Sustained steroid release in pulmonary inflammation model Harry Karmouty-Quintana a , Faleh Tamimi b , Toby K. McGovern a , Liam M. Grover c , James G. Martin a , Jake E. Barralet b, * a Meakins-Christie Laboratories, McGill University, 3626 Rue St Urbain, Montreal, Quebec, H2X 2P2, Canada b Faculty of Dentistry, Strathcona Anatomy & Dentistry, McGill University, 3640 University Street Montreal, Montreal, Quebec H3A 2B2, Canada c The Department of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, UK article info Article history: Received 31 March 2010 Accepted 12 April 2010 Available online 15 May 2010 Keywords: Calcium pyrophosphate Microsphere Controlled-release Anti-inflammatory Inhalation drug delivery abstract There is a need for particles which exhibit controlled release of therapeutic agents delivered via the inhalational route, for tissue specific applications such as anti-cancer, bronchodilators and antiviral agents as well as drugs for systemic action. The aim of this study was to assess the acute toxicity, distribution and capacity of the microspheres to exhibit controlled release properties in an in vivo model of airway inflammation. Calcium pyrophosphate nanofibrous microspheres were loaded with dexa- methasone phosphate (Dex-P); the profile of drug release was studied in vitro and validated in vivo. Unloaded microspheres were administered intra-tracheally (i.t.) to rats to assess the tissue reaction. The anti-inflammatory properties of the Dex-P loaded microspheres against an inflammatory agent (compound 48/80), were evaluated in vivo. Unloaded microspheres did not cause an inflammatory response when given at doses below 3 mg, and appeared to be eliminated through mucus clearance mechanisms. Microspheres loaded with Dex-P but not Dex-P alone, were capable of inhibiting eosinophil and total inflammatory cell increases in bronchoalveolar lavage fluid for 42 h following a single appli- cation. These observations demonstrated that calcium pyrophosphate nanofibrous microspheres dis- played in vivo controlled release properties, were well tolerated and did not accumulate in the lung. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Therapeutic agents are frequently delivered by inhalation, in particular for respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). However, to date, there are no controlled release inhalation systems available clinically [1]. Treatments for asthma, COPD, cancer, infectious disease or for systemic action would benefit from improvements in inhalation controlled release systems [1,2]. The treatment of chronic asthma often relies on the delivery by inhalation of corticosteroids comparable to dexamethasone [3,4]. In addition to the potential advantages in some settings of reduction of dose cycling, sustained release is important because it reduces the dose required, improves biological efficacy, requires less patient compliance and is less irritating to the bronchial tissues [5]. For example asthma is worse at night because endogenous anti-inflammatory mechanisms are least effective at this time [6,7]. However, most patients do not comply with four times or even twice daily dosing [8,9] and the ability to achieve sustained release for up to 12 h and beyond may be an important step forward in improving efficacy of several lung disease therapies. The use of aerosolised or dry powder inhalation therapy for asthma is common. The particle size is an important determinant of its site of deposition within the respiratory tree. However, the micronisation of drug particles often leads to large distribution in particle size, alteration of surface properties and renders the particles more cohesive leading to poor aerosolisation [10,11]. Furthermore, the use of lactose as a drug carrier and bulking agent for many drug formulations [11] can lead to poor inhalation performance [12]. Although used in many drug formulations, lactose is known to react with formoterol (a long-acting broncho- dilator used in asthma), peptides and proteins [13]. Aerosolisation of particles is often difficult as it is necessary to dissolve them in a suitable vehicle, a growing problem concerning large organic molecular entities, monoclonal antibodies and silencing RNA approaches [11,14]. Thus inert vehicles for the controlled release of medication aimed at treating respiratory conditions are of great interest to the field. In this study we used an experimental model of lung inflammation induced by compound 48/80, a condensation product of N-methyl-p-methoxyphenethylamine with formalde- hyde. It is a basic secretagogue that causes mast cell degranulation * Corresponding author. E-mail address: Jake.barralet@mcgill.ca (J.E. Barralet). Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials 0142-9612/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2010.04.025 Biomaterials 31 (2010) 6050e6059