The complement system is the first line of body's defense against intruders and it acts as a functional bridge between innate and adaptive arms of the immune system. This commentary examines the key roles of complement activation in response to nanomedicine administration, including nucleic acid complexes. These comprise beneficial (eg, adjuvanticity) as well as adverse effects (eg, infusion-related reactions). Pigs (and sheep) are often used as predictive models of nanomedicine-mediated infusion-related reactions in humans. The validity of these models in relation to human responses is questioned, and an alternative hypothesis is presented.
Get full access to this article
View all access options for this article.
References
1.
DunkelbergerJR and SongW-C. (2010). Complement and its role in innate and adaptive immune responses. Cell Res, 20:34–50.
2.
MoghimiSM, AndersenAJ, AhmadvandD, WibroePP, AndresenTL and HunterAC. (2011). Material properties in complement activation. Adv Drug Deliv Rev, 63:1000–1007.
3.
InturiS, WangG, ChenF, BandaNK, HoldersAM, WuLP, MoghimiSM and SimbergD. (2015). Modulatory role of surface coating of superparamagnetic iron oxide nanoworms in complement opsonization and leukocyte uptake. ACS Nano doi:10.1021/acsnano.5b05061.
4.
MoghimiSM, HunterAC and AndresenTL. (2012). Factors controlling nanoparticle pharmacokinetics: an integrated analysis and perspective. Annu Rev Pharmacol Toxicol, 52:481–503.
5.
JiangH, CooperB, RobeyFA and GewurzH. (1992). DNA binds and activates complement via residues 14–26 of the human C1q A chain. J Biol Chem, 267:25597–25601.
6.
PlankC, MechtlerK, SzokaFCJr and WagnerE. (1996). Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery. Human Gene Ther, 17:1437–1446.
7.
WuLP, FickerM, ChristensenJB, TrophopoulosPN and MoghimiSM. (2015). Dendrimers in medicine: therapeutic concepts and pharmaceutical challenges. Bioconjug Chem, 26:1198–1211.
8.
MoghimiSM, HamadI, AndresenTL, JørgensenK and SzebeniJ. (2006). Methylation of the phosphate oxygen moiety of phospholipid-methoxy(polyethylene glycol) conjugate prevents PEGylated liposome-mediated complement activation and anaphylatoxin production. FASEB J, 20:2591–2593.
9.
AndersenAJ, RobinsonJT, DaiH, HunterAC, AndresenTL and MoghimiSM. (2013). Single-walled carbon nanotube surface control of complement recognition and activation. ACS Nano, 7:1108–1119.
10.
HamadI, Al-HanbaliO, HunterAC, RuttKJ, AndresenTL and MoghimiSM. (2010). Distinct polymer architecture mediates switching of complement activation pathways at the nanosphere-serum interface: implications for stealth nanoparticle engineering. ACS Nano, 4:6629–6638.
11.
Von ZabernI. (2004). Effects of drugs, venoms and charged polymers on the complement system. 6c. Action of polyionic substances on the complement system. In: Activators and Inhibitors of Complement. SimRB, ed. Springer Science+Business Media, Dordrecht, pp 149–166.
12.
ManegoldCD, GravenorD, WoytowitzD, MezgerJ, HirshV, AlbertG, Al-AdhamiM, ReadettD, KriegAM and LeichmanCG. (2008). Randomized phase II trial of a toll-like receptor 9 agonist oligodeoxynucleotide, PF-3512676, in combination with first-line taxane plus platinum chemotherapy for advanced-stage non-small-cell lung cancer. J Clin Oncol, 26:3979–3986.
13.
SchneebergerA, WagnerC, ZemannA, LührsP, KutilR, GoosM, StinglG and WagnerSN. (2004). CpG motifs are efficient adjuvants for DNA cancer vaccines. J Invest Dermatol, 123:371–379.
14.
MagsboAM, SanchezJ, AngerK, LambrisJD, EkdahlKN, LoskogAS, NilssonB and TöttermanTH. (2009). Complement activation by CpG in a human whole blood loop system: mechanisms and immunomodulatory effect. J Immunol, 183:6724–6732.
15.
ZhangX, KimuraY, FangC, ZhouL, SfyroeraG, LambrisJD, WetselRA, MiwaT and SongW-C. (2007). Regulation of toll-like receptor-mediated inflammatory response by complement in vivo. Blood, 110:228–236.
16.
Song WC. (2012). Crosstalk between complement and toll-like receptors. Toxicol Pathol, 40:174–182.
17.
DempseyPW, AllisonME, AkkarajuS, GoodnowCC and FearonDT. (1996). C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science, 271:348–350.
18.
BajicG, YatimeL, Sim RBRB, Vorup-JensenT and AndersenGR. (2013). Structural insight on the recognition of surface-bound opsonins by the integrin I domain of complement receptor 3. Proc Natl Acad Sci U S A, 110:16426–16431.
19.
MoghimiSM, WibroePP, HelvigS, FarhangraziZS and HunterAC. (2012). Genomic perspectives in inter-individual adverse responses following nanomedicine administration: the way forward. Adv Drug Deliv Rev, 64:1385–1393.
20.
MoghimiSM and FarhangraziZS. (2013). Nanomedicine and the complement paradigm. Nanomed Nanotechnol Biol Med, 9:458–460.
21.
KlosA, TennerAJ, JohswichKO, AgerRR, ReisES and KöhlJ. (2009). The role of the anaphylatoxins in health and disease. Mol Immunol, 46:2753–2766.
22.
GuoRF and WardPA. (2005). Role of C5a in inflammatory responses. Annu Rev Immunol, 23:821–852.
23.
RittirschD, RedlH and Huber-LangM. (2012). Role of complement in multiorgan failure. Clin Dev Immunol. 962927.
24.
MrkiewskiMM, DeAngelisRA, BeneciaF, Ricklin-LichtsteinerSK, KoutoulakiA, GerardC, CoukosG and LambrisJD. (2008). Modulation of the antitumor immune responses by complement. Nat Immunol, 9:1225–1235.
25.
MoghimiSM and FarhangraziZS. (2014). Just so stories: the random act of anti-cancer nanomedicine performance. Nanomed Nanotechnol Biol Med, 10:1661–1666.
26.
Moghimi SM. (2014). Cancer nanomedicine and the complement system activation paradigm: anaphylaxis and tumour growth. J Control Release, 190:556–562.
27.
SabnaniMK, RajanR, RowlandB, MavinkurveV, WoodLM, GabizonAA and La-BeckNM. (2015). Liposome promotion of tumor growth is associated with angiogenesis and inhibition of antitumor immune responses. Nanomed Nanotechnol Biol Med, 11:259–262.
28.
SzebeniJ, MuggiaF, GabizonA and BarenholzY. (2011). Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliv Rev, 63:1020–1030.
29.
SzebeniJ. (2014). Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biological. Mol Immunol, 61:163–173.
30.
SzebeniJ, BedocsP, CsukásD, RosivallL, BüngerR and UrbanicsR. (2012). A porcine model of complement-mediated infusion reactions to drug carrier nanosystems and other medicines. Adv Drug Deliv Rev, 64:1706–1716.
31.
SzebeniJ, BaranyiL, SávayS, BodóM, MilosevitsJ, AlvingCR and BüngerR. (2006). Complement activation-related cardiac anaphylaxis in pigs: role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function. Am J Physiol Heart Cir Physiol, 290:H1050–H1058.
32.
SzebeniJ, FontanaJL, WassefNM, MorganPD, MorseDS, DobbinsDE, StahlGL, BüngerR and AlvingCR. (1999). Hemodynamic changes induced by liposomes and liposome-encapsulated hemoglobin in pigs: a model of pseudoallergic cardiopulmonary reactions to liposomes. Role of complement and inhibition by soluble CR1 and anti-C5a antibody. Circulation, 99:2302–2309.
33.
Chanan-KhanA, SzebeniJ, SavayS, LiebesL, RafiqueNM, AlvingCR and MuggiaFM. (2003). Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions. Ann Oncol, 14:1430–1437.
34.
Chitko-McKownCG and BlechaF. (1992). Pulmonary intravascular macrophages: a review of immune properties and functions. Ann Recherches Vétérinaires, 23:201–214.
35.
Warner AE. (1996). Pulmonary intravascular macrophages. Clin Chest Med, 17:125–135.
36.
MiyamotoK, ScultzE, HeathT, MitchellMD, AlbertineKH and StaubNC. (1988). Pulmonary intravascular macrophages and hemodynamic effects of liposomes in sheep. J Appl Physiol, 64:1143–1152.
37.
SoneY, SerikovVB and Staub SrNC. (1999). Intravascular macrophage depletion attenuates endotoxin lung injury in anesthetized sheep. J Appl Physiol, 87:1354–1359.
38.
StoneY, NicolaysenA and Staub SrNC. (1997). Effect of particles on sheep lung hemodynamics parallels depletion and recovery of intravascular macrophages. J Appl Physiol, 83:1499–1507.
39.
LongworthKE, WestgateAM, GradyMK, WestcottJY and StaubNC. (1992). Development of pulmonary intravascular macrophages function in newborn lambs. J Appl Physiol, 73:2608–2615.
40.
SchnebergerD, LewisD, CaldwellS and SinghB. (2011). Expression of toll-like receptor 9 in lungs of pigs, dogs and cattle. Int J Exp Pathol, 92:1–7.
41.
WassefA, JanardhanK, PearceJW and SinghB. (2004). Toll-like receptor 4 in normal and inflamed lungs and other organs of pig, dog and cattle. Histol Histopathol, 19:1201–1208.
42.
KawaiT and AkiraS. (2011). Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity, 34:637–650.
43.
SchnebergerD, Abaronson-RazK and SinghB. (2012). Pulmonary intravascular macrophages and lung health: what are we missing?. Am J Physiol Lung Mol Cell Physiol, 302:L498–L503.
44.
DehringDJ and WismarBL. (1989). Intravascular macrophages in pulmonary capillaries of humans. Am Rev Respir Dis, 139:1027–1029.
45.
KeyesJWJr, WilsonGA and QuinonestJD. (1973). An evaluation of lung uptake of colloid during liver imaging. J Nucl Med, 14:687–691.
46.
Imarisio JJ. (1975). Liver scan showing intense lung uptake in neoplasia and infection. J Nucl Med, 16:188–190.
47.
LanttoT, LuostarinenM and VorneM. (1986). Clinical significance of lung uptake in liver scanning. Nuklearmedizin, 25:15–18.
48.
Mit-NoiraultE, FaureL, GuichardY, MonthrauJ and Le PapeA. (2001). Scintigraphic in vivo assessment of the development of pulmonary intravascular macrophages in liver disease. Chest, 120:941–947.
49.
SmithJS, TianJ, LozierJN and ByrnesAP. (2004). Severe pulmonary pathology after intravenous administration of vectors in cirrhotic rats. Mol Ther, 9:932–941.
50.
SmithJS, TianJ, MullerJ and ByrnesAP. (2004). Unexpected pulmonary uptake of adenoviruses in animals with chronic liver disease. Gene Ther, 11:431–438.
51.
GillSS, SuriSS, JanardhanKS, CaldwellS, DukeT and Singh.B (2008). Role of pulmonary intravascular macrophages in endotoxin-induced lung inflammation and mortality in a rat model. Respir Res, 9:69.
52.
ThenappanT, GoelA, MarsboomG, FangYH, TothPY, ZhangHJ, KajimotoH, HongZ, PaulJ, et al. (2011). A central role for CD68+ macrophages in hepatopulmonary syndrome. Reversal by macrophage depletion. Am J Respir Crit Care Med, 183:1080–1091.
53.
MaroneG, PatellaV, de CrescenzoG, GenoveseA and AdtM. (1995). Human heart mast cells in anaphylaxis and cardiovascular disease. Int Arch Allergy Immunol, 107:72–75.
54.
MoghimiSM and SzebeniJ. (2003). Stealth liposomes and long-circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res, 42:463–478.
55.
LavermanP, CarstensMG, StormG and MoghimiSM. (2001). Recognition and clearance of methoxypoly(ethyleneglycol)2000-grafted liposomes by macrophages with enhanced phagocytic capacity. Implications in experimental and clinical oncology. Biochim Biophys Acta, 1526:227–229.
56.
MoghimiSM and GrayT. (1997). A single dose of intravenously injected poloxamine-coated long-circulating particles triggers macrophage clearance of subsequent doses in rats. Clin Sci, 93:371–379.
57.
MoghimiSM and MurrayJC. (1996). Poloxamer-188 revisited: a potentially valuable immune modulator?. J Natl Cancer Inst, 88:766–768.
58.
MoghimiSM, HedemanH, ChristyNM, IllumL and DavisSS. (1993). Enhanced hepatic clearance of intravenously administered sterically stabilized microspheres in zymosan-stimulated rats. J Leukoc Biol, 54:513–517.
59.
MoghimiSM and HunterAC. (2001). Capture of stealth nanoparticles by body's defences. Crit Rev Ther Drug Carrier Syst, 18:527–550.
60.
MoghimiSM, PeerD and LangerR. (2011). Reshaping the future of nanopharmaceuticals: ad iudicium. ACS Nano, 5:8454–8458.
61.
CastellsM. (2006). Desensitization for drug allergy. Curr Opin Allergy Clin Immunol, 6:476–481.
62.
ToyR, PeirisPM, GhaghadaKB and KarathanasisE. (2013). Shaping cancer nanomedicine: the effect of particle shape on the in vivo journey of nanoparticles. Nanomedicine (Lond), 9:121–133.
63.
ElmenW, LiW and KirschfinkM. (2010). Therapeutic complement inhibition: new developments. Semin Thromb Hemost, 36:660–668.
64.
RicklinD and LambrisJD. (2013). Progress and trends in complement therapeutics. Adv Exp Med Biol, 735:1–22.
65.
YatimeL, MaaschC, HoehligK, KlussmannS, AndersenGR and Vater.A (2015). Structural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer. Nat Commun, 6:6481.
