Dual drug-loaded porous silicon particles to provide controlled drug release for chronic retinal diseases

Abstract

Purpose : Most chorioretinal eye diseases are difficult to treat due to their chronic course and repeated occurrences. In addition, the pathophysiology is often multifaceted and combination therapy is necessary. The current study aims to load two therapeutic small molecules onto the same micron-sized porous silicon (pSi) particle which allows the simultaneous controlled release of two drugs once the system is delivered to the disease site.

Methods : pSi particles were fabricated by electrochemical etching of a silicon substrate. The resultant micro-sized pSi particles are imparted with nanometer scaled pores for drug loading. After thermal oxidation (800°C for 2 hours), the particles were grafted with amines via a reaction with aminopropyltriethoxysilane. Subsequently, carboxylic acid was introduced to the NH₂ groups through a reaction with succinic anhydride. Daunorubicin and dexamethasone were covalently loaded onto the pSi pore surface by binding to COOH/NH2 or COOH/OH. The dual drug-loaded pSi particles were subjected to thermogravimetric analysis (TGA) for determination of drug loading before a release study. The daunorubicin and dexamethasone in vitro release levels were quantitated by HPLC/MS/MS.

Results : The fabricated pSi particles had a size distribution between 20 µm and 40 µm, and a pore size distribution between 10 and 15 nm. TGA revealed that the loading rate was 5% for dexamethasone and 4% for daunorubicin by weight. The in vitro release demonstrated a sustained release of both drugs simultaneously for over 2 months at therapeutic concentrations (Fig1). The pharmacokinetic analysis demonstrated that half-life for Dex was 6.2 days and 26.6 days for DNR, otherwise the half-life of these small molecules is within a few hours. The ratio of Dex to DNR was linearly decay over the time course though Dex concentration was constantly higher.

Conclusions : It is feasible to load two drugs into properly functionalized pSi particles for controlled release and synergistic pharmacological effect. This system may be very useful to treat chronic chorioretinal diseases.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

Fig.1. Dexamethasone (Dex) and Daunorubicin (DNR) loaded porous silicon particles In Vitro release curves. The left Y axis is for DNR and the right Y axis is for Dex.