Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes.

Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation.

A structurally diverse library of safe-by-design citrem-phospholipid lamellar and non-lamellar liquid crystalline nano-assemblies.

Non-lamellar liquid crystalline aqueous nanodispersions, known also as ISAsomes (internally self-assembled 'somes' or nanoparticles), are gaining increasing interest in drug solubilisation and bio-imaging, but they often exhibit poor hemocompatibility and induce cytotoxicity. This limits their applications in intravenous drug delivery and targeting. Using a binary mixture of citrem and soy phosphatidylcholine (SPC) at different weight ratios, we describe a library of colloidally stable aqueous and hemocompatible nanodispersions of diverse nanoarchitectures (internal self-assembled nanostructures).

Soluble and immobilized graphene oxide activates complement system differently dependent on surface oxidation state.

Graphene oxide (GO) is believed to become applicable in biomedical products and medicine, thereby necessitating appropriate safety evaluation dependent on their applications and the route of administration. We have examined the effect of GO form (in solution versus immobilized) and oxidation state on two related elements of innate immunity: the complement system and interleukin-6 (IL-6) release in human blood. In solution, there was a decrease in GO-mediated complement activation with decreasing surface oxygen content (and altered oxygen functionality), whereas with immobilized GO complement response were reversed and increased with decreasing oxygen content.

An integrated assessment of morphology, size, and complement activation of the PEGylated liposomal doxorubicin products Doxil®, Caelyx®, DOXOrubicin, and SinaDoxosome.

In order to improve patient's benefit and safety, comprehensive regulatory guidelines on specificities of Non-Biological Complex Drugs (NBCDs), such as doxorubicin-encapsulated liposomes, and their follow-on versions are needed. Here, we compare Doxil® and its European analog Caelyx® with the two follow-on products DOXOrubicin (approved by the US Food and Drug Administration) and SinaDoxosome (produced in Iran) by cryogenic transmission electron microscopy, dynamic light scattering and Nanoparticle Tracking Analysis, and assess their potential in activating the complement system in human sera. We found subtle physicochemical differences between the tested liposomal products and even between the tested batches of Doxil® and Caelyx®.

Citrem modulates internal nanostructure of glyceryl monooleate dispersions and bypasses complement activation: Towards development of safe tunable intravenous lipid nanocarriers.

Unlabelled: 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.

Modulatory effect of human plasma on the internal nanostructure and size characteristics of liquid-crystalline nanocarriers.

The inverted-type liquid-crystalline dispersions comprising cubosomes and hexosomes hold much potential for drug solubilization and site-specific targeting on intravenous administration. Limited information, however, is available on the influence of plasma components on nanostructural and morphological features of cubosome and hexosome dispersions, which may modulate their stability in the blood and their overall biological performance. Through an integrated approach involving SAXS, cryo-TEM, and nanoparticle tracking analysis (NTA) we have studied the time-dependent effect of human plasma (and the plasma complement system) on the integrity of the internal nanostructure, morphology, and fluctuation in size distribution of phytantriol (PHYT)-based nonlamellar crystalline dispersions.

The Role of Complement in Antibody Therapy for Infectious Diseases.

The complement system is part of the innate immune system, eliciting central immunoregulatory functions. Detection of foreign surfaces is either achieved through complement-specific patternrecognition molecules or mediated by antigen recognition of antibodies. Immunoglobulin A (IgA), IgG, and IgM all have the potential to initiate a complement response, with the efficiency and response development closely related to the antibody isotype, multimeric state, and degree of glycosylation.

Structural profiling and biological performance of phospholipid-hyaluronan functionalized single-walled carbon nanotubes.

In spite of significant insolubility and toxicity, carbon nanotubes (CNTs) erupt into the biomedical research, and create an increasing interest in the field of nanomedicine. Single-walled CNTs (SWCNTs) are highly hydrophobic and have been shown to be toxic while systemically administrated. Thus, SWCNTs have to be functionalized to render water solubility and biocompatibility.

Polymeric particulate technologies for oral drug delivery and targeting: a pathophysiological perspective.

The oral route for delivery of pharmaceuticals is the most widely used and accepted. Nanoparticles and microparticles are increasingly being applied within this arena to optimize drug targeting and bioavailability. Frequently the carrier systems used are either constructed from or contain polymeric materials.

Polymeric particulate technologies for oral drug delivery and targeting: a pathophysiological perspective.

The oral route for delivery of pharmaceuticals is the most widely used and accepted. Nanoparticles and microparticles are increasingly being applied within this arena to optimize drug targeting and bioavailability. Frequently the carrier systems used are either constructed from or contain polymeric materials.

Perspectives on carbon nanotube-mediated adverse immune effects.

Carbon nanotubes are entities of different morphology and aspect ratios with anisotropic character. Due to their unique electronic, photonic, mechanical and chemical properties, carbon nanotubes are receiving increasing attention in nanomedicine research where examples include site-specific drug and nucleic acid delivery, photodynamic therapy and photoacoustic molecular imaging. The interaction of carbon nanotubes with the immune system, which plays a key role in the recognition and elimination of foreign materials, and consequential responses, is of central importance for the proposed successful biomedical applications of nanotubes.

Genomic perspectives in inter-individual adverse responses following nanomedicine administration: The way forward.

The underlying mechanism of intravenous infusion-related adverse reactions inherent to regulatory-approved nanomedicines still remains elusive. There are substantial inter-individual differences in observed adverse reactions, which may include cardiovascular, broncho-pulmonary, muco-cutaneous, neuro-psychosomatic and autonomic manifestations. Although nanomedicine-mediated triggering of complement activation has been suggested to be a significant contributing factor to these adverse events, complement activation may still proceed in non-responders.

Material properties in complement activation.

Uncontrolled complement activation can induce many inflammatory and life threatening conditions. Accordingly, the role of complement in initiation of adverse reactions to polymers and nanoparticulate drug carriers is receiving increasing attention and has prompted extensive 'structure-immune performance' relationship studies in nanomedicine research at many fronts. The interaction between nanomaterials and the complement system is complex and regulated by inter-related factors that include nanoscale size, morphology and surface characteristics.