Many nanosized particulate systems are being developed as intravascular carriers to increase the levels of therapeutic agents delivered to targets, with the fewest side effects. The surface of these carriers is often functionalized with biological recognition molecules for specific, targeted delivery. However, there are a series of biological barriers in the body that prevent these carriers from localizing at their targets at sufficiently high therapeutic concentrations. Here we show a multistage delivery system that can carry, release over time and deliver two types of nanoparticles into primary endothelial cells. The multistage delivery system is based on biodegradable and biocompatible mesoporous silicon particles that have well-controlled shapes, sizes and pores. The use of this system is envisioned to open new avenues for avoiding biological barriers and delivering more than one therapeutic agent to the target at a time, in a time-controlled fashion.

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Magnetic resonance imaging contrast agents are currently designed by modifying their structural and physiochemical properties in order to improve relaxivity and to enhance image contrast. Here we show a general method for increasing relaxivity by confining contrast agents inside the nanoporous structure of silicon particles. Magnevist, gadofullerenes and gadonanotubes were loaded inside the pores of quasi-hemispherical and discoidal particles. For all combinations of nanoconstructs, a boost in longitudinal proton relaxivity r1 was observed: for Magnevist, r1~14 mM-1s-1/Gd3+ion (~8.15×10+7 mM-1s-1/construct); for gadofullerenes, r1~200 mM-1s-1/Gd3+ion (~7×10+9 mM-1s-1/construct); for gadonanotubes, r1~150 mM-1s-1/Gd3+ion (~2×10+9 mM-1s-1/construct). These relaxivity values are about 4 to 50 times larger than that of clinically-available gadolinium-based agents (~4 mM-1s-1 /Gd3+ion). The enhancement in contrast is attributed to the geometrical confinement of the agents, which influences the paramagnetic behavior of the Gd3+ions. Thus, nanoscale confinement offers a new and general strategy for enhancing the contrast of gadolinium-based contrast agents.