Magnetometry based method for investigation of nanoparticle clearance from circulation in a liver perfusion model.

Nanoparticles (NPs) are among the most promising agents for advanced theranostics. However, their functioning in vivo is severely inhibited by the mononuclear phagocyte system (MPS), which rapidly removes all foreign entities from blood circulation. Little is known about the sequestration mechanisms and the ways to counteract them. New methods are highly demanded for investigation with high scrutiny of each aspect of NP clearance from blood. For example, while liver macrophages capture the majority of the administered particles, reliable investigation of this process in absence of other MPS components is hard to implement in vivo. Here, we demonstrate a novel method for real-time investigation hepatic uptake of NPs in an isolated perfused liver based on an extremely accurate magnetometric registration technique. The signal is obtained solely from the magnetic NPs without any 'background' from blood or tissues, which is a significant advantage over other techniques, e.g. optical ones. We illustrate the method capacity by investigation of behavior of different particles and show good correlation with in vivo studies. We also demonstrate notable suitability of the method for studying the NP clearance from the flow in the user-defined mediums, e.g. those containing specific serum components. Finally, the method was applied to reveal an interesting effect of short-term decrease of liver macrophage activity after the first interaction with small amounts of NPs. The developed perfusion model based on the high-performance magnetometry can be used for finding new mechanisms of NP sequestration and for development of novel 'stealth' nanoagents.

Nanoparticle-based drug delivery via RBC-hitchhiking for the inhibition of lung metastases growth.

Delivery of particle-based theranostic agents via their transportation on the surfaces of red blood cells, commonly referred to as RBC-hitchhiking, has historically been developed as a promising strategy for increasing the extremely poor blood circulation lifetime, primarily, of the large-sized sub-micron agents. Here, we show for the first time that RBC-hitchhiking can be extremely efficient for nanoparticle delivery and tumor treatment even in those cases when no circulation prolongation is observed. Specifically, we demonstrate that RBC-hitchhiking of certain small 100 nm particles, unlike that of the conventional sub-micron ones, can boost the delivery of non-targeted particles to lungs up to a record high value of 120-fold (and up to 40% of the injected dose). To achieve this remarkable result, we screened sub-200 nm nanoparticles of different sizes, polymer coatings and ζ-potentials and identified particles with the optimal RBC adsorption/desorption behavior. Furthermore, we demonstrated that such RBC-mediated rerouting of particles to lungs can be used to fight pulmonary metastases of aggressive melanoma B16-F1. Our findings could change the general paradigm of drug delivery for cancer treatment with RBC-hitchhiking. It is not the blood circulation lifetime that is the key factor for nanoparticle efficiency, but rather the complexation of nanoparticles with the RBC. The demonstrated technology could become a valuable tool for development of new strategies based on small nanoparticles for the treatment of aggressive and small-cell types of cancer as well as other lung diseases.