Effect of removing Kupffer cells on nanoparticle tumor delivery

Abstract

A recent metaanalysis shows that 0.7% of nanoparticles are delivered to solid tumors. This low delivery efficiency has major implications in the translation of cancer nanomedicines, as most of the nanomedicines are sequestered by nontumor cells. To improve the delivery efficiency, there is a need to investigate the quantitative contribution of each organ in blocking the transport of nanoparticles to solid tumors. Here, we hypothesize that the removal of the liver macrophages, cells that have been reported to take up the largest amount of circulating nanoparticles, would lead to a significant increase in the nanoparticle delivery efficiency to solid tumors. We were surprised to discover that the maximum achievable delivery efficiency was only 2%. In our analysis, there was a clear correlation between particle design, chemical composition, macrophage depletion, tumor pathophysiology, and tumor delivery efficiency. In many cases, we observed an 18-150 times greater delivery efficiency, but we were not able to achieve a delivery efficiency higher than 2%. The results suggest the need to look deeper at other organs such as the spleen, lymph nodes, and tumor in mediating the delivery process. Systematically mapping the contribution of each organ quantitatively will allow us to pinpoint the cause of the low tumor delivery efficiency. This, in effect, enables the generation of a rational strategy to improve the delivery efficiency of nanoparticles to solid tumors either through the engineering of multifunctional nanosystems or through manipulation of biological barriers.

New Strategies in the Design of Nanomedicines to Oppose Uptake by the Mononuclear Phagocyte System and Enhance Cancer Therapeutic Efficacy

“…[78] However,i tw as found that deleting Kupffer cells could increased elivery to the tumor by up to 150 times, whereas only 2% accumulated in the tumor.T his highlighted the importance of increasing the chance for drugs to breakt hrough the tumor microenvironment barrier. [79] In recent research, it was found that the velocity of hard nanomaterials decreased 1000 fold as the NPs passed through the liver,w hich sharply increased thec hances of interaction with the hepatic cells. [80] As ar esult, manipulationo ft he intraorganf low dynamics of NPs opens an ew avenue for reducing uptake by the macrophages.…”

Salicylic Acid‐Based Polymeric Contrast Agents for Molecular Magnetic Resonance Imaging of Prostate Cancer

“…The most common strategy to avoid nonspecific protein binding and phagocyte uptake is to engraft the polymers with neutrally charged linear chains of poly(ethylene glycol) (PEG). [16] Accordingly, our current focus is to modify compound 4 with an optimized number of PEG units (MW 1 – 5 kDa) to reduce the overall surface charge and also to increase circulation time. We also anticipate that the next generation compounds with targeting moieties attached to optimized PEG linkers might also allow higher access to receptor binding to provide higher tumor uptake and internalization within the PSMA(+) tumor compared to compound 4 .…”

Isolating the sources of heterogeneity in nanoparticle-cell interactions

“…Uncovering the biological and physical mechanisms that impact the ability of specific cells to associate with, and subsequently internalize, nanoparticles is necessary for informed nanoparticle design (1,2,7). The ability to reliably deliver nanoparticles to a target cell population such that the nanoparticles are rapidly internalized has the potential to transform disease treatment and diagnosis (34)(35)(36). However, the journey between nanoparticle creation and cellular internalisation is convoluted, and involves a multitude of intertwined biological, physical and chemical processes (1-4, 7).…”