title: Enhancing therapeutic efficacy through designed aggregation of nanoparticles.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Sadhukha
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Wiedmann
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: jpanyam@gmail.com.
authors.forename: Jayanth
authors.initials: J
authors.lastname: Panyam
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D003911:Dextrans / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D060328:Magnetic Phenomena; D058185:Magnetite Nanoparticles / Q000737:chemistry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D010316:Particle Size
chemical_list: D003911:Dextrans; D058185:Magnetite Nanoparticles; C065507:ferumoxides
keywords: Aggregation; Apoptosis; Autophagy; Magnetic hyperthermia; Necrosis; Superparamagnetic iron oxide