Magnetic nanoparticle biodistribution following intratumoral administration

Abstract

Recently, heat generated by iron oxide nanoparticles (IONPs) stimulated by an alternating magnetic field (AMF) has shown promise in the treatment of cancer. To determine the mechanism of nanoparticle-induced cytotoxicity, the physical association of the cancer cells and the nanoparticles must be determined. We have used transmission electron microscopy (TEM) to define the time dependent cellular uptake of intratumorally administered dextran-coated, core-shell configuration IONP having a mean hydrodynamic diameter of 100-130 nm in a murine breast adenocarcinoma cell line (MTG-B) in vivo. Tumors averaging volumes of 115 mm3 were injected with iron oxide nanoparticles. The tumors were then excised and fixed for TEM at time 0.1-120 h post-IONP injection. Intracellular uptake of IONPs was 5.0, 48.8 and 91.1% uptake at one, 2 and 4 h post-injection of IONPs, respectively. This information is essential for the effective use of IONP hyperthermia in cancer treatment.

Figure 1

Transmission Electron Micrographs of In vivo murine mammary adenocarcinoma cells. a: Tumor cells without IONPs. b: Tumor cells five minutes following intra-tumor administration of IONP. The vast majority of IONP are aggregated in the extracellular space (arrow). c: Tumor cells one hour following intra-tumor administration of the nanoparticles. Larger interstitial aggregates of nanoparticles can be seen (arrow).

Figure 2

Three hours following intra-tumor injection of IONP into a mouse mammary adenocarcinoma, a large number of INOP are aggregated within (black arrow) and outside (white arrow) tumor cells. a: Although some IONP remain outside of the cells, most IONPs are located within large intra-cytoplasmic vesicles. b: This micrograph demonstrates plasma membrane associated IONP and IONP in the process of trafficking through the membrane and cytoplasmic aggregation.

Figure 3

TEM of a mouse mammary adenocarinoma cell demonstrating aggregated IONPs within the cytoplasm (black arrow) and adjacent to the nuclear enveloped (white arrow), 24 hours after administration. All IONPs were either aggregated inside cells or had been eliminated from the tumor extracellular space.

Figure 4

One hour post intratumoral IONP injection (5 mg Fe/cm³ tumor), approximately 5% of nanoparticles were found to be intracellular (TEM assessment), whereas 4 hours post injection approximately 90% are intracellular. There is no additional uptake at 6 hours post injection. Error bars indicate standard deviation of the mean.

Figure 5

These figures demonstrate IONP movement from the extracellular location (1, left figure) to semi-aggregated intracellular (1) and extracellular (2) locations (center figure) to entirely intracellular aggregation (2, right figure). The intratumoral post-injection time is indicated beneath the photographs.