Colorectal cancer is the third most frequently diagnosed cancer malignancy and the second leading cause of cancer-related deaths worldwide. Therefore, it is of utmost importance to provide new therapeutic options that can improve survival. Sphingomyelin nanosystems (SNs) are a promising type of nanocarriers with potential for association of different types of drugs and, thus, for the development of combination treatments. In this work we propose the chemical modification of uroguanylin, a natural ligand for the Guanylyl Cyclase (GCC) receptor, expressed in metastatic colorectal cancer tumors, to favour its anchoring to SNs (UroGm-SNs). The anti-cancer drug etoposide (Etp) was additionally encapsulated for the development of a combination strategy (UroGm-Etp-SNs). Results from in vitro studies showed that UroGm-Etp-SNs can interact with colorectal cancer cells that express the GCC receptor and mediate an antiproliferative response, which is more remarkable for the drugs in combination. The potential of UroGm-Etp-SNs to treat metastatic colorectal cancer cells was complemented with an in vivo experiment in a xenograft mice model.

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Triple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.