Gold Nanoparticles as a Versatile Platform for Optimizing Physicochemical Parameters for Targeted Drug Delivery Jamie M. Bergen, a Horst A. von Recum, a,b Thomas T. Goodman, Archna P. Massey, Suzie H. Pun* Department of Bioengineering, University of Washington, Seattle, WA 98195, USA Fax: þ1 206-616-3928; E-mail: spun@u.washington.edu Received: March 28, 2006; Revised: May 9, 2006; Accepted: May 11, 2006; DOI: 10.1002/mabi.200600075 Keywords: drug delivery systems; gold colloids; liver; nanoparticles; targeting Introduction The ability of nanoparticulate drug carriers to target specific tissues and cell types is critical for efficient and effective drug delivery. A common approach for targeted delivery is active tissue targeting, where a ligand that recognizes a specific cell receptor is displayed on the delivery vehicle. A second approach, passive targeting, relies on the accumula- tion of drug carriers in target tissues due to nonspecific effects related to the physicochemical characteristics of the carrier. Therefore, in addition to the effect of displayed targeting ligands, the physicochemical properties of nanoparticles are major factors in the characteristic biodistribution and resi- dence times of these entities in vivo. [1,2] For example, extravasation of nanoparticles from the circulatory system is highly dependent on particle size; [3,4] particles smaller than 200 nm readily leave the liver sinusoids through fenestrations in the endothelial cell lining. [5] In cancer delivery applica- tions, tumors frequently have leaky blood vessels that allow nonspecific accumulation of certain sizes of nanoparticles in the tumor tissue. [6] Other physicochemical properties such as surface charge, [7,8] PEGylation (surface modification with polyethylene glycol as a particle stabilizer), [9] and hydro- phobicity [10] also impact nonspecific uptake and potential degradation in macrophage cells, which is generally undesir- able. The design of nanoparticles for any application of targeted delivery via systemic administration thus needs to take these factors into account. Ideally, the physicochemical properties of ligand-conjugated nanoparticles might be tailored to allow them to overcome relevant physiological transport barriers associated with delivery to the tissue of interest, thus combining the effects of both active and passive targeting to specific cells in the body. Elucidating the optimal physicochemical properties is a critical step in the design of targeted nanoparticulate drug delivery vehicles. Summary: The development of targeted vehicles for systemic drug delivery relies on optimizing both the cell-targeting ligand and the physicochemical characteristics of the nanoparticle carrier. A versatile platform based on modification of gold nanoparticles with thiolated polymers is presented in which design parameters can be varied independently and systemati- cally. Nanoparticle formulations of varying particle size, surface charge, surface hydrophilicity, and galactose ligand density were prepared by conjugation of PEG-thiol and galactose- PEG-thiol to gold colloids. This platform was applied to screen for nanoparticle formulations that demonstrate hepatocyte- targeted delivery in vivo. Nanoparticle size and the presence of galactose ligands were found to significantly impact the targeting efficiency. Thus, this platform can be readily applied to determine design parameters for targeted drug delivery systems. Modified gold nanoparticles are a suitable model for nano- particle-based gene carriers. Macromol. Biosci. 2006, 6, 506–516 ß 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 506 DOI: 10.1002/mabi.200600075 Full Paper a Equally contributing authors. b Current address: Biomedical Engineering, Case Western University, Cleveland, OH.