Catechol Containing Polyelectrolyte Complex Nanoparticles as Local Drug Delivery System for Bortezomib at Bone Substitute Materials

Abstract

The proteasome inhibitor bortezomib (BZM) is one of the most potent anti-cancer drugs in the therapy of multiple myeloma. In this study, an adhesive drug delivery system (DDS) for BZM was developed. Therefore, we extended the present DDS concept of polyelectrolyte complex (PEC) nanoparticle (NP) based on electrostatic interactions between charged drug and polyelectrolyte (PEL) to a DDS concept involving covalent bonding between PEL and uncharged drugs. For this purpose, 3,4-dihydroxyphenyl acetic acid (DOPAC) was polymerized via an oxidatively induced coupling reaction. This novel chemo-reactive polyanion PDOPAC is able to temporarily bind boronic acid groups of BZM via its catechol groups, through esterification. PDOPAC was admixed to poly(l-glutamic acid) (PLG) and poly(l-lysine) (PLL) forming a redispersible PEC NP system after centrifugation, which is advantageous for further colloid and BZM loading processing. It was found that the loading capacity (LC) strongly depends on the PDOPAC and catechol content in the PEC NP. Furthermore, the type of loading and the net charge of the PEC NP affect LC and the residual content (RC) after release. Release experiments of PDOPAC/PEC coatings were performed at medically relevant bone substitute materials (calcium phosphate cement and titanium niobium alloy) whereby the DDS worked independently of the surface properties. Additionally, in contrast to electrostatically based drug loading the release behavior of covalently bound, uncharged BZM is independent of the ionic strength (salt content) in the release medium.

Keywords

• catechol
• DOPAC
• bortezomib
• multiple myeloma
• polyelectrolyte complex nanoparticle
• drug delivery