Several classes of magnetic iron oxide nanoparticles, also known as superparamagnetic IONPs (SPIO) and ultrasmall SPIO (USPIO) developed in 1980s, has been approved by FDA (e.g., Feridex) for clinical applications with capabilities of traditional “blood pool” agents.20, 21
The important properties of cell phagocytosis of magnetic nanoparticles has expanded the applications of contrast enhanced MRI beyond the vascular and tissue morphology imaging, enabling many novel applications of magnetic IONPs for MRI diagnosis of liver diseases, cancer metastasis to lymph nodes, and in vivo tracking of implanted cell and grafts with MRI.21-26
However, the specificities of these dextran coated magnetic nanoparticles in disease diagnosis are limited. The magnitude of contrast effects also need to be improved for high sensitivity to the minimal changes in the disease and for biomarker specific detection. Therefore, the functionalized and engineered magnetic nanoparticles are developed to meet the increasing interests for non-invasive in vivo imaging of molecular and cellular activities that target a disease.
To gain the specificity and reduce the side effect and toxicity, biomarker targeted functional proteins or peptide fragments, such as RGD targeting αv
integrin, HER2/neu antibody, urokinase type plasminogen activator (uPA) amino-terminal fragment (ATF), and single chain anti-epidermal growth factor receptor (EGFR) antibody were conjugated on the surface of magnetic nanoparticles, rendering the nanoprobes being recognized and internalized by tumor cells over expressing the specific receptor.15, 27-30
For example, Yang and co-workers developed a novel cell surface receptor-targeted MRI nanoprobe by using a recombinant peptide ATF of uPA conjugated to magnetic iron oxide (ATF-IO) nanoparticles to target uPA receptor (uPAR).27
ATF-IO nanoparticles can bind specifically to breast cancer cells expressing uPAR followed by cellular internalization through receptor mediated endocytosis. This leads to prolonged and enhanced MRI contrast in subcutaneous and intraperitoneal mammary tumors in T2 weighted MRI (Figure ) after intravenous administration of ATF-IO nanoparticles into tumor bearing mice. Furthermore, the receptor targeted MRI can be confirmed by optical by near-infrared fluorescence (NIRF) fluorescence imaging in mouse tumor models by co-labeling ATF-IO nanoparticles with the NIRF dye molecule, Cy5.5. This study and the developed uPAR-targeted ATF-IO nanoparticles demonstrated capabilities of functionalized magnetic nanoparticles and showed a potential to improve the specificity of the detection of human cancer by receptor targeted molecular MRI with magnetic nanoparticle probes. More importantly, researchers recognized the importance of the size effect on the relaxivity of the magnetic nanoparticle based MRI contrast. Unlike the earlier studies that used size variable SPIO made mostly with co-precipitation methods in the aqueous medium, ATF-IONPs developed in this study were consisted of size uniformed IONPs (i.e., core size of 10 nm measured by TEM) engineered by using the heat-deposition approach with hydrophobic medium.
Figure 1 (a) Illustration of Cy5.5-ATF-IO nanoparticles; (b) dual modality imaging (T2-weighted MRI (left two) and NIRF imaging (right)) of subcutaneous 4T1 mouse mammary tumor using Cy5.5-ATF-IO nanoparticles (bottom), no contrast change or optical signal is (more ...)
Because one of the major limitations of MRI is its relative low sensitivity, the strategies of combining MRI with other highly sensitive, but less anatomically informative imaging modalities such as positron emission tomography (PET) and NIRF imaging, are extensively investigated. The complementary strengths from different imaging methods can be realized by using engineered magnetic nanoparticles via surface modifications and functionalizations. In order to combine optical or nuclear with MR for multimodal imaging, optical dyes and radio-isotope labeled tracer molecules are conjugated onto the moiety of magnetic nanoparticles.31-33
Xie et al. demonstrated the multifunctionalizations of magnetic nanoparticles via dopamine-human serum albumin (HSA) procedure.32
After exchanging the existing oleic acid/oleic amine, the dopamine modified magnetic nanoparticles can be easily encapsulated in HSA molecules for further functionalizing. In addition to MRI contrast enhancement from the core of the iron oxide nanoparticle, the covalent binding and absorption of 64
Cu-DOTA and Cy5.5 provide PET/NIRF imaging capabilities. The application of multimodality MRI/PET/NIRF imaging using this novel probe was demonstrated in the U87MG glioma tumor model bearing mice. Due to the prolonged circulation time, the multifunctional HSA-IO nanoparticles specifically accumulated in the tumor site through passively targeting based on the tumor growth associated enhanced permeability and retention (EPR) effect. Histological examinations and analyses showed that the nanoconstructs were distributed intra-vascularly at the tumor section and not related to the uptake of macrophages.
As an expansion from the molecular imaging for MRI based diagnosis, engineered magnetic nanoparticles have been also developed for the MRI-guided delivery of therapeutic agents. For example chemotherapeutic drug noscapine (Nos) was attached on the human ATF (hATF) peptide conjugated IONPs to target uPAR expressed prostate cancer, so that the MRI contrast generated from IONPs can be used to follow Nos-hATF-IO nanoparticles for MRI-directed prostate cancer therapy.34
The drug carrying uPAR targeting magnetic nanoparticles showed specific binding to uPAR expressing PC-3 cells. While these Nos-hATF-IO nanoparticles with drug molecules embedded in the hydrophobic coating layers of IONPs demonstrated a ~6-fold improvement in drug efficacy, compared to free drug, they also retained the MRI contrast effect from the IONPs cores. Besides small drug molecules, some specific antibodies or small interfering RNA (siRNA) which can inhibit the tumor growth have been also conjugated onto the magnetic nanoparticles for MRI-guided therapies. Hadjipanayis et al. crosslinked EGFRvIII antibodies to IONPs functionalized with carboxyl groups through the EDC/NHS reaction.35
Significant decrease in glioblastoma cells survival was observed after the treatment by EGFRvIII-IONPs. MRI-guide convection-enhanced delivery of EGFRvIII-IONPs increased the survival of animals bearing glioblastoma xenografts.
Since most functionalities assembled by magnetic nanoparticles are accomplished by the surface modifications, the chemical and physical properties of nanoparticle surface as well as surface coating materials have considerable effects on the function and ability of MRI contrast enhancement of the nanoparticle core. The alterations of MRI contrast due to the surface modifications and functionalization as well as novel features of coating materials may play roles in applications of MRI methods in detecting and quantitatively monitor nanodrug bioavailability in the tumor tissues in vivo.