Highly Branched Betulin Based Polyanhydrides for Self-Assembled Micellar Nanoparticles Formulation

Abstract

Polyanhydrides based on betulin are promising materials for use in controlled drug delivery systems. Due to the broad biological activity of betulin derivatives and lack of toxicity in vitro and in vivo, these polymers can be used both as polymeric prodrug and as carriers of other biologically active compounds. In this study, we develop a novel amphiphilic branched polyanhydrides synthesized by the two-step melt polycondensation of betulin disuccinate (DBB) and a tricarboxylic derivative of poly(ethylene glycol) (PEG_COOH). DBB and PEG_COOH were used as the hydrophobic and hydrophilic segments, respectively. The content of DBB in copolymers was from 10 to 95 wt%. Copolymers were assessed for their cytostatic activity against various cancer cell lines. Compared to linear DBB and PEG-based polyanhydrides, the branched polyanhydrides exhibited higher anticancer activity. The obtained polymers were able to self-assemble in water to form micelles with hydrodynamic diameters from 144.8 to 561.8 nm. and are stable over a concentration range from 12.5 µg/mL to 6.8 mg/mL. The formed micelles were found to be spherical in shape using a scanning electron microscope. It was found that the structure and composition of polyanhydrides affected the hydrodynamic diameter of the micelles. The branched betulin-based polyanhydrides have the potential to serve as biodegradable polymer prodrugs or carriers for other bioactive compounds.

Keywords

• betulin
• polyanhydrides
• biodegradable polymers
• cytostatic activity
• polymeric micelles