Micellar Solvents

Intravenous application of polyethoxylated surfactants, Cremophor-EL (CrEL) and Tween-80 (T80), also known as Polysorbate-80 is approved by the US Food and Drug Administration as well as the European Medicines Agency. They are used as excipients of various hydrophobic compounds, for example, vitamins, several antineoplastic and immunosuppressive agents, anesthetics and analgesics. Although these sufactants are generally considered safe serious forms of hypersensitivity reactions have been reported in a number of medicines containing CrEL and T80, including Paclitaxel and Taxotere, and a number of other experimental drug formulations (Hüttel 1986; Kris MG, O’Connell JP et al. 1986; Kris MG, O’Connell JP et al. 1988; Loos WJ, Szebeni J et al. 2002; Kloover JS, den Bakker MA et al., 2004; Szebeni J 2012 Eur J Nanomed). We have shown that these surfactants activate the complement system in vitro, in normal human serum and plasma as both Cremophor-EL and Tween-80 promoted the generation of biologically active complement products, C3a, C5a and C5b-9 (Weiszhar Zs 2011 Eur J Pharm). Consistently, Paclitaxel and Taxotere (Docetaxel), pharmaceuticals formulated in Cremophor-EL and Tween-80, activated the complement system to a similar extent. Moreover, comparison of serum reactivity against the drug-loaded and drug-free formulations exhibited a significant linear correlation, confirming the hypothesis that therapeutic side effects, such as acute hypersensitivity and systemic immunostimulation, caused by intravenous nanomedicines containing polyethoxylated detergents such as Cremophor-EL and Tween-80, can be attributed to complement activation-derived inflammatory mediators. Several micellar marketed drugs (see Table below) have been shown to cause infusion recation (reviewed in Szebeni 2012 EJN)

As far as the mechanism of complement activation is concerned, the current hypothesis is that repetitive ’OH-CH2-CH2-O-’ backbone segments which are displayed on mannan polymers as well as on the surface of micelles and vesicles of poloxamer block copolymers and also on the micelles of polyethoxylated surfactants such as CrEL, T80 and T20, can serve as a putative docking site for mannose binding lectin (MBL; Moghimi SM, Andersen AJ et al., 2011; Moghimi SM, Hunter AC et al., 2004). In addition, the nucleophilic hydroxyls in the terminal hydroxyl polyethoxylene segments are also favorable for complement activation by allowing thioester group-mediated fixation of nascent C3b. This way, surface bound C3b molecules can synergize with MBLs to induce the complement reaction cascade facilitating assembly and activation of C3 convertases and, subsequently, C5 convertase complexes.

Dogs but not pigs react to micellar lipids (such as Cremophor EL) in vivo and their response includes pronounced blood cell and vegetative neural changes (e.g., leukopenia followed by leukocytosis, thrombocytopenia, fluid excretions) as reviewed by Szebeni et al., 2007. This implies that both in vitro and in vivo tests exist to test reactogenicity of agents as well as susceptibility of a particular patient.Micellar solvents táblaMarketed micellar drugs causing infusion reactions

 

References

Kris MG, O’Connell JP, Burtin C, Renoux M, Chapuy E, Rodriguez M Study of histamine release induced by acute administration of antitumor agents in dogs. Cancer Chemother. Pharmacol. 1988; 21: 246-50.

Hüttel MS, Schou Olesen A, Stoffersen E Complement-mediated reactions to diazepam with Cremophor as solvent (Stesolid MR). Br. J. Anaesth. 1980; 52: 77-9.

Kloover JS, den Bakker MA, Gelderblom H, van Meerbeeck JP Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens. Br. J. Cancer. 2004; 90:304-5.

Kris MG, O’Connell JP, Gralla RJ, Wertheim MS, Parente RM, Schiff PB, Young CW Phase I trial of taxol given as a 3-hour infusion every 21 days. Cancer Treat. Rep. 1986; 70: 605-7.

Loos WJ, Szebeni J, Ten Tije AJ, Verweij J, van Zomeren DM, Chung KN, Nooter K, Stoter G, Sparreboom A Preclinical evaluation of alternative pharmaceutical delivery vehicles for paclitaxel. Anticancer Drugs. 2002; 13:767-75.

Moghimi SM, Hunter AC, Dadswell CM, Savay S, Alving CR, Szebeni J Causative factors behind poloxamer 188 (Pluronic F68, Flocor)-induced complement activation in human sera. A protective role against poloxamer-mediated complement activation by elevated serum lipoprotein levels. Biochim. Biophys. Acta. 2004; 1689: 103-13.

Moghimi SM, Andersen AJ, Hashemi SH, Lettiero B, Ahmadvand D, Hunter AC, Andresen TL, Hamad I, Szebeni J Complement activation cascade triggered by PEG-PL engineered nanomedicines and carbon nanotubes: the challenges ahead. J. Control Release. 2010; 146: 175-81.

Moghimi SM, Andersen AJ, Ahmadvand D, Wibroe PP, Andersen TL, Hunter AC Material properties in complement activation. Advanced Drug Delivery Reviews. 2011; 63(12):1000-7

Szebeni J, Alving CR, Rosivall L, Bünger R, Baranyi L, Bedöcs P, Tóth M, Barenholz Y Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles. J Liposome Res. 2007;17(2):107-17.

Szebeni J Haemocompatibility testing for nanomedicines and biologicals: Predictive assays for complement mediated infusion reactions. Eur. J. Nanomedicine, 2012; 4(1), 33-53

Weiszhár Z, Czúcz J, Révész C, Rosivall L, Szebeni J, Rozsnyay Z Complement activation by polyethoxylated pharmaceutical surfactants: Cremophor-EL, Tween-80 and Tween-20. Eur J Pharm Sci. 2012;45(4):492-8.