ORCID Identifier(s)

0000-0002-4056-2388

Graduation Semester and Year

Summer 2025

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Materials Science and Engineering

Department

Materials Science and Engineering

First Advisor

Yaowu Hao

Second Advisor

Kyung suk Yum

Third Advisor

Xiankai Sun

Fourth Advisor

Efstathios Meletis

Fifth Advisor

Yi Hong

Abstract

Glioblastoma (GBM) is a highly malignant form of brain cancer with a bleak prognosis. Current maximal treatment involves surgical resection followed by chemo-or radiotherapy. Two critical barriers make treating GBM a formidable challenge. First, the tumor's tendril-like proliferation throughout healthy brain tissue often makes complete surgical removal and conventional radiation insufficient. Second, the blood-brain barrier (BBB), which protects the brain, unfortunately also shields GBM from life-saving anti-cancer drugs. Here, we develop a radioactive nanoparticle-based therapy that directly confronts these limitations, offering a new strategy for GBM treatment.

Prostate-specific membrane antigen (PSMA) is a promising target for glioblastoma (GBM) treatment because it's highly expressed in the tumor's new blood vessels in at least 70% of patients yet is virtually absent in healthy blood vessels. We are developing PSMA-targeted Nanoseeds—ultrasmall radioactive nanoparticles conjugated with PSMA—to overcome the key challenges of treating GBM. Our approach works in two ways: 1. The tumor's finger-like tendrils are highly vascularized, giving our nanoseeds a direct route to reach the entire tumor volume. 2. The nanoseeds deliver radiation over a short distance, which means the therapeutic agent doesn't need to cross the BBB to be effective.

We've selected Copper-67 (67Cu) as our radiation source for its unique properties. 67Cu is ideal for both therapy and diagnostics because it emits beta particles for radionuclide therapy and gamma rays for single-photon emission computed tomography (SPECT) imaging. Its close relative, 64Cu, is commonly used for positron emission tomography (PET). This allows us to use a theranostic (therapeutic and diagnostic) approach. Before treatment, we can perform a PET scan with 64Cu or a SPECT scan with 67Cu. This imaging will act as a predictive biomarker to determine if a patient's tumor will respond to our therapy. By measuring the level of tumor uptake, doctors can make informed decisions about patient suitability and precisely tailor the dosage, bringing personalized precision medicine to GBM patients.

To make this possible, we focused on creating ultrasmall, renal-clearable, copper-based nanoparticles that can be easily conjugated with a targeting molecule. We've developed new synthesis methods for three types of copper nanoparticles: metal Cu, Cu2S, and Cu2Se. Metal Cu nanoparticles (CuNPs) are synthesized by liquid diffusion synthesis (LDS), Cu2S nanoparticles are synthesized by organic phase hot injection synthesis, and Cu2Se nanoparticles are synthesized via cation exchange with CdSe nanoparticles. At the same time, thiolated and PEGylated targeting ligands with a Lys-Urea-Glu motif were developed. This motif is ideal for binding to PSMA and, in addition to its targeting function, it makes the nanoparticles water-soluble and stable in a biological environment. Preliminary in vivo testing of our PSMA-targeted Nanoseeds has shown they are indeed renal-clearable and suitable for subsequent targeting of GBM, confirming their potential as a radiotherapeutic.

Keywords

nanoparticle, nanoseed, glioblastoma, PSMA, copper nanoparticle, Liquid Diffusion Synthesis, radiotherapeutics

Disciplines

Materials Science and Engineering | Other Materials Science and Engineering

License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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