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Advanced Drug Delivery Reviews (v.63, #12)
Complement monitoring of nanomedicines and implants
by S.M. Moghimi Theme Editor; A.C. Hunter Theme Editor (pp. 963-964).
Complement in health and disease by Maria V. Carroll; Robert B. Sim (pp. 965-975).
The complement system consists of about 35–40 proteins and glycoproteins present in blood plasma or on cell surfaces. Its main biological function is to recognise “foreign” particles and macromolecules, and to promote their elimination either by opsonisation or lysis. Although historically complement has been studied as a system for immune defence against bacteria, it has an important homeostatic role in which it recognises damaged or altered “self” components. Thus complement has major roles in both immune defence against microorganisms, and in clearance of damaged or “used” host components.Since complement proteins opsonise or lyse cells, complement can damage healthy host cells and tissues. The system is regulated by many endogenous regulatory proteins. Regulation is sometimes imperfect and both too much and too little complement activation is associated with many diseases. Excessive or inappropriate activation can cause tissue damage in diseases such as rheumatoid arthritis, age-related macular degeneration (AMD), multiple sclerosis, ischemia–reperfusion injury (e.g. ischemic stroke). Insufficient complement activity is associated with susceptibility to infection (mainly bacterial) and development of autoimmune disease, like SLE (systemic lupus erythematosus).Display Omitted
Keywords: Complement; Innate immunity; Blood plasma; Collectins; Inflammation; Phagocytosis; Opsonisation; Autoimmunity; Infection; Disease
Advances in assay of complement function and activation by Morten Harboe; Ebbe Billmann Thorgersen; Tom Eirik Mollnes (pp. 976-987).
The main function of the complement system is pattern recognition of danger. Typical exogenous danger signals are pathogen associated molecular patterns inducing a protective inflammatory response. Other examples are exposure to foreign surfaces of biomedical materials including nanoparticles, which principally induce the same inflammatory response. If a surface is “foreign” to the host, it induces complement activation. Development of monoclonal antibodies to neoepitopes on complement activation products introduced an entirely new set of methods for assay of complement activation. Activation of complement by a surface occurs by impairment of the fine balance of the control system, e.g. by preferred binding of factor B at the expense of factor H. Sensitive methods to detect complement activation on surfaces and in the fluid phase are a prerequisite for investigation of the biocompatibility of artificial materials. This information can be used to develop new materials with enhanced biocompatibility. Here we review available methods to study human and animal complement function and activation in vitro and in vivo.Display Omitted
Keywords: Complement; Activation; Assay; Neoepitopes; Danger signals; Nanoparticles; Animal
Surface plasmon resonance in monitoring of complement activation on biomaterials by Yusuke Arima; Mitsuaki Toda; Hiroo Iwata (pp. 988-999).
When artificial materials come into contact with blood, various biological responses are induced. For successful development of biomaterials used in biomedical devices that will be exposed to blood, understanding and control of these interactions are essential. Surface plasmon resonance (SPR) spectroscopy is one of the surface-sensitive optical methods to monitor biological interactions. SPR enables real-time and in situ analysis of interfacial events associated with biomaterials research. In this review, we describe an SPR biosensor and its application to monitor complement activation onto biomaterials surface. We also discuss the effect of surface properties of the material on complement activation.Display Omitted
Keywords: Complement activation; Surface plasmon resonance; Self-assembled monolayer; Polymer coating; Nonspecific protein adsorption; The classical pathway; The alternative pathway
Material properties in complement activation by S. Moein Moghimi; Alina J. Andersen; Davoud Ahmadvand; Peter P. Wibroe; Thomas L. Andresen; A. Christy Hunter (pp. 1000-1007).
Uncontrolled complement activation can induce many inflammatory and life threatening conditions. Accordingly, the role of complement in initiation of adverse reactions to polymers and nanoparticulate drug carriers is receiving increasing attention and has prompted extensive ‘structure-immune performance’ relationship studies in nanomedicine research at many fronts. The interaction between nanomaterials and the complement system is complex and regulated by inter-related factors that include nanoscale size, morphology and surface characteristics. Each of these parameters may affect complement activation differently and through different sensing molecules and initiation pathways. The importance of material properties in triggering complement is considered and mechanistic aspects discussed. Mechanistic understanding of complement events could provide rational approaches for improved material design and nanoengineering strategies for clinical medicine.Display Omitted
Keywords: Acute allergic reactions; Liposomes; Nanospheres; Polymers; Nanomedicine; Nanotoxicology
Protein ultrastructure and the nanoscience of complement activation by Thomas Vorup-Jensen; Thomas Boesen (pp. 1008-1019).
The complement system constitutes an important barrier to infection of the human body. Over more than four decades structural properties of the proteins of the complement system have been investigated with X-ray crystallography, electron microscopy, small-angle scattering, and atomic force microscopy. Here, we review the accumulated evidence that the nm-scaled dimensions and conformational changes of these proteins support functions of the complement system with regard to tissue distribution, molecular crowding effects, avidity binding, and conformational regulation of complement activation. In the targeting of complement activation to the surfaces of nanoparticulate material, such as engineered nanoparticles or fragments of the microbial cell wall, these processes play intimately together. This way the complement system is an excellent example where nanoscience may serve to unravel the molecular biology of the immune response.Display Omitted
Keywords: Abbreviations; AFM; atomic force microscopy; C; component; CR; complement receptor; EM; electron microscopy; EOM; ensemble optimization method; Ig; immunoglobulin; MASP; MBL-associated serine protease; MBL; mannan-binding lectin; NMR; nuclear magnetic resonance; n.s.; not stated; PGN; peptidoglycan; SANS; small-angle neutron scattering; SAS; small-angle scattering; SAXS; small-angle X-ray scattering; TED; thiol ester domain; XRC; X-ray crystallographyImmunology; Immunoglobulins; Nanoparticles; X-ray crystallography; Electron microscopy; Small-angle scattering; Atomic force microscopy
Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: Prediction and prevention by Janos Szebeni; Franco Muggia; Alberto Gabizon; Yechezkel Barenholz (pp. 1020-1030).
Some therapeutic liposomes and lipid excipient-based anticancer drugs are recognized by the immune system as foreign, leading to a variety of adverse immune phenomena. One of them is complement (C) activation, the cause, or major contributing factor to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA represents a novel subcategory of acute (type I) hypersensitivity reactions (HSR), which is mostly mild, transient, and preventable by appropriate precautions. However, in an occasional patient, it can be severe or even lethal. Because a main manifestation of C activation is cardiopulmonary distress, CARPA may be a safety issue primarily in cardiac patients. Along with an overview of the various types of liposome-immune system interactions, this review updates the experimental and clinical information on CARPA to different therapeutic liposomes and lipid excipient-based (micellar) anticancer drugs, including PEGylated liposomal doxorubicin sulfate (PLD, Doxil®) and paclitaxel (Taxol®). The substantial individual variation of in vitro and in vivo findings reflects an extremely complex immune phenomenon involving multiple, redundant pathways of C activation, signal transduction in allergy-mediating cells and vasoactive mediator actions at the effector cell level. The latest advances in this field include the proposal of doxorubicin-induced shape changes and aggregation of liposomes in Doxil as possible contributing factors to CARPA caused by PLD, and the finding that Doxil-induced immune suppression prevents HSR to co-administered carboplatin, a significant benefit of Doxil in combination chemotherapy with carboplatin. The review evaluates the use of in vitro C assays and the porcine liposome-induced cardiopulmonary distress model for predicting CARPA. It is concluded that CARPA may become a frequent safety issue in the upcoming era of nanomedicines, necessitating its prevention at an early stage of nanomedicine R&D.Display Omitted
Keywords: Nanomedicines; Cancer chemotherapy; Immune toxicity; Adverse drug effects; Hypersensitivity reactions; Allergy; CARPA
Complement activation by carbon nanotubes by Malgorzata J. Rybak-Smith; Robert B. Sim (pp. 1031-1041).
Carbon nanotube interaction with an important part of the innate immune system, complement, needs to be taken into account when envisaging their use in biomedical applications. Carbon nanotubes (CNTs) and other synthetic materials are recognized by various components of the complement system in human or mammalian blood and also collectins in the lungs. Modification of the surface chemistry of CNTs alters their interactions with complement proteins and collectins. Functionalizations of CNTs which have been tested so far do not completely prevent complement activation or plasma protein binding. The interaction of the functionalized CNTs with the complement system proteins in blood may influence the adhesion of CNTs to phagocytic cells and red blood cells. Excessive activation of complement can have a harmful effect on human tissues and therefore significantly limit CNT applications in biomedicine.Display Omitted
Keywords: Innate immune system; Complement; C1q; Human plasma; Collectin; Inflammation; Carbon nanotubes; HDL; Serum albumin; Fibrinogen; RNA
Innate immunity activation on biomaterial surfaces: A mechanistic model and coping strategies by Kristina N. Ekdahl; John D. Lambris; Hans Elwing; Daniel Ricklin; Per H. Nilsson; Yuji Teramura; Ian A. Nicholls; Bo Nilsson (pp. 1042-1050).
When an artificial biomaterial (e.g., a stent or implantable pump) is exposed to blood, plasma proteins immediately adhere to the surface, creating a new interface between the biomaterial and the blood. The recognition proteins within the complement and contact activation/coagulation cascade systems of the blood will be bound to, or inserted into, this protein film and generate different mediators that will activate polymorphonuclear leukocytes and monocytes, as well as platelets. Under clinical conditions, the ultimate outcome of these processes may be thrombotic and inflammatory reactions, and consequently the composition and conformation of the proteins in the initial layer formed on the surface will to a large extent determine the outcome of a treatment involving the biomaterial, affecting both the functionality of the material and the patient's life quality. This review presents models of biomaterial-induced activation processes and describes various strategies to attenuate potential adverse reactions by conjugating bioactive molecules to surfaces or by introducing nanostructures.Display Omitted
Keywords: Autoprotection; Biomaterial; Coagulation; Complement; Contact activation; Inflammation; Innate immunity