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utaneous melanoma is among the most aggressive skin cancers, known for its high metastatic potential and immune evasion. Traditional treatments like chemotherapy and surgery often yield limited success. Although radiotherapy offers an alternative, its effectiveness is often hindered by damage to healthy tissues surrounding the cancer.

To improve treatment precision and reduce side effects, radiotherapy with radioactive molecules (RTD) has emerged as a promising strategy. Lutetium-177 (177Lu) is a widely used radiometal in RTD due to its clinical success and commercial availability. To achieve targeted delivery of the radioisotope, it must be bound to a carrier molecule acting as a “Trojan horse.” Exosomes—nanometric extracellular vesicles—show great potential as natural nanosystems for this purpose, as they naturally migrate to tumor tissues.

This study hypothesizes that 177Lu-loaded exosomes can serve as vectorized therapy for melanoma by exploiting their tumor-targeting capabilities. Acting as “Trojan horses,” these radiolabeled exosomes would deliver radiotherapy directly to the tumor, improving efficacy and minimizing damage to healthy tissues. Additionally, the imaging properties of 177Lu enable non-invasive tumor localization via SPECT imaging.

The project’s main objective is to develop radiotherapeutic agents based on 177Lu-labeled exosomes and validate them in animal models of cutaneous melanoma. Three specific objectives guide this work (SO):

• SO1: Synthesis and characterization of [177Lu]RadioExo. Exosomes will be extracted from commercial goat milk and radioactively labeled with the 177Lu isotope using various radiochemical protocols.
• SO2: in vitro evaluation of [177Lu]RadioExo cytotoxicity: the cellular study will be performed in several tumor lines (B16F10, U87, HeLa) and controls (macrophages, epithelial cells, fibroblasts) using colorimetric studies (XTT, MTT, LDH) and apoptosis studies (FACS, confocal microscopy). Their uptake will be quantified by gamma counter.
• SO3: In vivo study of the teragnostic capacity of [177Lu]RadioExo. Finally, the therapeutic efficacy of the nanosystem will be evaluated in animal models of melanoma by means of tumor volume measurements as well as the diagnostic capacity by SPECT/CT imaging.

The success of this study would contribute to the development of new non-invasive, sensitive and rapid diagnostic tools as alternatives to invasive biopsies, as well as to the advancement in the monitoring and understanding of the physiology of natural exosomes.