Author ORCID Identifier

https://orcid.org/0000-0002-2395-0397

Semester

Spring

Date of Graduation

2026

Document Type

Dissertation (Campus Access)

Degree Type

PhD

College

Statler College of Engineering and Mineral Resources

Department

Chemical and Biomedical Engineering

Committee Chair

Margaret Bennewitz

Committee Member

Moriah Katt

Committee Member

Tracy Liu

Committee Member

Soumya Srivastava

Committee Member

Amanda Stewart

Abstract

Breast cancer remains the most frequently diagnosed malignancy among women worldwide. The accuracy of detection strongly influences patient prognosis, as early identification of localized disease enables timely intervention and significantly improves survival outcomes. Conventional imaging modalities such as mammography often fail to detect tumors in younger women with dense breast tissue and can misclassify benign lesions as malignant. Magnetic resonance imaging (MRI) provides superior soft-tissue contrast and higher sensitivity than mammography; however, its diagnostic precision remains limited by the non-specific behavior of gadolinium (Gd)-based contrast agents. These agents are always “ON,” producing signal enhancement in any vascularized region which contributes to false-positive findings. In addition, Gd-based contrast agents pose concerns regarding long-term tissue accumulation and toxicity. To address these limitations, tumor targeted, pH-sensitive Nano-Encapsulated Manganese Oxide (NEMO) particles were developed that remain “off” in the bloodstream but turn “on” after internalization by cancer cells. Upon internalization, NEMO particles are shuttled to low pH endosomes and lysosomes where they break apart and release manganese ions to activate bright T1 MRI signal specific for malignancy. To fabricate NEMO particles, manganese-oxide nanocrystals were encapsulated within poly(lactic-co-glycolic acid) and polyethylene glycol polymers and conjugated to an under-glycosylated mucin-1 (uMUC-1) targeting peptide to promote receptor-mediated uptake in breast cancer cells.

NEMO particles were evaluated through a combination of in vitro cell studies, in vivo mouse imaging, and immune-response assessments. During in vitro MRI experiments, targeted NEMO particles exhibited markedly greater signal enhancement in malignant mammary cells relative to benign controls, confirming selective cancer cell uptake and pH-activated contrast generation. Confocal microscopy revealed progressive localization within endosomal and lysosomal compartments. In vivo imaging in orthotopic breast tumor-bearing mice demonstrated that fractionated administration of NEMO particles produced strong and prolonged tumor contrast with minimal off-target enhancement, while conventional Gd agents exhibited rapid clearance and non-specific distribution. Immune compatibility studies indicated that NEMO particle uptake, cytokine release, oxidative stress and MRI signal generation in macrophages and neutrophils was lower compared to conventional Gd agents, further confirming the safety and specificity of NEMO particles. Collectively, these findings establish uMUC-1-targeted, pH-activatable NEMO nanoparticles as a promising class of smart MRI contrast agents that integrate molecular targeting, environmental responsiveness, and biodegradability. Our approach represents a step toward achieving more specific, durable, and safer MRI-based detection of breast cancer.

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Available for download on Friday, April 30, 2027

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