Delivery and Release of [¹²⁵I]Iododeoxyuridine via Nanocarriers for Auger-radiotherapy of Glioblastoma

This PhD thesis provides a comprehensive exploration into the realm of targeted drug delivery systems, with a particular emphasis on the potential of [¹²⁵I]IUdR-deoxyuridine ([¹²⁵I]IUdR) for Auger radiotherapy in the treatment of glioblastoma multiforme (GBM).The thesis is structured into five separate chapters:
Chapter 1: This chapter was a general introduction of the thesis. It started with the treatment and challenges of GBM, and the explorations of novel treatment approaches. It continued deeply into the Targeted Radionuclide Therapy (TRT), exploring the utilization of α emitters, β- emitters, and Auger electron emitters as the radiopharmaceutical agents for cancer therapy, with a special emphasis on Auger electrons, exemplified by [¹²⁵I]IUdR. This chapter also introduced the applications of nanoparticles in TRT, including both organic and inorganic nanoparticles. The radiolabelling strategies of nanoparticles is discussed  subsequently. Furthermore, the chapter described the delivery methods of nanoparticles to the tumor sites, including passive, active delivery and local administration, with CED detailed as an example of local administration. Finally, the chapter provided a short rationale for the entire study.
Chapter 2: In this chapter, the study embarked on the development of drug delivery systems, particularly focusing on liposomes. As nanoscale vesicles, liposomes have garnered attention for their ability to encapsulate and deliver therapeutic agents directly to tumor sites, enhancing the efficacy and reducing systemic side effects. Therefore, they are promising candidates for the delivery of Auger radiotherapy agent
[¹²⁵I]IUdR. Given the rapid degradation of free [¹²⁵I]IUdR in the body, strategic structural modifications were introduced. A key innovation was the incorporation of an ester linker, facilitating the creation of prodrugs with varying carbon chain lengths, referred as [¹²⁵I]IUdR-Cn. This design allowed for a controlled release of [¹²⁵I]. The loading and release study of the prodrug loaded liposomes were carried out. The in vitro efficacy study and in vivo biodistribution study were conducted.
Chapter 3. In this chapter, the exploration of [¹²⁵I]IUdR-Cn prodrugs was continued, with a focus on using polymeric micelles (PMs) as the nanocarrier. PMs, with their unique core-shell structure and small sizes, simple preparation methods and prolonged retention time in blood, have shown their abilities as the vesicle in the drug delivery system for cancer treatment. Therefore, in this chapter, the preparation methods of blank PMs, the loading of the prodrugs and the release of [¹²⁵I]IUdR from the loaded PMs were evaluated. Furthermore, DNA incorporation efficiency and in vitro efficacy study were investigated.
Chapter 4: The focus here was shifted to the exploration of polypept(o)ides, specifically a so called PeptoBrush (PB), for GBM’s Auger radiotherapy. Peptobrush, with their unique brush-like architecture, offer advantages in drug loading and release dynamics. The absence of PEG in PB make them particularly attractive, minimizing potential immune responses, such as the accelerated blood clearance (ABC) phenomenon. The chapter detailed the synthesis of PB and the use of click chemistry for drug loading, achieving remarkable drug loading efficiency. The relevant drug release and in vitro efficacy studies were investigated. 
Chapter 5: In the last chapter, the research delved into the relationship between nanoparticle sizes, distribution and retention in the brain, utilized by PET-guided intracranial CED administration. Understanding the distribution dynamics of nanoparticles is crucial, as it directly impacts therapeutic efficacy and safety. Therefore, two different nanoparticles, liposomes (130 nm) and gold nanoparticles (AuNPs, 8 and 40 nm), were prepared and investigated. The findings distinctly underscore the advantages of sizes in terms of distribution, setting the stage for future studies to optimize the in vivo characteristics of [¹²⁵I]IUdR-C_18-LIPs for GBM treatment.