Therapeutic aerosol bioengineering of targeted, inhalable microparticle formulations to treat Mycobacterium tuberculosis (MTb) C. Lawlor • M. P. O’Sullivan • B. Rice • P. Dillon • P. J. Gallagher • S. O’Leary • S. Shoyele • J. Keane • S.-A. Cryan Received: 4 August 2011 / Accepted: 30 November 2011 / Published online: 20 December 2011 Ó Springer Science+Business Media, LLC 2011 Abstract Therapeutic aerosol bioengineering (TAB) of Mycobacterium tuberculosis (MTb) therapies using inha- lable microparticles offers a unique opportunity to target drugs to the site of infection in the alveolar macrophages, thereby increasing dosing in the lungs and limiting sys- temic exposure to often toxic drugs. Previous work by us used sophisticated, high content analysis to design the optimal poly(lactide-co-glycolic) acid (PLGA) micropar- ticle for delivery of drugs to alveolar macrophages. Herein, we applied this technology to three different anti-MTb drugs. These formulations were then tested for encapsula- tion efficiency, drug-release, in vitro killing against MTb and aerosol performance. Methods for encapsulating each of the drugs in the PLGA microparticles were successfully developed and found to be capable of controlling the release of the drug for up to 4 days. The efficacy of each of the encapsulated anti-MTb drugs was maintained and in some cases enhanced post-encapsulation. A method of processing these drug-loaded microparticles for inhalation using standard dry powder inhaler devices was successfully developed that enabled a very high respirable dose of the drug to be delivered from a simple dry powder inhaler device. Overall, TAB offers unique opportunities to more effectively treat MTb with many potential clinical and economic benefits resulting. 1 Introduction Mycobacterium tuberculosis (MTb) is primarily a pul- monary pathogen. Current treatment regimens are based on oral and parenteral drug therapy requiring a minimum of 6–9 months for successful treatment. Traditional oral for- mulations are associated with a high risk of adverse drug reactions occurring. By localising therapy to the lungs via aerosol to target the site of MTb infection in the alveolar macrophage the occurrence of these adverse events can be diminished/eliminated and patient dosing requirements reduced [1–3]. Aerosol delivery maximises deposition and targeting of drugs at the site of infection. It is unlikely that pulmonary formulations will replace oral formulations in anti-tubercular therapy completely. However, pulmonary formulations may act as an adjunctive therapy to reduce treatment duration leading to a more rapid sputum con- version. Additionally, it is extremely likely that drugs delivered directly to the lungs will achieve a higher con- centration within the lungs than drugs administered orally, which must pass through first-pass metabolism before they enter circulation and can reach the lungs. Recent pharma- cokinetic studies have shown that inhaled anti-Mtb for- mulations can achieve not only greater levels of concentrations in the lung than oral formulations but also have longer residence time [4, 5]. Microparticle delivery systems have garnered great interest since they were first proposed as a vehicle for localising anti-tubercular therapy to the lungs and control- ling drug release [3]. Therapeutic aerosol bioengineering C. Lawlor Á B. Rice Á P. Dillon Á P. J. Gallagher Á S.-A. Cryan (&) School of Pharmacy, Royal College of Surgeons in Ireland, Dublin 2, Ireland e-mail: scryan@rcsi.ie C. Lawlor Á M. P. O’Sullivan Á S. O’Leary Á J. Keane Institute of Molecular Medicine, Trinity College Health Science Building, St. James’ Hospital, Dublin 8, Ireland S. Shoyele Department of Pharmaceutical Sciences, School of Pharmacy, Thomas Jefferson University, Edison Building, 130 South 9th Street, Philadelphia, PA 19107-5233, USA 123 J Mater Sci: Mater Med (2012) 23:89–98 DOI 10.1007/s10856-011-4511-4