Co-encapsulation of flavonoids with anti-cancer drugs: A challenge ahead

Flavonoids have been considered as promising molecules for cancer treatment due to their pleiotropic properties such as anti-carcinogenic, anti-angiogenic or efflux proteins inhibition. However, due to their lipophilic properties and their chemical instability, vectorization seems compulsory to administer flavonoids. Flavonoids have been co-encapsulated with other anti-cancer agents in a broad range of nanocarriers aiming to i) achieve a synergistic/additive effect at the tumor site, ii) delay drug resistance apparition by combining agents with different action mechanisms or iii) administer a lower dose of the anti-cancer drug, reducing its toxicity. However, co-encapsulation could lead to a change in the nanoparticles' diameter and drug-loading, as well as a decrease in their stability during storage. The preparation process should also take into accounts the physico-chemical properties of both the flavonoid and the anti-cancer agent. Moreover, the co-encapsulation could affect the release and activity of each drug. This review aims to study the formulation, preparation and characterization strategies of these co-loaded nanomedicines, as well as their stability. The in vitro assays to predict the nanomedicines' behavior in biological fluids, as well as their in vivo efficacy, are also discussed. A special focus concerns the evaluation of their synergistic effect on tumor treatment.