Absorption of Polyethylene Glycol (PEG) Polymers: The Effect of PEG Size on Permeability HEMA GURSAHANI, JENNIFER RIGGS-SAUTHIER, JUERGEN PFEIFFER, DAVID LECHUGA-BALLESTEROS, C. SIMONE FISHBURN Nektar Therapeutics, 201 Industrial Road, San Carlos, California 94070 Received 14 July 2008; accepted 20 October 2008 Published online 30 April 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21635 ABSTRACT: Polyethylene glycol (PEG) polymers are large amphiphilic molecules that are highly hydrated in solution. To explore the permeability properties of different sized PEG polymers across epithelial membranes in vivo, we examined the absorption of fluorescently labeled PEG conjugates sized 0.55–20 kDa from the lung, since this system provides a reservoir that limits rapid diffusion of molecules away from the site of delivery and enables permeability over longer times to be examined. Following intratracheal delivery in rats, the PEG polymers underwent absorption with first-order kinetics described by single exponential decay curves. PEG size produced a marked influence on the rate of uptake from the lung, with half-lives ranging from 2.4 to 13 h, although above a size of 5 kDa, no further change in rate was observed. PEG size likewise affected retention in alveolar macrophages and in lung tissue; whereas smaller PEG sizes (<2 kDa) were effectively cleared within 48 h, larger PEG sizes (>5 kDa) remained in lung cells and tissue for up to 7 days. These data demonstrate that PEG polymers can be absorbed across epithelial membranes and that PEG size plays a dominant role in controlling the rate and mechanism of absorption. ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2847–2856, 2009 Keywords: absorption; epithelial; delivery/permeability; pegylation; passive; diffusion/transport; permeability; pharamcokinetics; polymers INTRODUCTION Polyethylene glycol (PEG) conjugation to drugs provides an effective strategy for improving their therapeutic activity by altering the molecules’ physicochemical and biological properties. 1,2 PEG polymers are amphiphilic, highly hydrated, and flexible in solution, and serve to increase the solubility of conjugated drugs. 3 These polydis- perse polymers are composed of repeating ethy- lene glycol units, which associate in solution with approximately two water molecules per ethylene glycol unit, resulting in an effective overall molecular size that is 5–10 times greater than that of proteins or other macromolecules of similar molecular weight. 2 As a consequence of their high hydrophilicity and large molecular size, PEG poly- mers do not diffuse readily across lipid bilayers, and their absorption across epithelia is thought to occur via passive transport through the paracellular route. 4 Absorption of PEG has previously been exam- ined in the size range 0.6–2 kDa across the gastrointestinal and nasal epithelia. In both cases, size-dependent absorption was observed with little difference in the amount absorbed between PEG chains of 1 and 2 kDa in size. 5 The pulmonary epithelium displays different perme- ability characteristics from the GI epithelium 6 David Lechuga-Ballesteros’s present address is Aridis Phar- maceuticals, 5941 Optical Court, San Jose, CA 95138. Correspondence to: C. Simone Fishburn (Telephone: 650- 631-3482; Fax: 650-631-3150; E-mail: sfishburn@nektar.com) Journal of Pharmaceutical Sciences, Vol. 98, 2847–2856 (2009) ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 8, AUGUST 2009 2847