DOI
https://doi.org/10.25772/g2h8-8g31
Defense Date
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Paula Bos
Second Advisor
Sandro da Rocha
Abstract
Breast cancer is the most common type of cancer affecting women globally, with female breast cancer incident rates gradually increasing since the mid-2000s. A major clinical challenge in management of the disease is its ability to metastasize, in which the tumor cells disseminate to various organs, such as lymph nodes, lung, liver, and brain. Furthermore, metastatic breast cancer remains incurable and therapeutic options remain limited when cancer has spread to the central nervous system. Amongst these metastatic sites, breast cancer brain metastasis (BCBM), is associated with particularly poor prognosis. Consequently, there is an unmet clinical need to offer more effective therapies for the treatment of breast cancer (BC) and breast cancer metastasis, most notably BCBM.
The immune system plays a crucial role in regulating tumor progression, however, tumor cells possess the innate ability to remodel the environment towards an immunosuppressive, pro-tumorigenic state. This process induces substantial immune reprogramming, effecting multiple immune populations, with Natural Killer (NK) cells, platelets, T cells, B cells, monocytes, and macrophages being amongst a few susceptible immune cells. Amongst the immune cell populations utilized for initial tumor colonization, monocytes, immune cells of particular interest due to their plasticity, are one of the most notable immune cells when discussing the dynamic of solid tumors. Monocytes can constitute a substantial portion of tumor-associated immune cells following their differentiation and polarization.
Leveraging the innate migratory capabilities and phenotypical dependent on stimuli, this dissertation investigates a novel cell-based therapeutic treatment strategy utilizing monocyte biology with the potential held by nanotechnology to shift the tumor microenvironment (TME) towards a less immune-suppressive state. IFN-γ, a cytokine most notable for its pro-inflammatory properties, can induce anti-tumorigenic properties, however, this effect is not prolonged. As opposed to the transient anti-tumorigenic effects elicited by receptor-mediated activation, the modulation of a downstream transcription factor may provide a more robust therapeutic effect. Furthermore, this direct activation via surface receptor-ligand can be circumvented through mRNA lipid nanoparticle (LNP) mediated delivery. LNPs have emerged as one of the most successful nanodelivery systems for the delivery of RNA for therapeutic interventions.
We sought to utilize mRNA LNPs for the delivery of a pro-inflammatory transcription factor, a constitutively active form of Signal Transducer and Activator of Transcription 1 (STAT1-CA) to monocytes, prior to transfer into tumor-bearing hosts. Through various pilot studies, it was observed that although the particles enter the cell, there is still difficulty in translation of the mRNA contained in the mRNA-LNP. In the usage of THP-1 monocytic cells treated with STAT1-CA mRNA LNPs, before systemic administration, no impact was observed in the development of brain metastasis, however, an increase in extracranial metastatic burden relative to the control group was observed.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-6-2026