Drug Delivery DOI: 10.1002/ange.201001065 Probing the Kinetics of Short-Distance Drug Release from Nanocarriers to Nanoacceptors** Hong Wang, Jun Xu, Jinghao Wang, Tao Chen, Yong Wang, YanWen Tan, Haibin Su, Khai Leok Chan, and Hongyu Chen* Targeted delivery and controlled release of a drug to specific organs or cells would potentially maximize its therapeutic efficacy while minimizing the side effects. This is of particular importance for insoluble drugs, as there is a lack of means to transport them in a biological system. Many insoluble drug candidates failed clinical trials because of poor pharmacoki- netics. With an effective delivery system, these drugs could be reexplored to unleash their potential. So far, a variety of micro- and nanoscale materials have been developed as drug carriers. [1] Of paramount significance for biological applica- tion is an understanding of the pathway and the rate of drug release from these new materials. A model system for the study of kinetics entails the delivery of a model drug, typically an organic dye, from a carrier to an acceptor through a solvent. In contrast to the focus on nanocarriers, though, few systems in the literature included nanoscale acceptors to model biological acceptors such as proteins and lipid membranes. A practical concern is the lack of means to distinguish the drug molecules in carriers from those in acceptors. Dialysis-based methods separated nanocarriers from water by a semipermeable membrane, so the drug content on each side could be analyzed by methods such as UV/Vis spectroscopy, [2] fluorescence, [3] or chromatog- raphy. [4] Alternatively, a bulk organic phase was used to extract the released drug in water away from the nano- carriers. [5] In these examples, the released drug molecules have to diffuse through a bulk phase (water and/or an organic solvent) before being characterized. In a different approach, paramagnetic ions (Tl + ) [5d] were used to quench the fluores- cence of released drug, and Au nanoparticles (NPs) were used as quenchers for the loaded drugs in nanocarriers. [5c] Thus, the fluorescence change of the model drugs in the different media (solvent versus carriers) allowed real-time monitoring of the drug release without disrupting the delivery system. For drug release in a cellular environment, the nano- carriers would be intimately mixed with the nanoscale bioacceptors. Hence, short-distance diffusion (ca. 1 mm) would dominate, and the use of bulk-phase acceptors could not fully mimic this process. Recently, an enlightening work by Chen et al. used dual-labeled polymer micelles as nano- carriers, [6] so that the drug release could be studied in the presence of nanoacceptors. Herein, we report a new model delivery system, in which pyrene was incorporated in the polymer shells of AuNPs and then released to nanoacceptors (Figure 1). The fluorescence of pyrene was quenched in the vicinity of the AuNPs but reemerged upon its release, thus allowing in situ kinetics study by optical measurements. To mimic cell components, bovine serum albumin (BSA), l-a-phosphatidylcholine (a phospho- lipid) micelles, sodium dodecyl sulfate (SDS) micelles, and polystyrene-block-poly(acrylic acid) (PSPAA) micelles were used as nanoacceptors. The intimate mixing of the nano- carriers with the nanoacceptors creates a realistic model for Figure 1. A new kinetics model for drug release. a) Release of pyrene from the polymer shells of AuNPs: in the absence of nanoacceptors, the system quickly reaches equilibrium without significant material transfer; in the presence of excess free PSPAA micelles, the short- distance transfer of pyrene is fast. b,c) Transmission electron micros- copy (TEM) images of pyrene-loaded AuNP@PSPAA (b) and free PSPAA micelles (c). [*] H. Wang, J. Xu, T. Chen, Y. Wang, Y.W. Tan, Prof. H. Chen Division of Chemistry and Biological Chemistry Nanyang Technological University 21 Nanyang Link, Singapore 637371 (Singapore) Fax: (+ 65) 6791-1961 E-mail: hongyuchen@ntu.edu.sg Homepage: http://www.ntu.edu.sg/home/hongyuchen/ J. Wang, Prof. H. Su School of Materials Science and Engineering Nanyang Technological University, Singapore 639798 (Singapore) Dr. K. L. Chan Institute of Materials Research and Engineering (IMRE) and the Agency for Science, Technology, and Research (A*STAR) Singapore 117602 (Singapore) [**] We thank the Ministry of Education, Singapore (ARC 13/09) for financial support. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201001065. Zuschriften 8604  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2010, 122, 8604 –8608