Semester

Summer

Date of Graduation

2022

Document Type

Thesis

Degree Type

MS

College

Statler College of Engineering and Mineral Resources

Department

Chemical and Biomedical Engineering

Committee Chair

Margaret Bennewitz

Committee Co-Chair

Yuxin Liu

Committee Member

Yuxin Liu

Committee Member

Andrey Bobko

Abstract

Breast cancer is among the deadliest cancers in women, with approximately 2.3 million new cases and 685,000 deaths reported globally in 2020 alone. Magnetic Resonance Imaging (MRI) is commonly used to diagnose, stage, and develop treatment plans for patients predisposed to breast cancer. However, current MRI-based screening of breast cancer has high false-positive rates up to 25%, leading to unnecessary invasive follow-up screening and testing. The gold-standard intravenous gadolinium (Gd)-based contrast agents (GBCAs) account for false-positive rates because they are always “ON”, providing a constant MRI signal that highlights both benign and malignant tumors. The work detailed in this thesis presents Nano-, Encapsulated Manganese Oxide (NEMO) particles as potential replacements for GBCAs as T1-weighted or bright MRI contrast agents. To improve sensitivity and specificity, NEMO particles possess a unique pH-switchable signal that is responsive to low pH endosomes inside cancer cells (“OFF” to “ON” MRI signal conversion at low pH), superior paramagnetism, and peptide targeting against underglycosylated mucin-1 (uMUC-1), exclusively expressed on breast cancer cells. Thus, NEMO particles will remain “OFF” in benign tumors and healthy tissues as particles remain intact but will turn “ON” in malignant tumors as particles degrade in intracellular endosomes to release Mn2+.

In the present work, uMUC-1 targeted NEMO particles were synthesized, optimized, and studied within 3D microfluidic tumor models (MTMs). In-house and commercialized manganese oxide nanocrystals were systematically compared via several characterization techniques pre- and post-encapsulation within poly(lactic-co-glycolic acid) (PLGA), an FDA approved biocompatible and biodegradable polymer. Important nanoparticle (NP) characteristics were evaluated including size, chemistry, Mn2+ release rate, and resulting MRI signal. Using the best nanocrystal formulation, several parameters of polymer encapsulation, such as the concentration of the stabilizing agent, were selectively changed to optimize NEMO particles for in vivo applications. This work highlights the optimal phase of manganese oxide, polymer type, and encapsulation parameters needed to produce NEMO particles with the most robust MRI signal.

Developing a novel protocol to image 3D MTMs with MRI will expedite evaluation of contrast agent sensitivity, specificity, accumulation, and retention to reduce the number of required animal tests. This work combines confocal fluorescence microscopy with MRI of MTMs, which will allow for rapid optimization of contrast agent design through correlating NP-cell interactions, intratumoral distribution, cytotoxicity, and MRI signal. A novel 3-part apparatus to facilitate MRI of 3D MTMs was designed and tested. Overall, this work lays the foundation for future use of 3D MTMs to evaluate novel MRI contrast agents in the context of cancer. uMUC-1 targeted NEMO particles are widely applicable to other cancers and are expected to make breast MRI diagnosis faster, simpler, and more accurate.


Embargo Reason

Publication Pending

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Available for download on Tuesday, July 23, 2024

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