PET/NIRF/MRI triple functional iron oxide nanoparticles

Abstract

Engineered nanoparticles with theranostic functions have attracted a lot of attention for their potential role in the dawning era of personalized medicine. Iron oxide nanoparticles (IONPs), with their advantages of being non-toxic, biodegradable and inexpensive, are candidate platforms for the buildup of theranostic nanostructures; however, progress in using them has been limited largely due to inefficient drug loading and delivery. In the current study, we utilized dopamine to modify the surface of IONPs, yielding nanoconjugates that can be easily encapsulated into human serum albumin (HSA) matrices (clinically utilized drug carriers). This nanosystem is well-suited for dual encapsulation of IONPs and drug molecules, because the encapsulation is achieved in a way that is similar to common drug loading. To assess the biophysical characteristics of this novel nanosystem, the HSA coated IONPs (HSA-IONPs) were dually labeled with (64)Cu-DOTA and Cy5.5, and tested in a subcutaneous U87MG xenograft mouse model. In vivo positron emission tomography (PET)/near-infrared fluorescence (NIRF)/magnetic resonance imaging (MRI) tri-modality imaging, and ex vivo analyses and histological examinations were carefully conducted to investigate the in vivo behavior of the nanostructures. With the compact HSA coating, the HSA-IONPs manifested a prolonged circulation half-life; more impressively, they showed massive accumulation in lesions, high extravasation rate, and low uptake of the particles by macrophages at the tumor area.

Fig. 1

Schematic illustration of the multi-funtional HSA-IONPs. The pyrolysis-derived IONPs were incubated with dopamine, after which the particles became moderately hydrophilic and could be doped into HSA matrices in a way similar to drug loading.

Fig. 2

(a) TEM of oleate coated IONPs in hexane. (b) TEM of the HSA-IONPs in water. (c) Hydrodynamic size change of the HSA-IONPs when incubating in PBS at 37°C for 48 hours, monitored by DLS. (d) r2 relaxivity evaluations with HSA-IONPs and Feridex.

Fig. 3

(a) Representative in vivo NIRF images of mouse injected with HSA-IONPs. Images were acquired 1 h, 4 h and 18 h post injection. (b) In vivo PET imaging results of mouse injected with HSA-IONPs. Images were acquired 1 h, 4 h and 18 hours post injection. (c) MRI images acquired before and 18 h post injection.

Fig. 4

(a) Ex vivo PET imaging on tumor and the major organs. (b) Ex vivo NIRF imaging on tumor and the major organs.

Fig. 5

(a) Prussian blue staining on tumor sections. Blue spots, representing the Fe contents, were found across the tumor and the distribution was found in an inhomogeneous pattern. (b) Ex vivo examination of tumor sections by fluorescence microscope. Cy5.5 labeled HSA-IONPs were i.v. injected into mice. Then at the 18 h time point, FITC labeled tomato lectin was injected, and the mice were sacrificed 10 minutes later. The overlaid image was constructed by MataMorph Imaging Processing software. The red, green and blue colors represent Cy5.5-HAS-IONPs, FITC-lectin and DAPI, respectively.

Fig. 6

(a) CD31 and Prussian blue double staining of the tumor samples. Some particles were found within the vessels (upper left), while many others managed to extravasate (lower left). (b) F4/80 and Prussian blue double staining of the tumor samples. Although some particles were found within macrophages (upper right), most of them were found independent of macrophages (lower right).