In vitro and In vivo evaluation of 2-amino-7(8)-fluorophenazine N5,N10-dioxide within polymeric micelles as theranostic agents

DAVILA B; AFONSO J; CABRAL P.; SANCHEZ C.; CABRERA M; GLISONI R.J.; LECOT N.; FERNANDEZ LOMONACO M.; CERECETTO H.; GONZÁLEZ M.

Anaheim California

Conferencia; 20th Techconnect World Innovation Conference; 2018

Nano Science and Technology Institute

Breast cancer, one of the most common cancer in developing countries, is reported to feature high incidence, relatively high morbidity and mortality inwomen since the diagnosis and treatment is made in the later stages of the disease. It is a solid tumor characterized by a high level of hypoxic areaswhich are difficult to treat. We have developed bioreducible pro-drugs under hypoxic conditions in which 2-amino-7(8)-fluorophenazine N5,N10-dioxide(FNZ) stands out as a potent and selective anticancer agent (1). To improve its solubility and stability, the encapsulation was studied using pristinepolymeric micelles (PMs) and glycosylated derivatives (2) as a strategy to: (a) increase the solubility, (b) stabilize the aqueous formulation forintravenous application and (c) have nanoscale size which is suitable for the enhanced permeability and retention (EPR) effect for cancer diagnosis andimproved antitumor activity (3). This work presents the characterization, encapsulation and the In vitro-In vivo evaluation. We have studied thephysicochemical characterization of the nanosystems and the evaluation of the mutagenic properties in vitro (AMES test) (4) and its potential activity asan anti-cancer agent of FNZ and PMs/FNZ(5). Finally we explored its property as a diagnostic agent (99Tc-PMs/FNZ). The preliminary results indicatethat all the systems under study (Free-FNZ, pristine PMs/FNZ and glycosylated PMs/FNZ) were stable in particle size and Z-potential after itsresuspension in ultrapure water. The FNZ and PMs/FNZ exhibited mutagenicity in the TA 98 strain, while in the TA 100 PM-Glu/FNZ (F127-Glu/FNZ) didnot. The In vivo studies reveal an enhanced circulation time and a good performance of a theranostic agent in BALB/c mice with an induced 4T1 murinemammary tumor cell line.