Exerting Enhanced Permeability and Retention Effect Driven Delivery by Ultrafine Iron Oxide Nanoparticles with T1–T2 Switchable Magnetic Resonance Imaging Contrast

The poor delivery efficiency remains a major challenge in nanomaterial based tumor targeted imaging and drug delivery. This work demonstrated a strategy to improve nanoparticle delivery and intratumoral distribution using a sub-5 nm (3.5 nm core size) ultrafine iron oxide nanoparticles (uIONPs) that can easily extravasate from the tumor vasculature and readily diffuse into the tumor tissue compared to iron oxide nanoparticles (IONP) with larger sizes, followed by self-assembling in the acidic tumor interstitial space to limit their re-entering the circulation. By combining enhanced extravasation and reduced intravasation, improved delivery and tumor retention of nanoparticles are achieved. Multi-photon imaging of mice bearing orthotopic tumors co-injected with fluorescent dye labeled nanoparticles with different sizes showed that uIONPs exhibited more efficient extravasation out of tumor vessels and penetrated deeper into the tumor than larger sized IONP counterparts. Moreover, in vivo magnetic resonance imaging (MRI) revealed that uIONPs exhibited “bright” T 1 contrast when dispersed in the tumor vasculature and peripheral area at 1 hour after intravenous administration, followed by emerging “dark” T 2 contrast in the tumor after 24 hours. Observed T 1 –T 2 contrast switch indicated that uIONPs single-dispersed in blood with T 1 contrast may self-assemble into larger clusters with T 2 contrast after entering the tumor interstitial space. Improved passive targeting and intratumoral delivery along with increased tumor retention of uIONP are due to both easy extravasation into the tumor when single-dispersed and restricting intravasation back into circulation after forming clusters, thus, exerting the enhanced permeability and retention (EPR) effect for nanoparticle delivery to tumors.