Nanoparticles have become increasingly important in the development of new materials for enhanced drug delivery and imaging applications (Adams, M. L. et al., J. Pharmaceutical Sciences 2003, 92:1343-1355; Portney et al., Analytical and Bioanalytical Chemistry 2006, 384:620-630). Drug carriers such as liposomal (Kim, S. Drugs 1993, 46:618-638), polymeric vesicle (Discher et al., Science 2002, 297, 967-973) and micellar dispersions (Allen et al., Colloids and Surfaces B—Biointerfaces 1999, 16:3-27; Kwon, Critical Reviews in Therapeutic Drug Carrier Systems 1998, 15:481-512) consisting of particles 50-400 nm in diameter have shown great promise, for example, in the formulation of anticancer therapeutics that would be highly insoluble in aqueous media absent their incorporation into a carrier. Such carriers, besides affording more potent drug delivery, also provide opportunities for selective tumor targeting. More recently, inorganic nanoparticles, including quantum dots (Michalet et al, Science 2005, 307:538-544) gold nanospheres (West et al., Annual Review of Biomedical Engineering 2003, 5:285-292), nanoshells (Loo et al. Cancer Research and Treatment 2004, 3:33-40), and superparamagnetic metals (Mornet et al., Journal of Materials Chemistry 2004, 14:2161-2175) have been explored for nanoparticle-based biomedical functions, such as tagging, medical imaging, sensing, and separation.
Despite extensive innovation over the last decade, there remains a need for integrated, easily adaptable drug delivery and imaging modalities, especially those for the delivery and monitoring of highly toxic compounds in vivo. Polymeric nanoparticles in particular are a versatile medium for this purpose, due to their enhanced drug loading capacity, biological stability, and extended in vivo circulation times (Kwon et al., Advanced Drug Delivery Reviews 1995, 16:295-309).
Polymeric nanoparticles that carry drugs and other agents encapsulated in their cores have evolved. Initially, research efforts focused on combining polymeric carriers of drugs with organic fluorescent dyes for particle visualization, without regard to the “encapsulation” of either the drug or the dye. Fluorescent nanoparticless have been prepared by binding water-soluble fluorophores to the surfaces of pre-formed nanoparticles (O'Reilly et al., Journal of Polymer Science Part A—Polymer Chemistry 2006, 44: 5203-5217) or, more commonly, by chemically tethering a fluorescent dye to the hydrophobic terminus of an amphiphilic block copolymer and then permitting the polymer to self-assemble into a particle (Luo, et al., Bioconjugate Chemistry 2002, 13:1259-1265). Organic dyes and fluorophores, however, require direct visualization, and so are generally practical only for in vitro applications such as nanoparticle cellular uptake and localization studies (Savic et al., Science 2003, 300:615-618).
Nanoparticles having a metallic core that adds contrast to images acquired by magnetic resonance imaging, for example, or computed X-ray tomography are more suitable for in vivo biomedical applications (Bulte et al., NMR in Biomedicine 2004, 2004, 17: 484-499; Hainfeld et al., British Journal of Radiology 2006, 79:248-253). Typically, however, they are incompatible with body fluids because their surfaces are hydrophobic and they may also be incompatible because of toxicity. A number of coating strategies have been used to address these issues (Azzam et al., Langmuir 2007, 23:2126-2132; Kim et al., Langmuir 2007, 23: 2198-2202; Butterworth et al., Colloids and Surfaces A—Physicochemical and Engineering Aspects 2001, 179: 93-102; Gupta et al., Biomaterials 2005, 26: 3995-4021; Soo et al., Langmuir 2007, 23:4830-4836). Researchers have also functionalized the surfaces of such inorganic nanoparticles with receptor-specific peptides or protein ligands, allowing for targeted localization of the imaging particles (Paciotti et al., Drug Development Research 2006, 67:47-54; Zhang et al., Biomaterials 2002, 23:1553-1561; Zhou, et al., Biomaterials 2006, 27:2001-2008). Also, ligands (optionally together with drugs) can be covalently attached to the coating material instead of to the inorganic nanoparticle itself (Paciotti et al., Drug Delivery 2004, 11:169-183; Yu et al., Journal of Materials Chemistry 2004, 14: 2781-2786; Gupta et al., Biomaterials 2004, 25:3029-3040). Since the coating material is advantageously hydrophilic, however, the strategy of attaching hydrophobic moieties (e.g., drugs) to it is generally not practical.