Ease of synthesis, controllable sizes, and in vivo large-animal-lymph migration of polymeric nanoparticles.

Nanoparticles (NPs) are finding ever-increasing uses in a wide range of fields including photonics, catalysis and medicine, and identification of new compositions and synthetic methods is key to the continued discoveries with these materials. Within the medical arena, NPs are being investigated for drug delivery and medical imaging applications. Our efforts are focused on exploring synthetic procedures that will enable a greater diversity of polymer compositions, encapsulants and sizes, and thus greater resultant NP utility. We recently reported the preparation of responsive NPs from an acrylate monomer for the triggered release of paclitaxel. Here we further expand upon this synthetic approach and the use of two free-radical polymerization initiation methods. Both of these mild, roomtemperature reactions allow for a range of monomers to be used and for control of particle size. As our interest lies in the diagnosis and treatment of lung cancer at its various stages, including metastases, we evaluated these NPs for lymphatic migration in a large animal. NPs were prepared using a miniemulsion polymerization technique, which combines high-energy emulsification and free-radical polymerization of an acrylate monomer and crosslinker. This is in contrast to the more common solvent evaporation method for synthesizing NPs (e.g. , poly(lactic acidglycolic acid) NPs), which uses a previously synthesized polymer. Both photoinduced and base-catalyzed reactions were explored to initiate the free-radical polymerization. Specifically, NPs were prepared from monomers 1–5. The monomers were synthesized in good to high yields (59–88%) by reacting the primary hydroxy, secondary hydroxy or primary amine with methacryloyl chloride or methacrylic anhydride. The complete synthetic protocols can be found in the Supporting Information. These structures are representative of the diverse range of monomers that can be designed, synthesized and used to prepare NPs with specific properties, including those monomers based on a carbohydrate (glycerol), an amino acid (serine), and a fluorescent dye (coumarin). This NP procedure is also amenable to working with a variety of common chemical linkages, such as esters, amides, ethers, carbamates and acetals, which are present in our monomers. To prepare the NPs, the monomer (1–5) and a crosslinker (1,4-O-methacryloylhydroquinone, 6) were dissolved in a small amount of dichloromethane. The miniemulsion was formed by adding this organic solution to an aqueous solution of the surfactant sodium dodecyl sulfate (SDS) and sonicating the mixture under an argon blanket (Figure 1). Next, the free-radicalinitiation system was added. When using the photochemical initiation method, eosin Y dye, 1-vinyl-2-pyrrolidinone, and triethanolamine were added to the emulsion, followed by irradiation under a xenon arc lamp. When using the base-catalyzed reaction, ammonium persulfate (APS) and N,N,N’,N’-tetramethylethylenediamine (TEMED) were added to the emulsion while stirring under an argon blanket. Both initiation methods allow polymerization to be carried out under mild conditions at room temperature. The base-catalyzed initiation method also allows particles to be synthesized in the absence of light—critical when working with photosensitive monomers or encapsulants. Following polymerization using either method, the resultant NP suspensions were stirred overnight while open to the atmosphere to allow the remaining organic solvent to evaporate. The NPs were then dialyzed against phosphate buffer over two days to remove excess surfactant and salts. Dynamic light scattering (DLS) measurements revealed suspensions of relatively monodispersed, small-diameter NPs prepared from [a] K. A. V. Zubris, Dr. A. P. Griset, Prof. M. W. Grinstaff Departments of Biomedical Engineering and Chemistry Metcalf Center for Science and Engineering, Boston University 590 Commonwealth Avenue, Boston, MA 02215 (USA) Fax: (+1) 617-358-3186 E-mail : [email protected] [b] Dr. S. Gibbs-Strauss, Dr. J. V. Frangioni Division of Hematology/Oncology, Department of Medicine Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215 (USA) [c] Dr. O. V. Khullar, Dr. Y. L. Colson Division of Thoracic Surgery, Department of Surgery Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02215 (USA) Fax: (+1) 617-730-2853 E-mail : [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201000250.