreign particles by the immune system. In this work, a hybrid system integrating immune cells as carriers with lipid nanoparticles is proposed, employing a ‘Trojan horse’ strategy to achieve both targeted tumor migration and effective drug delivery. Monocyte-derived immune cells were chosen as the cellular component of this system due to their inherent ability to differentiate into macrophages and dendritic cells, which are the key players in immune surveillance and tumor targeting. The migration and infiltration potential of pro-inflammatory activated macrophages and dendritic cells were evaluated using transwell migration assay and static co-culture assessments on a 3D model of B16-F10 melanoma spheroids, revealing active tumor-targeted migration. Moreover, lipid nanoparticles (LNPs) encapsulating pramlintide, a synthetic peptide with known anticancer effects, were fabricated using a similar lipid composition to the latest COVID-19 mRNA vaccines. Neither bare nor drug-loaded LNPs exhibited toxicity toward immune cells or fibroblasts, yet promising anticancer effects were observed on melanoma cells after 72 hours. Furthermore, fluorescein-loaded LNPs were tested for visualizing the cellular uptake by immune cells. This experiment confirmed successful uptake by immune cells, providing valuable insights into the integration of nanoparticles. This hybrid system presents a novel approach to combining immune cell-mediated tumor targeting with the drug-delivery potential of nanoparticles. Future work will focus on engineering 'cellular backpacks' to maintain the pro-inflammatory phenotype of immune cells, thereby enhancing their trafficking to the tumor site and improving therapeutic efficacy.

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