Cell Culture Models of the Respiratory Tract Relevant to Pulmonary Drug Delivery

Abstract

The respiratory tract holds promise as an alternative site of drug delivery due to fast absorption and rapid onset of drug action, with avoidance of hepatic and intestinal first-pass metabolism as an additional benefit compared to oral drug delivery. At present, the pharmaceutical industry increasingly relies on appropriate in vitro models for the faster evaluation of drug absorption and metabolism as an alternative to animal testing. This article reviews the various existing cell culture systems that may be applied as in vitro models of the human air-blood barrier, for instance, in order to enable the screening of large numbers of new drug candidates at low cost with high reliability and within a short time span. Apart from such screening, cell culture-based in vitro systems may also contribute to improve our understanding of the mechanisms of drug transport across such epithelial tissues, and the mechanisms of action how advanced drug carriers, such as nanoparticles or liposomes, can help to overcome these barriers. After all, the increasing use and acceptance of such in vitro models may lead to a significant acceleration of the drug development process by facilitating the progress into clinical studies and product registration.

A Compact and Portable Deposition Chamber to Study Nanoparticles in Air-Exposed Tissue

“…But an extensive use of animal models is hampered by ethical, technical, and economic reasons, and therefore in vitro techniques are strongly favored. A realistic experimental setup to assess aerosol particle-lung interactions and associated potential toxic effects with in vitro studies should include the following essential parts: (1) (nano)particles need to be deposited onto the cell cultures as real aerosol particles, i.e., from a continuous air flow at realistic particle concentrations, composition, and size; (2) cell cultures used to assess nanoparticle effects need to closely mimic the complex multicell structure of the human lungs (13,14) ; and (3) the exposure and deposition scenario should mimic the corresponding processes in the lungs as accurately as possible.…”

“…In addition, suspending particles in a solvent can substantially alter their chemical and physical properties compared with conditions where they are freely suspended in air. (13,14) We present here a new instrument, which aims to mimic (nano)particle deposition and interaction with lung cells in in vitro experiments as accurately as possible compared with conditions in the lung. A first version of our exposure system introduced the concept of electrostatic deposition of bipolarly charged aerosol particles onto lung cell cultures from a continuous air flow, which is much more efficient than diffusional deposition.…”

Nanomedicine in pulmonary delivery

“…[201][202][203][204][205] The cell lines used include A427, A549, HBE14o, and the Calu line (-1, -2, and -3). [205][206][207][208][209][210] These are immortal (continuous) cell lines and hence have different membrane structural features compared with mortal cell lines which influence drug absorption and efflux. For example, A549 cell line represents the alveolar type II pulmonary epithelial cell, and has been reported to be an ideal model to study the metabolic and macromolecule mechanisms of drug delivery at the alveolar pulmonary epithelium because the endocytic ability of the pulmonary epithelium and localization of cytochrome P450 systems is largely a function of type II pneumocytes.…”

The biological and ethical basis of the use of human embryonic stem cells for in vitro test systems or cell therapy

“…> 1000 Ωcm 2 (elbert et al, 1999). Many cell culture models of the respiratory tract have been developed for pulmonary drug delivery studies (for a review see Steimer et al, 2005) and our model might also be used for safety and efficacy aspects in pharmaceutical research, since immune cells have been included. However, when a high epithelial tightness is required, the A549 or 16HBe14o cells might need to be replaced by other epithelial cells, i.e.…”