Iron oxide nanoparticles and the mechanisms of immune recognition of nanomedicines.

Abstract

Nanomaterials are foreign substances that are treated by the immune system just like foreign invading pathogens. The immune system (innate immunity for the most part) is trained to recognize regular arrangements of chemical groups, which is what engineered nanomaterials are. The immune recognition poses multiple challenges to the use of nanomaterials for drug and gene delivery. One of the untoward results of immune recognition to nanomaterials once they are injected into the circulation is activation of the complement cascade. The complement system is a central component of the innate immunity accounting for about 5% of globulins in serum and is responsible for recognizing, eliminating and destroying pathogens [1]. Uncontrolled complement activation is known to cause inflammation, immune cell activation, increased vascular permeability and even tumor growth [1–3]. Nanocarriers can cause complement activation-related pseudoallergy or CARPA (term introduced by Dr Szebeni [4]). CARPA is a known phenomenon following infusion of Doxil (liposomal doxorubicin), Taxol (cremophorpaclitaxel), Feridex (dextran iron oxide) and SandImmune (cremophor-cyclosporine A). Numerous reports demonstrated complement activation by carbon nanotubes [5], micelles [6], liposomes, [7] polymer [8] and gold nanoparticles [9] in vitro and in vivo. Additional effects of complement activation are nanoparticle opsonization with complement fragments and subsequent clearance by macrophages and leukocytes. Besides complement, other mechanisms of recognition and clearance of nanoparticles are known. Scavenger receptors (SRs) are professional phagocytic pattern recognition receptors that were discovered in 1979 [10] and are responsible for opsonin-independent binding and uptake of oxidized low-density lipoprotein (oxLDL), pathogens, environmental particles and apoptotic cells. The universal feature of SRs is that their ligands possess a pattern of negative charges. SRs are implicated in the immune uptake of numerous nanoparticle types [11]. The main criticism of studies of immune mechanisms of clearance of nanomedicines in order to prolong circulation and decrease complement activation could be summarized in two questions: why not make thousands of nanoparticulate compounds (by combinatorial approach) and one of them will work? How the immune recognition can be blocked after learning that proteins (receptors) X, Y and Z mediate nanoparticle clearance? The answer to these questions is complex. Can we use the rational knowledge to modify nanoparticle structure to avoid the immune receptors? Superparamagnetic iron oxides (SPIO) are a nice illustration of how understanding the mechanisms of immune recognition could be useful to decrease immune Iron oxide nanoparticles and the mechanisms of immune recognition of nanomedicines