Dexamethasone-loaded TiO2 nanoparticles to locally target wear-debris induced inflammation

Abstract

Event Abstract Back to Event Dexamethasone-loaded TiO2 nanoparticles to locally target wear-debris induced inflammation Melissa Rodrigues1, Stefano D. Perni1, 2, Alastair Sloan3 and Polina D. Prokopovich1, 2 1 Cardiff University, Pharmacy, United Kingdom 2 Massachusetts Institute of Technology,, Department of Biological Engineering, United States 3 Cardiff University, Dentistry School, United Kingdom Introduction: Like other parts of the body, joints become damaged or weakened by age, accidents or disease; joint degenerative diseases such arthritis affect the quality of life of millions worldwide.One of the ways to help such people is to have artificial joint replacement, although considered a successful procedure, these implants generate a large number of particles as result of wear with time/age. Such released particles, wear-debris, can compromise survival of joint implants by triggering an adverse inflammatory-response, which can lead to periprosthetic bone-loss, so called osteolysis[5]. During last decades, aseptic loosening due to osteolysis has been considered one of the most common causes for revision surgery[6]. Therefore the present project aims to develop an anti-inflammatory drug-eluting implant model system to prevent aseptic loosening following wear-induced osteolysis. Materials and Methods: Dexamethasone-loaded functionalized TiO2 nanoparticles were synthesized by covalently conjugating dexamethasone to carboxylic acid-amino functionalized nanoparticles. The functionalization of TiO2 nanoparticles was assessed by means of zeta potential measurements and thermogravimetric-analysis (TGA). Whilst dexamethasone release from TiO2 nanoparticles was quantified as function of time and pH using high-performance-liquid chromatography. Results and Discussion: The zeta potential measurements (Figure 1) show a more positive surface charge after amino-functionalization of TiO2 particles when compared to bare-TiO2. In contrast a more negative charge is observed after carboxyl and dexamethasone functionalization. As previously indicated in other studies, this is an indirect evidence showing that amino[2], carboxyl-acid groups[1], and dexamethasone[4] were successfully conjugated to TiO2-nanoparticles. Furthermore, TGA profile (Figure 2) shows an increase weight-loss after each step of functionalization. These results are related to an increase of organic material after each step of functionalization, thus confirming the successful attachment of functional groups and dexamethasone on the surface of TiO2-nanoparticles. After 24h, dexamethasone release from the functionalized-nanoparticles was suppressed at pH 7.0, 6.0 and 5.0; whilst at pH 4.0, a constant daily release of dexamethasone (10µg/mL) was observed over a period of 6 days (Figure 3). The results suggest that functionalized nanoparticles may remain stable and release more dexamethasone under acidic inflammatory conditions (pH=4)[3],[7] . Conclusions: Despite being one the most common complication after total joint replacement, there is no approved therapy to avoid aseptic-loosening following wear-induced osteolysis. Our study indicated that dexamethasone was successfully attached to TiO2 nanoparticles, with the advantage that the chemistry utilized could be applicable to conjugate other anti-inflammatory drugs. Furthermore, being controlled and constant drug release one of the most important features to modulate inflammation, dexamethasone-loaded-nanoparticles appears to be a potential approach to overcome the several limitations of current anti-osteolytic therapies e.g. lack of efficacy, systemic side-effects. Therefore more studies i.e. in vitro assessment of the anti-inflammatory effect are currently being performed by our research group to confirm safety and efficacy of drug-eluting-implant model system developed. Arthritis Research UK