Nanoparticles for Advancements in Radiopharmaceutical Technologies

Cancer is a significant burden on patients and healthcare worldwide and remains the second leading cause of death in the United States[1, 2]. Nuclear medicine has evolved over the decades to improve diagnosis, treatment, and better guide the resection of tumors through radiopharmaceuticals[3, 4]. Nanoparticles play an interesting role in the evolving field of radiopharmaceuticals due to their modularity and subsequent flexibility, providing new technologies for nuclear diagnosis and treatment of cancer[5-7]. Nanoparticles have high surface area to volume ratios, making them more amendable for surface modification[8]. Multiple radionuclides can bind to one nanoparticle, with or without a chelator, increasing specific activity without increasing particle number[9]. By fine-tuning size, morphology, composition, and functionalization, the blood circulation time can potentially be tuned for nanoparticles, ranging from 30 min to 24 h, which can be matched to a radionuclides’ half-life[8, 9]. Nanoparticles are also an effective carrier for the delivery of drugs or imaging agents [9, 10]. Radiolabeled nanoparticles have made their way into the clinic, e.g. for sentinel lymph node imaging[9]. This dissertation aims to highlight how nanoparticles can be utilized as ideal carriers of radiopharmaceuticals for improved cancer imaging and treatment. Among the most common forms of biomedical imaging are Positron Emission Tomography (PET)[2], Magnetic Resonance Imaging (MRI)[4], and fluorescence imaging [2, 4]. Our research in biomedical imaging in this dissertation centers around techniques related to Cerenkov Luminescence Imaging (CLI), which relies on Cerenkov Luminescence emitted from radioactive decay, and for which the research of Grimm and co-workers have made significant advances in clinical imaging [11]. CLI has the advantage of combining the availability, sensitivity, and specificity of nuclear tracers for molecular imaging with the higher resolution, lower cost, and faster acquisition times of optical imaging[12]. This work investigates a unique contrast enhancement approach for CL that would enhance the signal without increasing the radioactive dose for patients. In our research towards cancer therapeutics, we explored further the potential of certain heavy radionuclides for curative therapy, which, besides gamma radiation, also emit subatomic particles such as alpha (a) -particles, beta (b) -particles, and Auger electrons[8]. Therapeutic efficacy is maximized when the effective range, particle decay pathway and linear energy transfer (LET) of the radionuclide matches the tumor size, density, radiosensitivity, and heterogeneity[13]. Targeted Alpha Therapy (TAT) provides high cell-killing efficiency and short effective range, sparing healthy untargeted tissue as compared to beta-radiation therapy[13]. In an attempt to reduce ancillary effects to healthy organs from TAT, this work investigates the use of core-shell nanoparticles as a technology for sequestering decay daughters without inhibiting therapeutic a-emission[14-17].