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

Poor delivery efficiency remains a major challenge in nanomaterial-based tumor-targeted imaging and drug delivery. This work demonstrates a strategy to improve nanoparticle delivery and intratumoral distribution using sub-5 nm (3.5 nm core size) ultrafine iron oxide nanoparticles (uIONP) that can easily extravasate from the tumor vasculature and readily diffuse into the tumor tissue compared to the iron oxide nanoparticle (IONP) with larger sizes, followed by self-assembling in the acidic tumor interstitial space to limit their re-entering into circulation. By combining enhanced extravasation and reduced intravasation, we achieved improved delivery and tumor retention of nanoparticles. Multiphoton 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 imagi...