Citrem modulates internal nanostructure of glyceryl monooleate dispersions and bypasses complement activation: Towards development of safe tunable intravenous lipid nanocarriers.
Lyotropic non-lamellar liquid crystalline (LLC) aqueous nanodispersions hold a great promise in drug solubilization and delivery, but these nanosystems often induce severe hemolysis and complement activation, which limit their applications for safe intravenous administration. Here, we engineer and characterize LLC aqueous nanodispersions from a binary lipid mixture consisting of 2,3-dihydroxypropyl oleate (glyceryl monooleate) and medium-chain triglycerides with tunable internal nanostructures and improved hemocompatibility controlled by citrem as stabilizer. Citrem, in a concentration-dependent manner, modulates the internal nanostructure of LLC dispersions from a biphasic H2/L2 feature to a neat L2 phase, where the latter resembles "thread-like" swollen micelles. Citrem stabilization totally overcomes hemolysis and complement activation, thus realizing the potential of the engineered LLC aqueous nanodispersions for exploitation in intravenous delivery of drugs and contrast agents.


BACKGROUND
The complement system often gets activated after intravenous injection of nano drug-carriers. This may result in detrimental systemic effects. The authors described in this article the use of citrem as a stabilizing agent and showed the ability of this agent to abolish complement activation. Hence, citrem may prove to be an important component of tunable LLC nanocarriers that may be useful in future clinical setting.
Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen Ø, Denmark.
Peter P
PP
Wibroe
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen Ø, Denmark.
Intan D
ID
Mat Azmi
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen Ø, Denmark.
Christa
C
Nilsson
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen Ø, Denmark.
Anan
A
Yaghmur
Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen Ø, Denmark; NanoScience Centre, University of Copenhagen, Copenhagen Ø, Denmark. Electronic address: moein.moghimi@gmail.com.
S Moein
SM
Moghimi
D019343:Citric Acid / Q000009:adverse effects / Q000031:analogs & derivatives*; D003167:Complement Activation / Q000187:drug effects; D004337:Drug Carriers / Q000009:adverse effects / Q000737:chemistry*; D004951:Esterification; D005079:Excipients / Q000009:adverse effects / Q000737:chemistry*; D005989:Glycerides / Q000009:adverse effects / Q000737:chemistry*; D006801:Humans; D050866:Liquid Crystals / Q000009:adverse effects / Q000737:chemistry; D049329:Nanostructures / Q000009:adverse effects / Q000737:chemistry*; D053838:Scattering, Small Angle; D014280:Triglycerides / Q000009:adverse effects / Q000737:chemistry*; D014961:X-Ray Diffraction
D004337:Drug Carriers; D005079:Excipients; D005989:Glycerides; D014280:Triglycerides; D019343:Citric Acid; C005953:monoolein
Citrem; Complement system; Hexosomes; Hierarchical materials; Synchrotron small-angle X-ray scattering (SAXS)