Advances in our understanding of the genetic basis of disease susceptibility, coupled with prominent successes for molecular targeted therapies, have resulted in an emerging strategy of personalized medicine. This approach envisions risk stratification and therapeutic selection based on an individual’s genetic makeup and physiologic state (the latter assessed through cellular or molecular phenotypes). Molecularly targeted nanoparticles can play a key role in this vision through non-invasive assessments of molecular processes and specific cell populations in vivo, sensitive molecular diagnostics ex vivo, and targeted delivery of therapeutics.1-3 Derivatized dextran coated magnetic nanoparticles4, 5 are a powerful platform for these applications, as they support diagnostic imaging by magnetic resonance (MRI), optical and PET modalities, and constitute a versatile platform for conjugation to targeting ligands. Pharmacokinetic and toxicity studies have revealed these nanomaterials to be sufficiently non-toxic and biodegradable6, 7 with extended vascular retention times. Certain nanoparticles of this class are now FDA-approved.
Experimental dextran-coated superparamagnetic iron oxide nanoparticles are a well-established platform for the synthesis of multifunctional imaging agents. These include monocrystalline iron oxide nanoparticles (or MION)8, 9 and the related nanoparticles where the dextran is covalently cross-linked (cross-linked iron oxide nanoparticles, or CLIO) to form amine groups that are ready substrates for conjugation to targeting ligands. Several nanoparticles with iron cores and carbohydrate coatings have been approved for human use. In 1996, the US Food and Drug Administration (FDA) approved Feridex I.V.® (ferumoxides) as the first nanoparticle-based iron oxide imaging agent for the detection of liver lesions. A smaller monodisperse version, Combidex® (ferumoxtran-10) has been used to image occult prostate cancer lymph-node metastases in humans. Finally, Feraheme® (ferumoxytol) has been approved to treat iron deficiency anemia in adult patients with chronic kidney disease. Ferumoxytol is also under clinical investigation for the detection of central nervous system (CNS) inflammation, brain neoplasms and cerebral metastases from lung or breast cancer.
This account will describe our recent efforts in the development of an integrated system of nanoparticles, conjugation chemistries, screening methods, and detection technologies, with wide applications in biologic discovery, molecular imaging, diagnostic analyte detection, and therapeutic decision-making and monitoring.