Targeting and Cellular Trafficking of Magnetic Nanoparticles for Prostate Cancer Imaging

Abstract

Antibody-conjugated iron oxide nanoparticles offer a specific and sensitive tool to enhance magnetic resonance (MR) images of both local and metastatic cancer. Prostate-specific membrane antigen (PSMA) is predominantly expressed on the neovasculature of solid tumors and on the surface of prostate cells, with enhanced expression following androgen deprivation therapy. Biotinylated anti-PSMA antibody was conjugated to streptavidin-labeled iron oxide nanoparticles and used in MR imaging and confocal laser scanning microscopic imaging studies using LNCaP prostate cancer cells. Labeled iron oxide nanoparticles are internalized by receptor-mediated endocytosis, which involves the formation of clathrin-coated vesicles. Endocytosed particles are not targeted to the Golgi apparatus for recycling but instead accumulate within lysosomes. In T 1 -weighted MR images, the signal enhancement owing to the magnetic particles was greater for cells with magnetic particles bound to the cell surface than for cells that internalized the particles. However, the location of the particles (surface vs internal) did not significantly alter their effect on T 2 -weighted images.Our findings indicate that targeting prostate cancer cells using PSMA offers a specific and sensitive technique for enhancing MR images.P ROSTATE CANCER accounts for 9% of all male cancer deaths in the United States, and there is a 1 in 6 lifetime probability of developing prostate cancer. 1 On screening or regular medical checkups, men with an abnormal digital rectal examination or elevated prostatespecific antigen test are further referred for biopsy to prove or disprove the presence of prostate cancer. However, up to 28% of prostate cancers are missed even when sextant biopsy procedures are used. 2 In the presence of an elevated prostate-specific antigen value, this creates anxiety among patients and represents a medical dilemma for the physician. Currently, diagnostic screening with conventional magnetic resonance (MR) imaging has high spatial resolution but lacks specificity. The goal of our research is to increase the specificity of MR imaging for prostate cancer by creating targeted iron oxide nanoparticles (ie, contrast agents) that specifically recognize plasma membrane antigens elevated in tumor cells.Iron oxide nanoparticles offer significant advantages over other potential contrast agents in that they have very strong signal effects in MR imaging, 3 with a detection limit in the subnanomolar range. 4 The MR signal is due to the response of surrounding water molecules (ie, protons) to an external magnetic field. Radiofrequency energy is used to excite the water protons, and as the water protons relax, they create signals detected in MR imaging. Contrast agents enhance both the longitudinal and transverse relaxation rates, creating regions with positive and negative enhancement. 3 Labeled with the appropriate antibodies to plasma membrane antigens, nanoparticles offer great specificity in addition to sensitivity. 5,6 One potential cell surface antig...

Prostate stem cell antigen-targeted nanoparticles with dual functional properties: in vivo imaging and cancer chemotherapy

“…9 Labeled with the appropriate antibodies to tumor membrane antigens, nanoparticles offer great specificity and sensitivity. 10 One potential candidate, overexpressed in both local and metastatic prostate cancer, is prostate stem cell antigen. 11,12 In contrast with other prostate cancer-associated tumor antigens, prostate stem cell antigen has been recognized as a truly prostate-specific membranebound protein, which participates in membrane recycling and becomes internalized by ligand-induced endocytosis.…”

Recent Development and Trends in Molecular Imaging Probes for Prostate Cancer

“…These probes were based on potential capitalization on PSMA as a relevant biologic target for imaging and therapy of prostate cancer. Other works indicated that biotinylated anti-PSMA antibody conjugated to streptavidin-labeled iron oxide nanoparticles could be used as the MRI probe for detection of prostate cancer cells [37]. T1-weighted signal was greater for cells with magnetic particles bound to cell surface than for cells that internalized the particles, whereas no such effect was noted with T2-weighted images.…”

Synthesis of bombesin-functionalized iron oxide nanoparticles and their specific uptake in prostate cancer cells

“…The difference was statistically significant (P<0.0001). High resolution confocal imaging suggested that internalized nanoparticles localized to the late endosomal/lysosomal compartment, as would be expected following receptor-mediated uptake (Serada et al 2007). In addition, the nanoparticles co-localized with viral nanoparticles that have been previously demonstrated to localize to the late endosomal compartment (data not shown) (Lewis et al 2006).…”

“…However, there are only a few recent examples of MRI contrast agents targeted specifically to prostate cancer cells. Antibodies (Serada et al 2007) and aptamers (Wang et al 2008) targeting the prostate-specific membrane antigen expressed on prostate cancer cells have been conjugated to SPIO, facilitating selective binding and uptake. Selective imaging of prostate cancer cells in vivo was also recently achieved by the conjugation of SPIO to peptides targeting hepsin, a prostate cancer biomarker (Kelly et al 2008).…”