Development of Core-Shell UCNPs@SiO¿ Nanoplatforms as Nanocarriers of Co(III) Complexes Containing Bioactive Ligands for Breast Cancer Treatment

• Grant number: 25/21312-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: November 01, 2025
• End date: January 31, 2029
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Sidney José Lima Ribeiro
• Grantee: Ana Maria Romão Polez
• Host Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated research grant: 21/08111-2 - Development of rare earth based light converters: luminescent markers, optical sensors, and amplifiers, AP.TEM

Abstract

Breast cancer (BC) is the most prevalent malignant neoplasia among women in Brazil and worldwide, representing one of the leading causes of female mortality. Despite advances in early diagnosis and available therapeutic modalities, such as surgery, radiotherapy, chemotherapy, hormone therapy, and targeted therapies, BC treatment still faces significant challenges, particularly in aggressive cases such as triple-negative tumors (TNBC). These subtypes are characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), resulting in higher recurrence rates, reduced survival, and limited targeted therapeutic options. Consequently, there is an urgent need for the development of novel therapeutic approaches that combine higher selectivity, efficacy, and reduced side effects. In this context, photoactivated prodrugs emerge as promising alternatives, as they allow localized activation of cytotoxic activity in response to light irradiation. However, many of these strategies remain limited by their dependence on oxygen for reactive species generation and the use of short-wavelength radiation, which exhibits low tissue penetration and may damage healthy tissues. An attractive alternative involves the use of metal complexes that undergo light-induced ligand substitution reactions, independent of oxygen presence, and can be activated under hypoxic conditions typical of the tumor microenvironment.Although compounds derived from precious metals (Ru, Ir, Pt, Re, and Rh) exhibit favorable photophysical properties, there is an increasing global demand for the use of earth-abundant metals due to sustainability concerns. In this context, Co(III) complexes have attracted increasing attention, as they undergo photoisomerization, photoredox, and photosubstitution reactions under ultraviolet (UV) and/or visible light irradiation. The strategy relies on coordinating a drug to a kinetically inert Co(III) complex, rendering it inactive under normal physiological conditions. However, in the presence of a high excess of reducing agents and a hypoxic environment, as found in tumors, the Co(III) center is reduced to labile Co(II), releasing the coordinated drug. Moreover, since Co(III) complexes are also susceptible to light-mediated photoreduction and photosubstitution, the release of the ligand and/or generation of phototoxic products can be triggered by the wavelength of visible light irradiation. This project aims to develop novel composites with antitumor properties based on lanthanide-doped NaYF¿:Yb³¿/Er³¿ upconversion nanoparticles (UCNPs) coated with silica and functionalized with Co(III) complexes of the type [Co(NN)¿(L)]NO¿ (NN = 2,2'-bipyridine, 1,10-phenanthroline, and 1,4,7,10-tetraazacyclododecane; L = nitroxoline, curcumin).The novelty of these materials lies in their ability to minimize damage to surrounding healthy tissue by avoiding short-wavelength activation of Co(III) complexes through controlled irradiation with low-energy lasers in the near-infrared (NIR) region. The UCNPs absorb NIR photons and emit higher-energy photons in the ultraviolet (UV) and/or visible (Vis) regions, promoting photoreduction of Co(III) to Co(II), thereby triggering the release of bioactive ligands and/or the generation of reactive oxygen species (ROS). This approach enhances antitumor efficacy, ensuring deeper tissue penetration for treating cancers in internal organs, while providing higher selectivity in hypoxic tumor regions. (AU)