Polysaccharides meet dendrimers to fine-tune the stability and release properties of polyion complex micelles

Dendritic-polysaccharide polyion complex (PIC) micelles represent promising delivery systems where dendritic rigidity and polysaccharide stiffness synchronize to determine the stability and compactness of the micelles, their kinetics of intracellular drug release, and cytotoxicity. A screening using three charged polysaccharides (chitosan, alginate, hyaluronic acid) with varying molecular weights (MW) confirmed PEG-dendritic block copolymers as privileged structural components for the preparation of otherwise unfeasible PIC micelles from PEG-linear copolymers. The superior stability of dendritic PIC micelles is associated to the intrinsic rigidity and globular nature of dendrimers. Indeed, large differences in local dynamics between linear polymers and dendrimers have been described. Remarkably, lower polydispersity and longer-term micelle stability were revealed on reducing the polysaccharide MW, an effect not previously observed for PIC and associated to the high stiffness of charged polysaccharides. The polysaccharide MW-dependent properties of these micelles were analyzed in detail by encapsulating the fluorescent anticancer drug doxorubicin, which confirmed a higher compactness and slower intracellular drug release of micelles prepared from shorter polysaccharides. Overall, a control of the stability, release properties, and cytotoxicity of PIC micelles that is not attainable with linear polymers is feasible with dendrimers by selecting the MW of an oppositely charged polysaccharide.