Multifunctional iron oxide nanoparticles for biomedical applications

Abstract

This dissertation focuses on the preparation of multifunctional nanoparticles through the integration of iron oxide nanoparticles with other desired moieties. Iron oxide nanoparticles have been widely explored in localized therapy, targeted delivery, and magnetic resonance imaging. However, inaccessible MRI instruments for most research labs and lack of targeting ligands limits the further exploration of iron oxide nanoparticles in routine tumor diagnosis and efficient therapy. Therefore, the preparation of dual-imaging or targeted nanoparticles is highly desirable. In our studies, fluorescent gold nanoclusters or anti&ndashdisialoganglioside&ndashGD2 monoclonal antibodies are integrated onto iron oxide nanoparticle surfaces. The gold nanoclusters provide additional fluorescent imaging capability, which can be easily accessed in common research labs. The conjugation of cancer cell&ndashtargeting antibodies allows for specific localization of nanoparticles. Indeed, these are the two central themes of this dissertation. To prepare multifunctional nanoparticles, high&ndashquality iron oxide nanoparticles were first synthesized in organic solvents following a modified &ldquoheat&ndashup&rdquo method. During synthesis, a modification was made by introducing a co&ndashsurfactant (trioctylphosphine oxide&ndashTOPO). TOPO facilitated the subsequent ligand exchange process because it weakly bound to nanoparticle surfaces and prevented the formation of densely&ndashpacked surfactant coatings. As a result, hydrophilic molecules (such as polyacrylic acid, polyethylenimine, glutathione and dopamine) were capable of replacing the original ligands, yielding water&ndashsoluble iron oxide nanoparticles. In addition to water solubility, dopamine coatings offered nanoparticles additional conjugation capability upon surface oxidization. These surface&ndashoxidized nanoparticles can directly conjugate with amine and/or thiol group&ndashcontained molecules through Michael addition and/or Schiff base formation. Using this conjugation strategy, dual&ndashimaging nanoparticles were prepared by integrating dopamine&ndashcoated nanoparticles with protein (such as bovine serum albumin, trypsin and lysozyme) &ndash encapsulated fluorescent gold nanoclusters. All integrated nanoparticles maintained their functionalities and structural integrity in biological environments. Furthermore, effects of protein characteristics on the photo&ndashchemical properties of gold nanoclusters and integrated nanoparticles were systematically examined. Similarly, cancer cell&ndashtargeting molecules (e.g. anti&ndashGD2 monoclonal antibodies) were conjugated onto dopamine&ndashcoated nanoparticles. After conjugation, antibodies retained their high targeting specificity, suggested by our cellular targeting studies. More promisingly, conjugated nanoparticles were capable of transporting into cytosols, which opens up new possibilities in cancer&ndashcuring drug loading and targeted therapy. Besides these already&ndashpublished works, we have studied the biological responses of human monocytes to different surface&ndashcharged iron oxide nanoparticles (manuscript in preparation). For dual&ndashimaging nanoparticles, their stability and bio&ndashimaging potential will be evaluated in phorbol myristate acetate (PMA)&ndashtreated monocytes using differential interference contrast (DIC) and confocal microscopy.