Thesis: Juan José Esteve Moreno

Directors: Alba García Fernández, Paula Díez Sanchéz y Ramón Martínez Máñez

Title: Smart Nanoparticles for Enhanced Melanoma Therapy: From Controlled Drug Release to Self-Propelled Nanomotors

Abstract: The present doctoral thesis, entitled “Smart nanoparticles for improved melanoma therapy: from controlled drug release to self-propelled nanomotors”, focuses on the development of innovative therapeutic strategies against melanoma through the use of smart nanoparticles. Specifically, it addresses the synthesis, characterization, and evaluation of nanodevices for controlled drug release. These systems are designed to overcome key barriers associated with melanoma, such as immune evasion, the tumor extracellular matrix, and premature drug degradation, while reducing adverse effects on healthy tissues.
The first chapter provides an introduction to cancer, and especially to melanoma, describing its main biological features, mechanisms of metastasis, and immune evasion. It also reviews the evolution of therapeutic strategies and the limitations that affect their efficacy. Subsequently, the application of nanotechnology in medicine and its main oncological applications are introduced. Finally, controlled drug delivery systems, prodrugs, and the stimuli capable of triggering their activation are analyzed, with special attention to gold nanostars and mesoporous silica nanoparticles as promising platforms for melanoma treatment.
The second chapter presents the objectives of the thesis.
The third chapter describes a bioorthogonal nanotherapeutic platform based on gold nanostars for the controlled photoactivation of doxorubicin prodrugs using near-infrared (NIR) light. Two complementary strategies were developed: a doxorubicin prodrug inactivated by 2-nitrobenzyl groups and the same molecule covalently anchored to the surface of the nanostars. NIR irradiation induces the controlled release of active doxorubicin. Both formulations showed high stability under physiological conditions and were activated only upon irradiation. In addition, intracellular activation of the prodrug was demonstrated in melanoma and cervical cancer cells, minimizing photothermal effects. In vitro and in vivo studies in murine melanoma models showed efficient drug release, significant inhibition of tumor growth, and selective therapeutic activity only under NIR irradiation.
The fourth chapter focuses on the development of self-propelled nanomotors to improve drug distribution in deep tumor regions. The system is based on platinum Janus nanoparticles functionalized with lactate oxidase and loaded with doxorubicin. These nanoparticles exploit lactate from the tumor microenvironment as an endogenous fuel, providing autonomous propulsion and metabolic depletion. The nanomotors showed self-propulsion and specific drug release under physiological conditions. In melanoma cells, they produced a marked reduction in cell viability at low concentrations, while in tumor spheroids they achieved greater intratumoral penetration than passive systems. In vivo studies demonstrated a significant reduction in tumor size and an increase in CD8+ lymphocyte infiltration, suggesting a decrease in immune evasion associated with lactate metabolism.
Finally, the fifth and sixth chapters present the general discussion, future perspectives, and conclusions. Overall, the results demonstrate the versatility of plasmonic nanostars and metabolite-driven nanomotors as platforms for innovative anticancer therapies. These strategies combine controlled prodrug activation, autonomous propulsion, and remodeling of the tumor microenvironment to improve drug delivery against melanoma and other accessible tumors.