Yuming Zhang: Magnetic Nanoparticle-Based Formulations for Colorectal Cancer Theranostics

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. Conventional treatments, including surgery and chemotherapy, are invasive and often result in poor patient compliance, underscoring the need for less invasive and more targeted therapeutic alternatives.

Superparamagnetic iron oxide nanoparticles (SPIONs) offer a versatile platform for cancer therapy and diagnosis owing to their unique magnetic properties. For therapy, they generate heat under an alternating magnetic field (AMF) for magnetic hyperthermia. For diagnosis, they are used as contrast agents in magnetic resonance imaging (MRI). The combination of these functionalities makes SPIONs promising candidates for cancer theranostics.

Non-invasive delivery of SPIONs can be achieved via oral and rectal routes. This thesis explores SPION-based formulations engineered for non-invasive CRC theranostics, encompassing both standalone nanoparticles and SPION composites.

The first part of this thesis demonstrates the development of PEGylated SPIONs as standalone nanoparticles for CRC theranostics with targeting properties and intended for oral delivery. PEGylation improved the particles’ colloidal stability in biological media. Their MRI contrast enhancement was quantified in a tumor phantom, and their magnetic hyperthermia performance was evaluated in both cell models and in vivo. To achieve tumor targeting, a bioorthogonal pretargeting strategy was established by introducing azide groups onto the PEGylated SPION surface, enabling strain-promoted click conjugation with DBCO-functionalized, CRC-specific antibodies pre-administered to the tumor site.

The second part focuses on SPION-based composites. Two formulations were developed: a magnetic hydrogel and a SPION–wax capsule. The magnetic hydrogel, which can be applied topically or via injection, undergoes a sol–gel transition at physiological temperature and generates heat under an AMF for localized tumor ablation. The SPION–wax capsule, intended for oral delivery, was fabricated by blending SPIONs with a wax matrix. It can withstand gastrointestinal conditions, be detected by ultrasound, and, upon reaching the lesion, release its drug cargo through AMF-triggered melting of the wax.

Overall, this thesis establishes SPION-based formulations for non-invasive CRC theranostics, underscoring their potential in advancing current cancer management strategies.