Polymeric nanoparticles hold tremendous potential in medicine, especially if modes of biofunctionality can be incorporated into them. Such biofunctionality could include sensitivity to particular biological environmental signals (here, oxidative environments, reductive environments), targeting capacities (here, targeting of the lymph nodes and dendritic cells therein), and binding capacity (here, binding to cartilage). We present novel chemical schemes by which to achieve such biofunctionality in polymer systems with watery cores for delivery of bioactive macromolecules and with hydrophobic cores for delivery of low molecular weight hydrophobic drugs. Our laboratory has recently described a novel family of AB and ABA block copolymeric amphiphiles that are capable of forming micelles and vesicles (1, 2). As a hydrophilic block, we employ polyethylene glycol (PEG), because of its well known toxicological profile and its well defined and low polydispersity. As a hydrophobic block, we have selected polypropylene sulfide (PPS), a low Tg polymer that can be synthesized by a ring opening polymerization also with low polydispersity (3). In previous work, we have demonstrated that these polymers form mesoscopic aggregates that are sensitive to oxidative environments, as might be found in inflammatory sites: for example, vesicles that are stable under non-oxidative conditions rapidly transition under oxidative conditions to cylindrical micelles and then to spherical micelles and unimers (2). In current work, we are seeking to render these same structures sensitive to reduction, to allow destabilization of vesicles within the early endosome after endocytosis. To accomplish this, we have synthesized block copolymers with disulfide linkages between the hydrophobic PPS and hydrophilic PEG blocks. When exposed to cysteine levels that are encountered within the endosome, these vesicles are rapidly destabilized, and when endocytosed, the contents of the reduction-sensitive vesicles are rapidly released. Our laboratory has also recently described an emulsion polymerization process by which to form very small (20 – 200 nm) crosslinked PPS nanoparticles, and we have demonstrated that these rubbery-core nanoparticles are useful in carrying hydrophobic drugs (4, 5). We are seeking to employ these nanoparticles to target the lymph notes for delivery of antigen to intranodal dendritic cells, a potentially more powerful immunization strategy than delivery to Langerhans cells in resident in the skin. The size nanoparticles is key in this biofunctionality (6). When injected into the dermal interstitium, nanoparticles of diameter 100 nm remain substantially entrapped within the interstitial matrix and find their way into lymphatic capillaries poorly, whereas much smaller 20 nm PPS nanoparticles are rapidly swept into the lymphatic capillary network under the interstitial convection that exists between the blood and lymphatic capillary systems. When in the lymph nodes, these nanoparticles are phagocytosed by dendritic cells resident within the nodes, and these dendritic cells become activated. Thus, these particles may be useful for antigen delivery. We are also developing chemistries by which to functionalize the nanoparticle surfaces with danger signals for specific dendritic cell activation. Finally, we are developing schemes by which to provide specific biofunctionality for tissue binding. As an example, we are employing peptide-on-phage ligand discovery approaches to seek novel peptide ligands that bind to the surface of cartilage; such ligands would be useful for biofunctionalization of polymeric micelles and nanoparticles for injection within the joint capsule for treatment of osteoarthritis, for example. References: 1. S. Cerritelli et al., Macromolecules 38, 7845 (2005). 2. A. Napoli, M. Valentini, N. Tirelli, M. Muller, J. A. Hubbell, Nature Materials 3, 183 (2004). 3. A. Napoli, N. Tirelli, G. Kilcher, J. A. Hubbell, Macromolecules 34, 8913 (2001). 4. A. Rehor, J. A. Hubbell, N. Tirelli, Langmuir 21, 411 (2005). 5. A. Rehor, N. Tirelli, J. A. Hubbell, Macromolecules 35, 8688 (2002). 6. S. T. Reddy, A. Rehor, H. G. Schmoekel, J. A. Hubbell, M. A. Swartz, J Controlled Release 112, 26 (2006).