Peripherally Administered Nanoparticles Target Monocytic Myeloid Cells, Secondary Lymphoid Organs and Tumors in Mice

Abstract

Nanoparticles have been extensively developed for therapeutic and diagnostic applications. While the focus of nanoparticle trafficking in vivo has traditionally been on drug delivery and organ-level biodistribution and clearance, recent work in cancer biology and infectious disease suggests that targeting different cells within a given organ can substantially affect the quality of the immunological response. Here, we examine the cell-level biodistribution kinetics after administering ultrasmall Pluronic-stabilized poly(propylene sulfide) nanoparticles in the mouse. These nanoparticles depend on lymphatic drainage to reach the lymph nodes and blood, and then enter the spleen rather than the liver, where they interact with monocytes, macrophages and myeloid dendritic cells. They were more readily taken up into lymphatics after intradermal (i.d.) compared to intramuscular administration, leading to ∼50% increased bioavailability in blood. When administered i.d., their distribution favored antigen-presenting cells, with especially strong targeting to myeloid cells. In tumor-bearing mice, the monocytic and the polymorphonuclear myeloid-derived suppressor cell compartments were efficiently and preferentially targeted, rendering this nanoparticulate formulation potentially useful for reversing the highly suppressive activity of these cells in the tumor stroma.

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

“…Upon intradermal injection, sufficiently small nanoparticles take advantage of interstitial flow into the dermal lymphatics to efficiently drain through lymphatic vessels and target skindraining LNs (21). Although intratumor, intra-LN, or subcutaneous administrations have been explored to target LNs with cancer immunotherapies, our experimental model permitted passive but direct and efficient targeting of nanoparticles from the skin to the tdLN (Supplementary Fig.…”

“…Nanoparticles developed by our group target skin-draining LNs and resident antigen-presenting cells (APC) upon intradermal administration (20,21). To determine whether nanoparticles could be targeted to the tdLN harnessing lymphatic drainage, we polarized one side of the mouse as being tumordraining by inoculating 10 6 E.G7-OVA tumor cells intradermally on one side of the back of mice, thus defining an ipsi tumor-draining side and the contra non-tumor-draining side ( Supplementary Fig.…”

“…Strategies based on delivering adjuvants or antigens carried by nanoparticles or liposomes have led to improved targeting of LNs, activation of LN-resident DCs, and enhanced induction of antigen-specific CD8 þ T cells, hence better protection in tumor challenge studies (14)(15)(16)(17)(18)(19). Ultrasmall, functionalizable nanoparticles (NP) developed in our laboratory effectively target DCs in skin-draining LNs upon intradermal delivery (20,21). These nanoparticles lead to antigen crosspresentation by DCs and to enhanced cytotoxic antigenspecific CD8 þ T-cell immunity when coupled with an antigen or an adjuvant (22)(23)(24).…”

Harnessing Nanoparticles for Immune Modulation

“…Once there, NPs rarely escape the lymph node, which generally contains foreign antigenic material to limit the spread of invasive pathogens. Only ultrafine NPs (30 nm in size) seem to circumvent this sequestration [54]. However, this size of NP is associated with increased potential for oncogenesis and toxicity.…”

15 years on siRNA delivery: Beyond the State-of-the-Art on inorganic nanoparticles for RNAi therapeutics

“…Nanoparticles can also be delivered subcutaneously by intradermal injection [157], epidermal electroporation [158] or via microneedles [159] but also as topical applications using hydrogel scaffolds or patches [154].…”