In the past 20 years several liposomal medicines have reached European and US markets and many more are being tested in preclinical stages or undergoing clinical trials (Allen TM, Cullis PR, 2004 Science). Following introduction into the body liposomes may trigger the innate immune system, notably the complement cascade (which following activation participates in a broad range of immunological and inflammatory processes) and macrophage clearance mechanisms, which could also be complement-mediated (Moghimi SM, Hamad I 2008 J Liposome Res).
There is conclusive evidence that PEGylated liposomes are well capable of triggering complement (Szebeni et al., 2002; Moghimi SM, Hamad I et al., 2006 J Liposome Res). The longevity of PEGylated liposomes in the blood now appear to arise from the steric hindrance by the projected polymer chains of the binding of opsonized vesicles to their corresponding macrophage receptors (Moghimi SM, Hamad I et al., 2006 J Liposome Res; Dos Santos N, Allen C et al. 2007 Biochim Biophys Acta.). However, activated macrophages are still capable of recognizing and internalizing polymer-coated nanoparticles, including PEGylated liposomes, independent of opsonization processes (Moghimi SM, Gray T 1997 Clin Sci (Lond); Laverman P, Carstens MG et al. 2001 J Pharmacol Exp Ther.).
Liposomes may also induce immunogenicity; this result in antibody production against their various components and/or the encapsulated cargo. Indeed, liposomes have all long been used as adjuvants for vaccine formulations, particularly to enhance immunogenicity of sub-unit vaccines through protection and enhanced targeting to professional antigen-presenting cells for cross-presentation to MHC class I/II and CD1 pathways (Peachman KK, Rao M et al. 2005 Immunobiology; Alving CR, Rao M 2008 Vaccine; Karasavvas et al., 2008).
Another common, yet poorly understood immune side effect of liposomal drug therapy is infusion-related hypersensitivity reaction. This is an acute transient malaise that develops in a high percentage (2–45%) of patients within minutes of vesicle infusion and is due, at least in part, to activation of the complement system with subsequent generation of anaphylatoxins C3a and C5a (Szebeni J, Alving CR 1999 Artif Cells Blood Substit Immobil Biotechnol; Szebeni, 2005). Because of the lack of IgE mediation, this phenomenon has been referred to as complement activation-related pseudoallergy (CARPA) (reviewed in Szebeni J 2005 Toxicology). The haemodynamic, respiratory, cutaneous and subjective manifestations include hypotension or hypertension, dyspnea, flushing, rash and feeling of choking.
At present, more than a dozen liposomal drugs are in the market, and more in advanced clinical trials. The Figure below lists those liposomal drugs in the market that have been reported to cause CARPA). The frequency of reactions reported to different drugs varies between 3 % and 45 % (Szebeni 1998) . Out of these, the reactions to Doxil have been studied in most detail, in humans as well as animals. Complement activation by Doxil, documented in several studies (Szebeni J, Baranyi B et al. 2000 J Liposome Res; Szebeni J, Bedocs P et al. 2012 Nanomedicine NBM), have been correlated with clinical symptoms in humans (Chanan-Khan A, Szebeni J 2003 Ann Oncol) and pigs (Szebeni J, Bedocs P et al. 2012 Nanomedicine NBM) .
Alving CR, Rao M Lipid A and liposomes containing lipid A as antigens and adjuvants. Vaccine. 2008 Jun 6;26(24):3036-45.
Allen TM, Cullis PR Drug delivery systems: entering the mainstream. Science. 2004;303(5665):1818-22.
Chanan-Khan A, Szebeni J, Savay S, Liebes L, Rafi que NM, Alving CR, et al. Complement activation following fi rst exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions. Ann Oncol 2003;14:1430-7
Dos Santos N, Allen C, Doppen AM, Anantha M, Cox KA, Gallagher RC, Karlsson G, Edwards K, Kenner G, Samuels L, Webb MS, Bally MB. Influence of poly(ethylene glycol) grafting density and polymer length on liposomes: relating plasma circulation lifetimes to protein binding. Biochim Biophys Acta. 2007;1768(6):1367-77
Laverman P, Carstens MG, Boerman OC, Dams ET, Oyen WJ, van Rooijen N, Corstens FH, Storm G. Factors affecting the accelerated blood clearance of polyethylene glycol-liposomes upon repeated injection. J Pharmacol Exp Ther. 2001;298(2):607-12.
Moghimi SM, Hamad I, Bünger R, Andresen TL, Jørgensen K, Hunter AC, Baranji L, Rosivall L, Szebeni J. Activation of the human complement system by cholesterol-rich and PEGylated liposomes-modulation of cholesterol-rich liposome-mediated complement activation by elevated serum LDL and HDL levels. J Liposome Res. 2006;16(3):167-74.
Moghimi SM, Gray T. A single dose of intravenously injected poloxamine-coated long-circulating particles triggers macrophage clearance of subsequent doses in rats. Clin Sci (Lond). 1997;93(4):371-9.
Moghimi SM, Hamad I. Liposome-mediated triggering of complement cascade. J Liposome Res. 2008;18(3):195-209.
Peachman KK, Rao M, Alving CR, Palmer DR, Sun W, Rothwell SW. Human dendritic cells and macrophages exhibit different intracellular processing pathways for soluble and liposome-encapsulated antigens. Immunobiology. 2005;210(5):321-33.
Szebeni J, Baranyi L, Savay S, Milosevits J, Bunger R, Laverman P, Metselaar JM, Storm G, Chanan-Khan A, Liebes L, Muggia FM, Cohen R, Barenholz Y, Alving CR. Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes: experimental and clinical studies. J Liposome Res. 2002;12(1-2):165-72
Szebeni J, Alving CR. Complement-mediated acute effects of liposome-encapsulated hemoglobin. Artif Cells Blood Substit Immobil Biotechnol. 1999;27(1):23-41
Szebeni J. The interaction of liposomes with the complement system. Crit Rev Ther Drug Carrier Syst 1998;15:57 – 88.
Szebeni J, Baranyi B, Savay S, Lutz LU, Jelezarova E, Bunger R, et al. The role of complement activation in hypersensitivity to pegylated liposomal doxorubicin (Doxil), J Liposome Res 2000;10:347 – 61.
Szebeni J, Bedocs P, Rozsnyay Z, Weiszhár Zs, Urbanics R, Rosivall L, et al. Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome. Nanomedicine NBM 2012;8:176 – 84.
Szebeni J. Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity. Toxicology. 2005;216(2-3):106-21.