Search

Pluronic F127-stabilized non-lamellar liquid crystalline aqueous nanodispersions are promising injectable platforms for drug and contrast agent delivery. These nanodispersions, however, trigger complement activation in the human blood, where the extent of complement activation and opsonization processes may compromise their biological performance and safety. Here, we introduce a broad family of nanodispersions from glycerol monooleate (GMO) and oleic acid (OA) in different weight ratios, and stabilized with a plethora of nonionic methoxypoly(ethylene glycol) (mPEG)-lipids of different PEG chain length and variable lipid moiety (monounsaturated or saturated diglycerides or D-α-tocopheryl succinate). Through an integrated biophysical approach involving dynamic light scattering, synchrotron small-angle scattering, and cryo-transmission electron microscopy, we examine the impact of nonionic mPEG-lipid stabilization on size, internal self-assembled architecture, and gross morphological characteristics of nanodispersions. The results show how the nonionic mPEG-lipid type and concentration, and dependent on GMO/OA weight ratio, can variably modulate the internal architectures of nanoparticles. Assessment of complement profiling from selected nanodispersions with diverse structural heterogeneity further suggests a variable modulatory role for the lipid type of the nonionic mPEG-lipid in the extent of complement activation, which span from no activation to moderate to high levels. We comment on plausible mechanisms driving the observed complement activation variability and discuss the potential utility of these nanodispersions for future development of injectable nanopharmaceuticals.

Hexosomes are nanoparticles enveloping inverted discontinuous hexagonal (HII) liquid crystalline phases that offer exceptional physicochemical characteristics for drug encapsulation and targeted drug delivery. However, the fate of subcutaneously injected hexosomes has rarely been investigated. Here, we have followed the lymphatic fate of a technetium-99 m [99mTc]-labeled hexosome preparation on subcutaneous injection into the rat footpads with single-photon emission computed tomography (SPECT) in combination with CT. Hexosomes were composed of phytantriol and oleic acid and sterically stabilized with Pluronic F127. High tracer loading efficiency was achieved by chelating [99mTc]-pertechnetate to 1,12-diamino-3,6,9-triazadodecane-oleic acid conjugates incorporated within the ordered interior nanocompartments of hexosomes. The preparation was characterized by synchrotron small angle X-ray scattering, cryogenic transmission electron microscopy and nanoparticle tracking analysis. On footpad injection, hexosomes rapidly drained into the lymphatic microvessels and distributed not only to the sentinel (popliteal) lymph node, but also to wider lymph nodes (inguinal and iliac nodes) situated along the pathway of the lymph drainage. The observed hexosome drainage kinetics from the injection site and lymphatic distribution pattern is in line with previously established poly(ethylene oxide) configuration attributes of Pluronic F127 in minimizing nanoparticle aggregation at the injection site, and interaction with the ground substance of interstitium, without interfering with macrophage uptake. Accordingly, we discuss the potential utility of Pluronic F127-stabilized hexosomes for lymphatic targeting and future development of simple, yet effective multifunctional lymphotropic agents and theranostics.

Cryo-transmission electron microscopy (Cryo-TEM), and its technological variations thereof, have become a powerful tool for detailed morphological characterization and 3D tomography of soft lipid and polymeric nanoparticles as well as biological materials such as viruses and DNA without chemical fixation. Here, we review and discuss recent advances in Cryo-TEM analysis of lipid-based drug nanocarriers with particular emphasis on morphological and internal nanostructure characterization of lyotropic liquid crystalline nanoparticles such as cubosomes and hexosomes.

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. Whether these reactions share similar immunological mechanisms and underpinning genetic factors with drug hypersensitivity syndrome remains to be investigated. Genetic association studies could be a powerful tool to dissect causative factors and reveal the multiple molecular pathways that induce infusion related adverse reactions. It is envisaged that such research may lead to the design of reliable in vitro profiling tests for risk assessment and treatment decisions, thereby revolutionizing the practice of medicine with nanopharmaceuticals. Such procedures may further improve regulatory approval processes for nanomedicines currently in the pipeline and decrease the overall cost of health care. Here we discuss some key innate immunity genes and their polymorphisms in relation to nanomedicine infusion-mediated symptomatic responses.

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. A group of serum proteins constitutes the central effector functions of complement, thus allowing direct cell lysis, opsonization, and inflammation. These effector functions can be used in antibody therapies, especially against infectious diseases, as the target membranes lack complement regulatory proteins. The relative contribution of each function and the interplay with direct antibody-mediated clearance is not fully exploited, thus suggesting an option for further rational optimization of antibody therapies.