Mold-Templated Inorganic−Organic Hybrid Supraparticles for Codelivery of Drugs James W. Maina, †,‡ Jiwei Cui, †,‡ Mattias Bjö rnmalm, †,‡ Andrew K. Wise, §,∥,⊥ Robert K. Shepherd, §,∥,⊥ and Frank Caruso* ,†,‡ † ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, ‡ Department of Chemical and Biomolecular Engineering, § Department of Otolaryngology, and ∥ Department of Medical Bionics, The University of Melbourne, Parkville, Victoria 3010, Australia ⊥ Bionics Institute, East Melbourne, Victoria 3002, Australia * S Supporting Information ABSTRACT: This paper reports a facile and robust mold- templated technique for the assembly of mesoporous silica (MS) supraparticles and demonstrates their potential as vehicles for codelivery of brain-derived neurotrophic factor (BDNF) and dexamethasone (DEX). The MS supraparticles are assembled using gelatin as a biodegradable adhesive to bind and cross-link the particles. Microfabricated molds made of polydimethylsiloxane are used to control the size and shape of the supraparticles. The obtained mesoporous silica-gelatin hybrid supraparticles (MSG-SPs) are stable in water as well as in organic solvents, such as dimethyl sulfoxide, and efficiently coencapsulate both BDNF and DEX. The MSG-SPs also exhibit sustained release kinetics in simulated physiological conditions (>30 days), making them potential candidates for long-term delivery of therapeutics to the inner ear. ■ INTRODUCTION Inner ear ailments, such as sensorineural hearing loss and Mé niè re’s disease, are common health issues that affect a large number of people at all ages. 1−3 Many of these diseases are difficult to treat, as the inner ear is secluded from systemic blood circulation by a cochlea−blood barrier, limiting the access of systemically administered therapeutics. 4,5 Macro-, micro-, and nanoscale drug delivery systems can provide new and improved ways of treating diseases, including facilitating the spatiotemporal codelivery of therapeutics. 6−8 To improve the treatment efficacy of inner ear drugs, several local drug delivery techniques have been developed. Intratympanic delivery relies on the permeability of the round window membrane (RWM) in the middle ear, where therapeutic agents are deposited using delivery vehicles such as hydrogels, nanoparticles, or mini osmotic pumps to slowly diffuse into the inner ear. 9−11 However, drugs with limited diffusion capacity, such as neurotrophins, are more effective when placed directly into the intracochlear fluid inside the inner ear (intracochlear delivery) through an incision on the RWM or a perforation on the cochlear bony wall. 4 This mode of delivery, however, presents new sets of safety challenges. 12−15 Intra- cochlear delivery using mini osmotic pumps, for example, shows improved efficacy in animal models, but may be challenging to translate to the clinic, as it can promote bacterial infection in the inner ear. 12 The use of smaller carriers, such as nanoparticles or viral vectors, also risk delivering the medication to unintended sites, such as the brain, as they can be transported through the cochlear aqueduct. 13−15 Carriers providing longer-term release of therapeutics that are large enough to reduce these safety issues, yet small enough to enable local release, are therefore of considerable interest. Recently, we reported a new class of mesoporous silica based supraparticles (MS-SPs) as effective vehicles for the sustained delivery of brain-derived neurotrophic factor (BDNF) to the inner ear. 16 The particles were prepared by confining mesoporous silica particles in small droplets followed by drying under airflow and calcination at 823 K for 6 h. Compared to smaller micrometer- or nanometer-sized particles, the ∼800 μm sized supraparticles are less likely to be carried to the brain where the drug may have unwanted side effects. The particles also had a high loading capacity for BDNF and exhibited long- term release profiles, which resulted in enhanced neural protection upon implantation in the cochlea of a guinea pig, thus demonstrating that therapeutically relevant doses of functional BDNF can be delivered using supraparticles. However, the supraparticle preparation technique is time- consuming, and the manual production process poses challenges in achieving monodisperse MS-SPs. Increasing throughput and reproducibility, as well as facilitating coencapsulation of diverse biomolecules, are therefore key challenges for advancing this technique. Several new methods, Received: August 10, 2014 Revised: September 22, 2014 Published: October 16, 2014 Article pubs.acs.org/Biomac © 2014 American Chemical Society 4146 dx.doi.org/10.1021/bm501171j | Biomacromolecules 2014, 15, 4146−4151