Herein, we present a new magnetic iron oxide nanoparticle (MION) with a succinylated heparin monolayer coating, which exhibits the highest T1 relaxivity at 7 T and the lowest r 2/r 1 reported for any MION at these high-field conditions. While the recent proliferation of 7 T MRI instruments in hospitals worldwide has enabled widespread access to higher quality, more finely detailed, diagnostic imaging, clinically available contrast agents have not kept pace due to the general phenomenon of reduced efficacy of T1 relaxation as magnetic field strength is increased. Development of new MION agents is one strategy to address this need, and to this end, we demonstrate the in vitro magnetic properties of the MIONs reported here to extend to in vivo applications, providing greatly increased contrast in tumor imaging in a murine xenograft subject at 7 T. While MION-based contrast agents can have side effects in clinical application, these are generally thought to be less than those of gadolinium-based agents and here are further reduced by the small size allowing direct glomerular filtration from the blood followed by renal-excretion. Finally, we show the succinylated heparin monolayer coating to provide class leading magnetic properties over a homologous series of particles with core size ranging from 2 to 18 nm and show the properties to be strongly related to the surface area. We suggest the increased porosity and hydrophilicity of the coating to increase water accessibility to the surface resulting in the increased magnetic properties.

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The rapid development and advances in nanomaterials and nanotechnology in the past two decades have made profound impact in our approaches to individualized disease diagnosis and treatment. Nanomaterials, mostly in the range of 10-200 nm, developed for biomedical applications provide a wide range of platforms for building and engineering functionalized structures, devices, or systems to fulfill the specific diagnostic and therapeutic needs. Driven by achieving the ultimate goal of clinical translation, sub-5 nm nano-constructs, in particular inorganic nanoparticles such as gold, silver, silica, and iron oxide nanoparticles, have been developed in recent years to improve the biocompatibility, delivery and pharmacokinetics of imaging probes and drug delivery systems, as well as in vivo theranostic applications. The emerging studies have provided new findings that demonstrated the unique size-dependent physical properties, physiological behaviors and biological functions of the nanomaterials in the range of the sub-5 nm scale, including renal clearance, novel imaging contrast, and tissue distribution. This advanced review attempts to introduce the new strategies of rational design for engineering nanoparticles with the core sizes under 5 nm in consideration of the clinical and translational requirements. We will provide readers the update on recent discoveries of chemical, physical, and biological properties of some biocompatible sub-5 nm nanomaterials as well as their demonstrated imaging and theranostic applications, followed by sharing our perspectives on the future development of this class of nanomaterials.

Effectively delivering therapeutics for treating brain tumors is hindered by the physical and biological barriers in the brain. Even with the compromised blood–brain barrier and highly angiogenic blood–tumor barrier seen in glioblastoma (GBM), most drugs, including nanomaterial‐based formulations, hardly reach intracranial tumors. This work investigates sub‐5 nm ultrafine iron oxide nanoparticles (uIONP) with 3.5 nm core diameter as a carrier for delivering DNA topoisomerase inhibitor 7‐ethyl‐10‐hydroxyl camptothecin (SN38) to treat GBM. Given a higher surface‐to‐volume ratio, uIONP shows one‐ or three‐folds higher SN38 loading efficiency (48.3 ± 6.1%, mg/mg Fe) than those with core sizes of 10 or 20 nm. SN38 encapsulated in the coating polymer exhibits pH sensitive release with <10% over 48 h at pH 7.4, but 86% at pH 5, thus being protected from converting to inactive glucuronide by UDP‐glucuronosyltransferase 1A1. Conjugating αvβ3‐integrin‐targeted cyclo(Arg‐Gly‐Asp‐D‐Phe‐Cys) (RGD) as ligands, RGD‐uIONP/SN38 demonstrates targeted cytotoxicity to αvβ3‐integrin‐overexpressed U87MG GBM cells with a half‐maximal inhibitory concentration (IC50) of 30.9 ± 2.2 nm. The efficacy study using an orthotopic mouse model of GBM reveals tumor‐specific delivery of 11.5% injected RGD‐uIONP/SN38 (10 mg Fe kg−1), significantly prolonging the survival in mice by 41%, comparing to those treated with SN38 alone (p < 0.001).

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