(632a) 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.