Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery

Abstract

Drug delivery, magnetic resonance and fluorescence imaging, magnetic manipulation, and cell targeting are simultaneously possible using a multifunctional mesoporous silica nanoparticle. Superparamagnetic iron oxide nanocrystals were encapsulated inside mesostructured silica spheres that were labeled with fluorescent dye molecules and coated with hydrophilic groups to prevent aggregation. Water-insoluble anticancer drugs were delivered into human cancer cells; surface conjugation with cancer-specific targeting agents increased the uptake into cancer cells relative to that in non-cancerous fibroblasts. The highly versatile multifunctional nanoparticles could potentially be used for simultaneous imaging and therapeutic applications.

Figure 1

Schematic illustration of multifunctional nanoparticles showing iron oxide nanocrystals encapsulated within mesoporous silica, hydrophobic anticancer drugs stored inside the pores, and surface modifications with phosphonate and folic acid targeting ligands.

Figure 2

(Left) As-synthesized oleate-capped iron oxide nanocrystals in chloroform and (right) water-soluble CTAB-stabilized nanocrystals.

Figure 3

(Left) Scanning electron microscope and (right) transmission electron microscope images of the iron oxide incorporated within the mesoporous silica NPs.

Figure 4

Aqueous suspension of NPs modified with phosphonate (b) compared with those of calcined NPs (a) and NPs without phosphonate (c). After the NPs were dried, they were redispersed in water (5 mg/mL), sonicated thoroughly, and placed next to the magnet. Unlike the other two NPs (a and c), the phosphonate-modified NPs (b) were highly dispersed in the solution and remained suspended even in the presence of the magnetic field. After a longer period of time, the phosphonate-modified NPs were collected by the magnet (right).

Figure 5

Fluorescence microscopy images of the nanoparticle uptake by human pancreatic cancer cells PANC-1 and BxPC3. The cell membranes (red fluorescence) were stained with WGA, and the clusters of NPs (green fluorescence) were modified with FITC.

Figure 6

(Top) T2-weighted MR images of (a) water, (b) plain mesoporous silica NPs (2 mg/mL), and iron oxide–mesoporous silica NPs at (c) 4, (d) 2, and (e) 1 mg/mL. (Bottom) Cross-section T2-weighted MR images of the centrifuge tubes at different tube heights. PANC-1 cells that were treated with iron oxide–mesoporous silica NPs (labeled with arrows) appeared dark compared to the other samples.

Figure 7

UV/vis absorption measurements show that most of the water-insoluble drug molecules were trapped inside the pores when the NPs were dispersed in water, but they were quickly released in organic solvents.

Figure 8

Cell growth inhibition assay for the drug-loaded NPs. Human pancreatic cancer cells PANC-1 and BxPC-3 were treated for 24 h with nanoparticles (NP), camptothecin-loaded nanoparticles (CPT-NP), or paclitaxel-loaded nanoparticles (TXL-NP). The concentration of the NPs used was 20 μg/mL.

Figure 9

Western blot (left) and RT-PCR (right) analyses show that the α-folate receptor (FR) was overexpressed in PANC-1 cells, but not in HFF.

Figure 10

Fluorescence microscopy images showing the effect of folic acid modification on the NPs (green fluorescence). The cell nuclei were stained with DAPI (blue fluorescence), and the membranes were stained with WGA (red fluorescence). Top figures: HFF treated with (a) NPs and (b) folate-modified NPs. Bottom figures: PANC-1 treated with (c) NPs and (d) folate-modified NPs. Increased uptake of the folate-modified NPs was observed with the PANC-1 cells (overexpressed folate receptor) but not with the HFF.

Figure 11

Cell growth inhibition assay of the folate-modified materials. The cells were treated for 24 h with nanoparticles only (NP), camptothecin-loaded nanoparticles (CPT-NP), or camptothecin-loaded nanoparticles modified with folic acid (CPT-FA-NP). The enhanced uptake of NPs by PANC-1 cells through folate modification led to an increase in the delivery of camptothecin. This effect was not observed on HFF, which do not overexpress folate receptors. The concentration of the NPs used was 20 μg/mL.