Alina Joukainen Andersen

Complement activation cascade triggered by PEG-PL engineered nanomedicines and carbon nanotubes: The challenges ahead

Since their introduction, poly(ethylene glycol)-phospholipid (PEG-PL) conjugates have found many applications in design and engineering of nanosized delivery systems for controlled delivery of pharmaceuticals especially to non-macrophage targets. However, there are reports of idiosyncratic reactions to certain PEG-PL engineered nanomedicines in both experimental animals and man. These reactions are classified as pseudoallergy and may be associated with cardiopulmonary disturbance and other related symptoms of anaphylaxis. Recent studies suggest that complement activation may be a contributing, but not a rate limiting factor, in eliciting hypersensitivity reactions to such nanomedicines in sensitive individuals. This is rather surprising since PEGylated structures are generally assumed to suppress protein adsorption and blood opsonization events including complement. Here, we examine the molecular basis of complement activation by PEG-PL engineered nanomedicines and carbon nanotubes and discuss the challenges ahead.

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

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.

Perspectives on carbon nanotube-mediated adverse immune effects

Carbon nanotubes are entities of different morphology and aspect ratios with anisotropic character. Due to their unique electronic, photonic, mechanical and chemical properties, carbon nanotubes are receiving increasing attention in nanomedicine research where examples include site-specific drug and nucleic acid delivery, photodynamic therapy and photoacoustic molecular imaging. The interaction of carbon nanotubes with the immune system, which plays a key role in the recognition and elimination of foreign materials, and consequential responses, is of central importance for the proposed successful biomedical applications of nanotubes. Research in this avenue, however, is scant and the limited available data are rather contradictory. In this progress article we have collected some of the most important experimental results obtained thus far on carbon nanotube-mediated immune toxicity with an emphasis on cardiovascular exposure, including activation of the complement system, macrophage recognition and clearance, and overall effects on the functionality of different immune cells. Mapping these immune-related risks as well as understanding their molecular mechanisms is a crucial step in the development of any carbon nanotube-containing nanopharmaceuticals.

Complement activation by PEG-functionalized multi-walled carbon nanotubes is independent of PEG molecular mass and surface density

UNLABELLED Carboxylated (4%) multi-walled carbon nanotubes were covalently functionalized with poly(ethylene glycol)₁₀₀₀ (PEG₁₀₀₀), PEG₁₅₀₀ and PEG₄₀₀₀ with a PEG loading of approximately 11% in all cases. PEG loading generated non-uniform and heterogeneous higher surface structures and increased nanotube width considerably, but all PEGylated nanotube species activated the complement system in human serum equally. Increased PEG loading, through adsorption of methoxyPEG₂₀₀₀(or ₅₀₀₀)-phospholipid conjugates, generated fewer complement activation products; however, complement activation was never completely eliminated. Our observations address the difficulty in making carbon nanotubes more compatible with innate immunity through covalent PEG functionalization as well as double PEGylation strategies. FROM THE CLINICAL EDITOR Complement-mediated toxicity is a major limiting factor in certain nanomedicine applications. This study clarifies that PEGylation of carbon nanotubes is unlikely to address this complication.

Complement system and the brain: Selected pathologies and avenues toward engineering of neurological nanomedicines

Several nanoparticle systems and supramolecular assemblies are under investigation as potential therapeutic entities for Alzheimers disease and other neurological disorders through both brain-specific targeting and peripheral effects. However, activation of the complement system, a complex innate immune network of over 30 circulating and membrane-bound proteins, remains a serious concern related to the use of these prospective neurological nanomedicines. The role of complement in processes of neurodegeneration in the injured or aged and diseased central nervous system is well known. Nanoparticle-mediated complement activation cannot only induce adverse cardiopulmonary distress in sensitive subjects, but may further aggravate the already-compromised condition of neurological disorders and diseases. This minireview briefly examines the role of complement in neurological diseases and outlines the current status of the development of key neurological nanomedicines with respect to complement activation. Understanding of these topics is crucial for rational design and development of safe neurological nanomedicines.