Abstract
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 imaging revealed that uIONPs exhibited "bright" T(1) contrast when dispersed in the tumor vasculature and peripheral area at 1 h after intravenous administration, followed by emerging "dark" T(2) contrast in the tumor after 24 h. 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 uIONPs 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 effect for nanoparticle delivery to tumors.