INDUCTION OF CYTOKINES BY NUCLEIC ACID NANOPARTICLES (NANPS) DEPENDS ON THE TYPE OF DELIVERY CARRIER
Recent insights into the immunostimulatory properties of nucleic acid nanoparticles (NANPs) have demonstrated that variations in the shape, size, and composition lead to distinct patterns in their immunostimulatory properties. While most of these studies have used a single lipid-based carrier to allow for NANPs' intracellular delivery, it is now apparent that the platform for delivery, which has historically been a hurdle for therapeutic nucleic acids, is an additional means to tailoring NANP immunorecognition. Here, the use of dendrimers for the delivery of NANPs is compared to the lipid-based platform and the differences in resulting cytokine induction are presented.
SCALABLE NANOPRECIPITATION OF NICLOSAMIDE AND IN VIVO DEMONSTRATION OF LONG-ACTING DELIVERY AFTER INTRAMUSCULAR INJECTION
The control of COVID-19 across the world requires the formation of a range of interventions including vaccines to elicit an immune response and immunomodulatory or antiviral therapeutics. Here, we demonstrate the nanoparticle formulation of a highly insoluble drug compound, niclosamide, with known anti SARS-CoV-2 activity as a cheap and scalable long-acting injectable antiviral candidate that also shows immunomodulatory activity.
SAFETY ASSESSMENT OF A NEW NANOEMULSION-BASED DRUG-DELIVERY SYSTEM REVEALS UNEXPECTED, DRUG-FREE, ANTICOAGULANT ACTIVITY
Aim: A preclinical safety assessment of a novel nanoemulsion drug-delivery system, initially developed to improve the posology of efavirenz (EFV), was conducted with a specific focus on possible immunological and hematological complications. Materials & methods: Assessment of common acute toxicities, such as complement activation and cytokine secretion, was performed using validated assays known to have good correlation with in vivo end points. Results & conclusion: Compared with a standard aqueous solution of EFV, the EFV nanoemulsion showed no significant effect on immune cell function or phenotype. Prolongation of activated partial thromboplastin time was observed for EFV-loaded nanoemulsions (88% at 4 μg/ml) as well as unloaded nanoemulsions (52%) highlighting the potential for drug-free anticoagulant activity and warranting further investigation of the mechanism and utility of these materials.
IN VITRO DETERMINATION OF THE IMMUNOGENIC IMPACT OF NANOMATERIALS ON PRIMARY PERIPHERAL BLOOD MONONUCLEAR CELLS
Investigation of the potential for nanomaterials to generate immunogenic effects is a key aspect of a robust preclinical evaluation. In combination with physicochemical characterization, such assessments also provide context for how material attributes influence biological outcomes. Furthermore, appropriate models for these assessments allow accurate in vitro to in vivo extrapolation, which is vital for the mechanistic understanding of nanomaterial action. Here we have assessed the immunogenic impact of a small panel of commercially available and in-house prepared nanomaterials on primary human peripheral blood mononuclear cells (PBMCs). A diethylaminoethyl-dextran (DEAE-dex) functionalized superparamagnetic iron oxide nanoparticle (SPION) generated detectable quantities of tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and IL-10, the only tested material to do so. The human leukemia monocytic cell line THP-1 was used to assess the potential for the nanomaterial panel to affect cellular oxidation-reduction (REDOX) via measurement of reactive oxygen species and reduced glutathione. Negatively charged sulfonate-functionalized polystyrene nanoparticles demonstrated a size-related trend for the inhibition of caspase-1, which was not observed for amine-functionalized polystyrene of similar sizes. Silica nanoparticles (310 nm) resulted in a 93% increase in proliferation compared to the untreated control (p < 0.01). No other nanomaterial treatments resulted in significant change from that of unstimulated PBMCs. Responses to the nanomaterials in the assays described demonstrate the utility of primary cells as ex vivo models for nanomaterial biological impact.
ASSESSMENT OF INTERACTIONS OF EFAVIRENZ SOLID DRUG NANOPARTICLES WITH HUMAN IMMUNOLOGICAL AND HAEMATOLOGICAL SYSTEMS
Recent work has developed solid drug nanoparticles (SDNs) of efavirenz that have been demonstrated, preclinically, improved oral bioavailability and the potential to enable up to a 50% dose reduction, and is currently being studied in a healthy volunteer clinical trial. Other SDN formulations are being studied for parenteral administration, either as intramuscular long-acting formulations, or for direct administration intravenously. The interaction of nanoparticles with the immunological and haematological systems can be a major barrier to successful translation but has been understudied for SDN formulations. Here we have conducted a preclinical evaluation of efavirenz SDN to assess their potential interaction with these systems. Platelet aggregation and activation, plasma coagulation, haemolysis, complement activation, T cell functionality and phenotype, monocyte derived macrophage functionality, and NK cell function were assessed in primary healthy volunteer samples treated with either aqueous efavirenz or efavirenz SDN
LACK OF INTERACTION OF LOPINAVIR SOLID DRUG NANOPARTICLES WITH CELLS OF THE IMMUNE SYSTEM
Aim: We previously demonstrated that solid drug nanoparticles (SDNs) lopinavir (LPV) dispersed into aqueous media display favorable pharmacokinetics. Methods: The impact of LPV SDNs on the function and phenotype of primary human T cells and macrophages (primary sites of HIV replication) was investigated. Results: LPV significantly increased IL-1β (ninefold higher than untreated cells; p = 0.045) and TNF-α (sixfold higher than untreated cells; p = 0.018) secretion from monocyte-derived macrophages, whereas LPV SDNs did not elicit these responses at comparable drug concentrations. LPV SDNs were demonstrated to be immunologically inert to human T cells and monocyte-derived macrophages. Conclusion: The LPV SDN was demonstrated to exhibit comparable, or favorable behavior compared with an LPV aqueous solution in the employed biocompatibility assessments.
DETERMINING THE RELATIONSHIP BETWEEN NANOPARTICLE CHARACTERISTICS AND IMMUNOTOXICITY: KEY CHALLENGES AND APPROACHES
The growing wealth of information regarding the influence that physicochemical characteristics play on nanoparticle biocompatibility and safety is allowing improved design and rationale for their development and preclinical assessment. Accurate and appropriate measurement of these characteristics accompanied by informed toxicological assessment is a necessity for the development of safe and effective nanomedicines. While particle type, formulation and mode of administration dictate the individual causes for concern through development, the benefits of nanoformulation for treatment of the diseased state are great. Here we have proposed certain considerations and suggestions, which could lead to better-informed preclinical assessment of nanomaterials for nanomedicine, as well as how this information can and should be extrapolated to the physiological state of the end user.