title: Inhalable, bioresponsive microparticles for targeted drug delivery in the lungs.
abstract: OBJECTIVE
  There is a growing interest in developing bioresponsive drug delivery systems to achieve greater control over drug release than can be achieved with the conventional diffusion controlled polymeric delivery systems. While a number of such systems have been studied for oral or parenteral delivery, little or no work has been done on bioresponsive delivery systems for inhalation. Using the raised elastase levels present at sites of lung inflammation as a proof-of-concept model, we endeavoured to develop a prototype of inhalable elastase sensitive microparticles (ESMs).
  
  
  METHODS
  Microparticles degradable by the enzyme elastase were formed by crosslinking the polymer alginate in the presence of an elastase substrate, elastin, using Ca(+2) ions and subsequent spray drying.
  
  
  RESULTS
  The bioresponsive release of a protein cargo in the presence of elastase demonstrated the enzyme-specific degradability of the particles. The microparticles showed favorable properties such as high drug encapsulation and good powder dispersibility. Potential polymer toxicity in the lungs was assessed by impinging the microparticles on Calu-3 cell monolayers and assessing changes in transepithelial permeability and induction of cytokine release. The microparticles displayed no toxic or immunogenic effects.
  
  
  CONCLUSIONS
  With a manufacturing method that is amenable to scale-up, the ability to be aerosolised efficiently from a first-generation inhaler device, enzyme-specific degradability and lack of toxicity, the ESMs show significant promise as pulmonary drug carriers.
authors.affiliation: School of Pharmacy, Royal College of Surgeons in Ireland, York House, Dublin, Ireland.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Sivadas
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Cryan
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000336:Aerosols; D000464:Alginates / Q000737:chemistry; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D004549:Elastin / Q000737:chemistry*; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D020723:Glucuronic Acid / Q000737:chemistry; D006415:Hematoporphyrins; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D019272:Leukocyte Elastase; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008863:Microspheres; D008954:Models, Biological; D010316:Particle Size; D012710:Serum Albumin, Bovine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
chemical_list: D000336:Aerosols; D000464:Alginates; D006415:Hematoporphyrins; D006603:Hexuronic Acids; C039217:fluorescein isothiocyanate bovine serum albumin; C091193:haematoporphyrin-bovine serum albumin conjugate; D012710:Serum Albumin, Bovine; D020723:Glucuronic Acid; D004549:Elastin; D019272:Leukocyte Elastase; D016650:Fluorescein-5-isothiocyanate