Enhancing therapeutic efficacy through designed aggregation of nanoparticles.

Particle size is a key determinant of biological performance of sub-micron size delivery systems. Previous studies investigating the effect of particle size have primarily focused on well-dispersed nanoparticles. However, inorganic nanoparticles are prone to aggregation in biological environments. In our studies, we examined the consequence of aggregation on superparamagnetic iron oxide (SPIO) nanoparticle-induced magnetic hyperthermia. Here we show that the extent and mechanism of hyperthermia-induced cell kill is highly dependent on the aggregation state of SPIO nanoparticles. Well-dispersed nanoparticles induced apoptosis, similar to that observed with conventional hyperthermia. Sub-micron size aggregates, on the other hand, induced temperature-dependent autophagy through generation of oxidative stress. Micron size aggregates caused rapid membrane damage, resulting in acute cell kill. Overall, this work highlights the potential for developing highly effective anticancer therapeutics through designed aggregation of nano delivery systems.