Understanding the kinetics of macrophage uptake and the metabolic fate of iron-carbohydrate complexes used for iron deficiency anemia treatment.

Iron-carbohydrate complexes (ICCs) are widely used nanomedicines to treat iron deficiency anemia, yet their intracellular fate and the mechanisms of action underlying their differences in treatment outcomes remain poorly understood. Here, we thus performed a comprehensive dynamic characterization of two structurally distinct ICCs - iron sucrose (IS) and ferric carboxymaltose (FCM) - in primary human macrophages, key cells to the iron metabolism. By employing innovative correlative microscopy techniques, elemental analysis, and in vitro pharmacokinetic profiling, we demonstrate that the uptake, intracellular trafficking, and biodegradation of ICCs depend on their physicochemical properties.

Challenging Traditional ADME Assumptions for Physiologically Based Pharmacokinetic Models for Intravenous Administration of Iron-Carbohydrate Nanomedicines: Potential Utility of Gold Nanoparticle Models as a Roadmap.

Intravenous iron-carbohydrate complexes are a class of nanomedicines that are widely used globally to treat iron deficiency and iron deficiency anemia associated with a wide spectrum of disease states. Despite being widely used in clinical practice for more than seven decades, the understanding of their in vivo disposition including tissue biodistribution and kinetics of the nanoparticle degradation at the cellular level is not well-understood. Moreover, the critical quality attributes that influence in vivo pharmacokinetics have not been fully defined.

Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of desmoglein 3-peptide-coupled tolerizing nanoparticles in pemphigus.

Background: Pemphigus vulgaris (PV) is a CD4+ T cell-dependent, autoantibody-mediated blistering disease associated with human leukocyte antigen class II molecules. IgG autoantibodies against the primary autoantigen desmoglein 3 (Dsg3), a desmosomal adhesion protein on epidermal keratinocytes, cause loss of epidermal cell adhesion.

Objective: To assess the clinical applicability of an innovative nanoparticle platform for the induction of immune tolerance exploiting the natural tolerance potential of liver sinusoidal endothelial cells.

Tracking Intracellular Labile Iron with a Genetically Encoded Fluorescent Reporter System Based on Protein Stability.

Here, we developed IronFist, a genetically encoded fluorescent reporter that enables dynamic tracking of labile ferrous ions (Fe) in live cells. IronFist is a bicistronic system combining the iron-sensitive hemerythrin-like (Hr) domain from the F-box and leucine-rich repeat protein 5 (FBXL5), fused to the bright fluorescent protein (FP) mNeonGreen, alongside mCherry as a reference FP signal. When labile iron levels are low, Hr-mNeonGreen undergoes ubiquitination and degradation, leading to a low green-to-red fluorescence ratio.

Nanoparticle platform preferentially targeting liver sinusoidal endothelial cells induces tolerance in CD4+ T cell-mediated disease models.

Introduction: Treating autoimmune diseases without nonspecific immunosuppression remains challenging. To prevent or treat these conditions through targeted immunotherapy, we developed a clinical-stage nanoparticle platform that leverages the tolerogenic capacity of liver sinusoidal endothelial cells (LSECs) to restore antigen-specific immune tolerance.

Methods: efficacy was evaluated in various CD4 T cell-mediated disease models, including preventive and therapeutic models of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), ovalbumin-sensitized delayed-type hypersensitivity (DTH), and the spontaneous type 1 diabetes model.

Iron-carbohydrate complexes treating iron anaemia: Understanding the nano-structure and interactions with proteins through orthogonal characterisation.

Intravenous (IV) iron-carbohydrate complexes are widely used nanoparticles (NPs) to treat iron deficiency anaemia, often associated with medical conditions such as chronic kidney disease, heart failure and various inflammatory conditions. Even though a plethora of physicochemical characterisation data and clinical studies are available for these products, evidence-based correlation between physicochemical properties of iron-carbohydrate complexes and clinical outcome has not fully been elucidated yet. Studies on other metal oxide NPs suggest that early interactions between NPs and blood upon IV injection are key to understanding how differences in physicochemical characteristics of iron-carbohydrate complexes cause variance in clinical outcomes.

Uncovering the dynamics of cellular responses induced by iron-carbohydrate complexes in human macrophages using quantitative proteomics and phosphoproteomics.

Iron-carbohydrate complexes are widely used to treat iron deficiencies. Macrophages play a crucial role in the uptake and fate of these nanomedicines, however, how complexed iron carbohydrates are taken up and metabolized by macrophages is still not fully understood. Using a (phospho-)proteomics approach, we assessed differences in protein expression and phosphorylation in M2 macrophages triggered by iron sucrose (IS).

Dynamic Light Scattering Analysis for the Determination of the Particle Size of Iron-Carbohydrate Complexes.

Intravenously administered iron-carbohydrate nanoparticle complexes are widely used to treat iron deficiency. This class includes several structurally heterogeneous nanoparticle complexes, which exhibit varying sensitivity to the conditions required for the methodologies available to physicochemically characterize these agents. Currently, the critical quality attributes of iron-carbohydrate complexes have not been fully established.

Critical nanomaterial attributes of iron-carbohydrate nanoparticles: Leveraging orthogonal methods to resolve the 3-dimensional structure.

Intravenous iron-carbohydrate nanomedicines are widely used to treat iron deficiency and iron deficiency anemia across a wide breadth of patient populations. These colloidal solutions of nanoparticles are complex drugs which inherently makes physicochemical characterization more challenging than small molecule drugs. There have been advancements in physicochemical characterization techniques such as dynamic light scattering and zeta potential measurement, that have provided a better understanding of the physical structure of these drug products in vitro.

Putting square pegs in round holes: Why traditional pharmacokinetic principles cannot universally be applied to iron-carbohydrate complexes.

Intravenous iron-carbohydrate complexes are nanomedicines that are commonly used to treat iron deficiency and iron deficiency anemia of various etiologies. Many challenges remain regarding these complex drugs in the context of fully understanding their pharmacokinetic parameters. Firstly, the measurement of the intact iron nanoparticles versus endogenous iron concentration fundamentally limits the availability of data for computational modeling.

Nanoparticle-mediated targeting of autoantigen peptide to cross-presenting liver sinusoidal endothelial cells protects from CD8 T-cell-driven autoimmune cholangitis.

Autoimmune diseases are caused by adaptive immune responses to self-antigens. The development of antigen-specific therapies that suppress disease-related, but not unrelated immune responses in general, is an important goal of biomedical research. We have previously shown that delivery of myelin peptides to liver sinusoidal endothelial cells (LSECs) using LSEC-targeting nanoparticles provides effective protection from CD4 T-cell-driven autoimmune encephalomyelitis.