Theranostic nanocarriers for targeted delivery of monoclonal antibodies and siRNA

Resumo

In recent years, medicine has evolved towards a more personalized approach, where therapies are designed to target specific therapeutic sites and optimize their accumulation in affected tissues. In this context, therapies based on small interfering ribonucleic acids (siRNA) and monoclonal antibodies (mAbs) have emerged as potential therapeutic strategies. However, their clinical application remains limited due to their poor ability to cross biological barriers and their low accumulation in target organs, which restricts their bioavailability and efficacy. Nanotechnology has emerged as a key tool to overcome these challenges, enabling the development of nanoparticles capable of encapsulating, protecting, and transporting these biotherapeutics, facilitating their controlled release at the site of action. This thesis explores the use of nanosystems to enhance the delivery of siRNA and mAbs in lung cancer and central nervous system diseases. Furthermore, it emphasizes the use of molecular imaging tools, such as Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT), to assess the in vivo distribution and behavior of these nanosystems, with the aim of optimizing their development and facilitating their clinical translation. Chapter 1 describes the development of radiolabeling strategies to study the biodistribution of siRNA nanoemulsions (NEs) in healthy and tumor-bearing animal models using PET and SPECT imaging. These NEs, previously optimized for cancer treatment, were evaluated in terms of in vitro silencing efficiency and tissue accumulation. Chapter 2 focuses on the design of a novel nanosystem based on poly(ß-amino esters) (PBAE) for siRNA delivery. Using the Design of Experiment methodology, its composition was optimized to achieve favorable physicochemical properties and high in vitro silencing efficiency. The ability of these nanosystems to inhibit the expression of KRAS oncoprotein and block colony formation in lung cancer cell lines was evaluated. Additionally, its surface was functionalized with the tumor-penetrating peptide truncated LyP-1 to improve tumor accumulation. Finally, two radiolabeling strategies with 89Zr were developed for PET imaging assessment. Chapter 3 evaluates two nanosystems with distinct structures and physicochemical properties for the encapsulation and intracellular release of mAbs. Their internalization capacity in different brain cell types was compared through in vitro studies. Additionally, PET imaging and immunohistochemistry were used to analyze their distribution in brain tissue and their interaction with specific central nervous system cells. In conclusion, this work highlights the potential of various nanostructures for siRNA and mAb delivery in two distinct contexts: lung cancer and brain diseases. Moreover, it demonstrates the utility of nuclear imaging for evaluating the in vivo behavior of these nanosystems, underscoring their translational potential and relevance in the development of advanced nanomedicine-based therapies.