pH-responsive Release of Chlorhexidine
Objectives: Stimuli-responsive drug release provides on-demand drug activity locally, thus avoiding systemic antibiotics and potentially reducing antibiotic resistance. The objective of this study is to develop pH-responsive drug-delivery systems which release chlorhexidine in response to the pH-variation in oral environments.
Methods: Lab-synthesized meso-porous silica nanoparticles (MSN) were surface functionalized and used as carriers for chlorhexidine (CHX). The MSN was surface functionalized with Azo-quaternary pyridinium salt (Azo-QPS) through silanization and Menshutkin reaction, sequentially, and produced Azo-MSN. CHX was chemically bound onto Azo-MSN through a stoichiometrically controlled acid-base reaction and produced Azo-MSN-CHX. Each functionalization step and CHX loading were confirmed using FTIR and X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA) and electron microscopies (EM). The pH-responsive release kinetics were investigated in buffers at four pH values (pH = 4.1, 5.8, 7.0 or 7.9) by studying the temporal concentration changes using UV-vis spectroscopy. In addition, the interaction between CHX and Azo-QPS in solutions was characterized using nuclear magnetic resonance (NMR), dynamic light scattering (DLS) and small angle neutron scattering (SANS).
Results: The lab-synthesized MSN has an average particle diameter of 150nm±30nm (by EM and DLS), surface area of 1150±20m2/g and pore diameter of 3.1±0.2nm (by N2 adsorption). The successful surface functionalization and CHX loading were confirmed by XPS and FTIR and quantified by TGA. The CHX release was acid-enhanced: There was no release at pH above 7.0; and the release rate increased when the buffers became more acidic (from pH=5.8 to pH=4.1). NMR, DLS and SANS results indicated that the interaction between CHX and Azo-QPS compounds produced stable complexes of CHX and Azo-QPS.
Conclusions: pH-responsive CHX-release within a clinically-relevant pH range was achieved. The methods and the materials developed are also useful in drug delivery for targeted treatment of bacteria or diseases which produce acid or generate local acidic environments.