Transepithelial Transport of Biodegradable Polyester Dendrimers Across Model Lung Epithelia and Their Aerosol Formulation

Transepithelial Transport of Biodegradable Polyester Dendrimers

Across Model Lung Epithelia and their Aerosol Formulation

Rodrigo S. Heyder^1,2, Reinaldo C. Bazito², and Sandro R.P. da Rocha¹

¹Department of Chemical Engineering and Materials Science, Wayne State University, Detroit MI, 48202

²Institute of Chemistry, Department of Chemistry, University of São Paulo, São Paulo, SP, Brazil, 05508-000

Oral inhalation (OI) is not only the preferred mode of administration of therapeutics intended for the regional delivery to the lungs, but it has also been recognized as a promising route for the non-invasive delivery of drugs through the lungs, as suggested by the many ongoing clinical trials of OI formulations dealing with therapeutics intended for systemic circulation.  Some of the potential advantages of the OI route include the large surface area, low proteolytic activity, and the thin cellular barrier of the lung tissue, which may be explored to enhance drug bioavailability and transport to the bloodstream.  Polymeric nanocarriers (PNCs), in special dendrimer nanocarriers (DNCs), may be successfully explored in combination with OI formulations for the controlled and targeted local delivery of therapeutics to the lung tissue, and to modulate the transport of drugs across the airway epithelia. Such advancements hold great promise in the delivery of both small molecules and biomacromolecules for the treatment of medically relevant diseases of the lung tissue and systemic ailments alike. Pressurized metered-dose inhalers (pMDIs) are important devices within the context of drug delivery to the lungs as they are the least expensive and most widely used OI devices.  pMDIs are portable, have long shelf life, are reliable, and can be used even in patients with compromised lung function as they are propellant based.

In this work, biodegradable (polyester) dendrimers of generation 3 and 4, and their PEGylated grafts are synthesized and characterized.  The impact of the dendrimer generation and chemistry on their transport across the lung epithelium, their cellular internalization, their degradation profile in vitro, and their formulation in pMDIs will be discussed.  The materials show very low cytotoxicity, and engineering technologies allow us to formulate these carriers in pMDIs having aerosols with excellent deep lung deposition profiles.  The transport of surface-modified dendrimers across polarized epithelial monolayers is seen to be dependent on their surface functionalization.  Polyester-based dendrimers are thus shown as potential carriers for the local and systemic delivery of therapeutics via OI, and can serve as attractive alternatives to non-degradable hyperbranched/dendrimeric polymers.

Key words: Polyester dendrimer, biodegradable, PEGylation, pressurized metered-dose inhalers (pMDI), drug delivery, transport modulation, non-invasive lung delivery.