Nanoformulations

Carbon nanotubes (CNTs), gold and magnetic iron oxide nanoparticles, dendrimers, polystyrene microsperes as well as polyethylenimine and polyethylenimine-graft-poly(ethylene glycol) block copolymers, and phospholipid microbubbles are solid phase platforms of drug delivery. Since water solubility is essential to use them as an infusion component, the majority of these agents must be solubilized by covalent functionalization of their surface with different chemical groups or by adsorption of amphiphilic molecules, such as poly-ethylene glycol – phospholipids (PEG–lipids) (Moghimi SM, Andersen AJ 2010J Controlle Release).

These nanoformulations often cause adverse HSRs in medical practice, which patho-mechanisms are not fully understood, but in the majority of cases it could be connected to a strong complement activation (Moghimi SM, Andersen AJ 2010J Controlle Release; Merkel OM, Urbanics R 2011 Biomaterials; Szebeni J, Bedocs P, 2012 Advanced drug delivery reviews) by different pathways. For example non-functionalized CNTs cause complement activation due to adsorption of C1q (Salvador-Morales C, Flahaut E 2006 Molecular immunology). Covalent functionalization often decrease their complement activating potential (Salvador-Morales C, Basiuk EV 2008 Journal of nanoscience and nanotechnology). Moreover, covering the structures with PEG–lipids may results in uniform particles in immunological aspects as they usually activate the complement system even les manner by lectin pathway (Moghimi SM, Andersen AJ 2010J Controlle Release; Hamad I, Hunter AC 2006 2008; Moghimi SM, Hunter AC 2001 Pharmacological reviews; Moghimi SM, Szebeni J 2003 Progress in lipid research).

Our porcine model (Link) (Szebeni J, Bedocs P, 2012 Advanced drug delivery reviews) is especially sensitive for nanoformulation colloids because of the substantial pulmonary intravascular macrophage (PIM) (Chitko-McKown CG, Blecha F  1992 Annales de recherches veterinaires Annals of veterinary research; Winkler GC 1988 The American journal of anatomy) population in pigs, which can be activated by receptor mediated by endocytosis of opsonised particles, being born a consequence of complement fragments (C3b, C5b). Although the function and the origin of these cells are similar to liver Kupffer cells (Liu Z, Davis C 2008 Proceedings of the National Academy of Sciences of the United States of America) in humans and rodents, since both cells types are responsible for the elimination of debris sized particles, PIM cells seems to have further additional immunological role in response to intravenous agents.

References

Moghimi SM, Andersen AJ, Hashemi SH, Lettiero B, Ahmadvand D, Hunter AC, et al. Complement activation cascade triggered by PEG-PL engineered nanomedicines and carbon nanotubes: the challenges ahead. Journal of controlled release : official journal of the Controlled Release Society 2010;146:175-81.

Merkel OM, Urbanics R, Bedocs P, Rozsnyay Z, Rosivall L, Toth M, et al. In vitro and in vivo complement activation and related anaphylactic effects associated with polyethylenimine and polyethylenimine-graft-poly(ethylene glycol) block copolymers. Biomaterials 2011;32:4936-42.

Szebeni J, Bedocs P, Csukas D, Rosivall L, Bunger R, Urbanics R. A porcine model of complement-mediated infusion reactions to drug carrier nanosystems and other medicines. Advanced drug delivery reviews 2012;64:1706-16.

Salvador-Morales C, Flahaut E, Sim E, Sloan J, Green ML, Sim RB. Complement activation and protein adsorption by carbon nanotubes. Molecular immunology 2006;43:193-201.

Salvador-Morales C, Basiuk EV, Basiuk VA, Green ML, Sim RB. Effects of covalent functionalization on the biocompatibility characteristics of multi-walled carbon nanotubes. Journal of nanoscience and nanotechnology 2008;8:2347-56.

Hamad I, Hunter AC, Szebeni J, Moghimi SM. Poly(ethylene glycol)s generate complement activation products in human serum through increased alternative pathway turnover and a MASP-2-dependent process. 20062008;46:225-32.

Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacological reviews 2001;53:283-318.

Moghimi SM, Szebeni J. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Progress in lipid research 2003;42:463-78.

Chitko-McKown CG, Blecha F. Pulmonary intravascular macrophages: a review of immune properties and functions. Annales de recherches veterinaires Annals of veterinary research 1992;23:201-14.

Winkler GC. Pulmonary intravascular macrophages in domestic animal species: review of structural and functional properties. The American journal of anatomy 1988;181:217-34.

Liu Z, Davis C, Cai W, He L, Chen X, Dai H. Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy. Proceedings of the National Academy of Sciences of the United States of America 2008;105:1410-5.