While major advances have been made in developing and engineering nanomaterials for in vivo applications of biomedical imaging and therapeutics delivery, major challenges in delivery efficiency, effective biomarker targeting, and appropriate control of the pharmacokinetics and clearance profiles remained to be further addressed. Here we present our strategy to these limitations by “going smaller” with 3 nm core-sized ultrafine iron oxide nanoparticles (uIONPs) developed in our lab. Using this sub-5 nm nanoparticle platform, a series of imaging experiments in vivo and ex vivo and quantitative image analysis, we demonstrate that the intratumoral delivery can be facilitated by exerting the extravasation of the nanoparticles from the tumor vasculature, one of the main factors in the enhanced permeability and retention (EPR) effect that is not fully utiized with larger sized nanoparticles. When surface functionalized with targeting ligands, such as transferrin (Tf) to target transferrin receptor (TfR) over expressed tumors, Tf-uIONP (3 nm core size) exhibited substantially improved active targeting with higher ratio of ligand-mediated targeted delivery vs. just EPR driven passively targeted delivery when comparing to the non-targeted uIONP and larger IONPs (30 nm core size) in a 4T1 breast cancer tumor model. These new findings not only support the rationale and value of pursuing ligand-mediated biomarker targeted delivery of nanoimaging probes and nanotherapeutics via active targeting, but also suggest the potential to improve biomarker quantification in vivo with imaging and quantitative monitoring of a targeted treatment in precision medicine. For future clinical translation, sub-5 nm uIONPs showed favorable pharmacokinetics profile for imaging and drug delivery and moderate renal clearance complementary to typical slow clearance and long retention time of large nanoparticles by the reticuloendothelial system (RES), which has been an increasing concern for in vivo applications of nanomaterials.

Promoting intratumoral delivery, active targeting and clearance with sub-5 nm ultrafine magnetic iron oxide nanoparticles

256th National Meeting (2018)

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