Single-Walled Carbon Nanotube Surface Control of Complement Recognition and Activation

Abstract

Carbon nanotubes (CNTs) are receiving considerable attention in site-specific drug and nucleic acid delivery, photodynamic therapy, and photoacoustic molecular imaging. Despite these advances, nanotubes may activate the complement system (an integral part of innate immunity), which can induce clinically significant anaphylaxis. We demonstrate that single-walled CNTs coated with human serum albumin activate the complement system through C1q-mediated classical and the alternative pathways. Surface coating with methoxypoly(ethylene glycol)-based amphiphiles, which confers solubility and prolongs circulation profiles of CNTs, activates the complement system differently, depending on the amphiphile structure. CNTs with linear poly(ethylene glycol) amphiphiles trigger the lectin pathway of the complement through both L-ficolin and mannan-binding lectin recognition. The lectin pathway activation, however, did not trigger the amplification loop of the alternative pathway. An amphiphile with branched poly(ethylene glycol) architecture also activated the lectin pathway but only through L-ficolin recognition. Importantly, this mode of activation neither generated anaphylatoxins nor induced triggering of the effector arm of the complement system. These observations provide a major step toward nanomaterial surface modification with polymers that have the properties to significantly improve innate immunocompatibility by limiting the formation of complement C3 and C5 convertases.

Insidious pathogen-mimicking properties of nanoparticles in triggering the lectin pathway of the complement system

“…Similar observations have been reported with carbon nanotubes coated with PEG-conjugated molecules or covalently functionalized with PEG, where gross surface polymer architectural changes not only triggered lectin pathway, but further modulated the mode of lectin pathway activation through binding of different lectin pathway initiating molecules (e.g., MBL vs. L-ficolin) (13).…”

“…Although long believed that such strategies could suppress opsonization events in the blood (33,34), recent studies have demonstrated that some of these engineered entities can, indeed, incite complement and depending on surface polymer configuration complement activation may proceed exclusively through the lectin pathway (12,13,(17)(18)(19)21). For example, alteration of poloxamine 908 copolymer architecture on polystyrene nanospheres of 220 nm in size from a flat to mushroombrush configuration switched complement activation from the C1q-dependent classical pathway to a lectin pathway in human serum (12).…”

“…In case of the latter, attention has been mostly towards the classical and alternative pathways (3). Compelling evidence now suggest that many such nanoparticles insidiously incite complement through the lectin pathway, which involve carbohydrate recognition, but these nanoparticles natively do not express surface-exposed sugars (12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

Smart polymers in drug delivery: a biological perspective

“…53,60,61 In terms of bacterial or viral presence, the complement system recognizes these infective entities through pattern recognition. A similar mechanism is thought to Fig.…”

Preparation and biological activity of a paclitaxel-single-walled carbon nanotube complex

“…There are 2 main kinds of CNTs: single-wall CNTs (SWCNTs) and multi-wall CNTs. Studies have found that CNTs have a unique feature defined as a transmembrane, which enables them to pass through various cell membranes passively (Andersen et al, 2013). However, CNTs are highly hydrophobic, are insoluble in both water and organic solvents, and their biocompatibility is very poor.…”