Size Switchable Self-Assembled Iron Oxide Aggregations Loaded with Doxorubicin for Deep Penetration and Enhanced Chemotherapy of Cancer.

Iron oxide nanoparticles (Fe 3 O 4 NPs) have been reported to be a promising agent for cancer therapy due to their outstanding ability in catalyzing the Fenton reaction and causing peroxidation. Generally, particles with size of hundreds of nanometers exhibit enhanced accumulation in tumor due to the enhanced permeation and retention effect. However, the large size hinders penetration within the dense collagen matrix. Here, we propose a multistage system to realize pH-responsive size switch for efficient drug delivery. In this system, ultrasmall Fe 3 O 4 (∼4 nm) NPs are simultaneously modified with hydrophilic mPEG and hydrophobic N , N -dibutylethylenediamine (DBE) to form pH-responsive self-assembled iron oxide aggregations (SIOA). In the acidic tumor microenvironment, the protonation of DBE makes it transit from the hydrophobic to hydrophilic state, causing the disassembly of the SIOA and the release of loaded doxorubicin. The multistage Fe 3 O 4 NPs demonstrate enhanced accumulation and efficient diffusion within the tumor, holding a promise for drug delivery and cancer therapy.