The complexity and aggressiveness of cancer, as well as its increasing incidence and mortality worldwide, prompts the search for novel and alternative therapeutic strategies with improved effectiveness and safety. In this sense, the identification of therapeutic targets, the discovery of new molecules with antitumor potential, and the design of drug delivery systems create opportunities for a successful cancer management.
Among compounds with promising anticancer activity are metal-based complexes and hybrid molecules, with some already approved for clinical use and others undergoing clinical trials or in preclinical research. In the present work, two compounds with promising anticancer potential were studied, the Cu2+ complex Cuphen [Cu(phen)Cl2] and a dual acting hybrid molecule, HM, containing two moieties – a DNA alkylating triazene and a ʟ-tyrosine analogue, 4-S-CAP, with high specificity for tyrosinase. Cuphen may act through the modulation of aquaporins (AQPs), inhibiting AQP3-mediated glycerol transport and affecting cell migration. In turn, the dual acting HM demonstrated a superior antiproliferative activity compared to the clinically approved temozolomide. Also, HM significantly inhibited tyrosinase activity and arrested cell cycle in G0/G1 phase.
Following these promising in vitro results, the next goal was to maximize the in vivo therapeutic efficacy of these compounds by exploring the versatility of the most successful lipid-based nanosystem, liposomes. Long circulating liposomal formulations, with suitable physicochemical properties for each molecule, were designed and evaluated in preclinical studies. In the case of Cuphen, liposomes with pH-sensitive properties were designed to promote a locally-triggered release at the slightly acidic tumor microenvironment. In vivo, liposomal Cuphen significantly reduced melanoma and colon cancer progression, compared to free form. Furthermore, Cuphen liposomes displaying magnetic properties were successfully developed for further increase their accumulation at tumor sites upon application of an external magnetic field.
For HM, an efficient incorporation in long circulating liposomes was obtained. In a subcutaneous murine melanoma model, liposomal HM remarkably reduced tumor progression, compared to free HM. Moreover, in a syngeneic metastatic melanoma model, a reduction on the number of lung metastases was observed for liposomal HM compared to all groups, including the positive control temozolomide. Remarkably, in the subcutaneous melanoma model, biodistribution studies of LIP HM showed that, 48 h post-administration, 4% of the injected dose per gram of tumor was attained, correlating with the obtained therapeutic activity.
Importantly, all developed nanoformulations, for both anticancer compounds, demonstrated to be safe for parenteral administration, in healthy animals, not eliciting hepatic toxic side effects neither hemolytic activity. Furthermore, the long-term stability of liposomes in lyophilized form was achieved using an appropriate cryoprotectant.
In conclusion, these encouraging results demonstrate the advantages of exploring novel therapeutic targets and compounds, particularly when associated to liposomes as a delivery system, to potentiate their safety and therapeutic effectiveness for cancer management
