ICAM-1 Targeted Nanogels Loaded with Dexamethasone Alleviate Pulmonary Inflammation

Abstract

Lysozyme dextran nanogels (NG) have great potential in vitro as a drug delivery platform, combining simple chemistry with rapid uptake and cargo release in target cells with “stealth” properties and low toxicity. In this work, we study for the first time the potential of targeted NG as a drug delivery platform in vivo to alleviate acute pulmonary inflammation in animal model of LPS-induced lung injury. NG are targeted to the endothelium via conjugation with an antibody (Ab) directed to Intercellular Adhesion Molecule-1(ICAM-NG), whereas IgG conjugated NG (IgG-NG) are used for control formulations. The amount of Ab conjugated to the NG and distribution in the body after intravenous (IV) injection have been quantitatively analyzed using a tracer isotope-labeled [125I]IgG. As a proof of concept, Ab-NG are loaded with dexamethasone, an anti-inflammatory therapeutic, and the drug uptake and release kinetics are measured by HPLC. In vivo studies in mice showed that: i) ICAM-NG accumulates in mouse lungs (∼120% ID/g vs ∼15% ID/g of IgG-NG); and, ii) DEX encapsulated in ICAM-NG, but not in IgG-NG practically blocks LPS-induced overexpression of pro-inflammatory cell adhesion molecules including ICAM-1 in the pulmonary inflammation.

Biomimetic channel modeling local vascular dynamics of pro-inflammatory endothelial changes

“…This parameter, widely used in the literature 49,[60][61][62] as a conventionally accepted readout of functional status of these cells, is one of many manifestations of proinflammatory endothelial activation. They include cellular contraction and other surface alterations such as reduction of surface density of thrombomodulin, endothelial protein C receptor, and angiotensin-converting enzyme, as well as appearance of tissue factor, selectins, Willebrand factor, and other pro-coagulant and pro-inflammatory molecules.…”

The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities

“…For example, antioxidants conjugated with antibodies to the endothelial determinant Platelet/Endothelial Cell Adhesion Molecule 1 (PECAM-1) inhibited endothelial activation and reduced VCAM-1 expression in murine lung injury 34. Similarly, dexamethasone-loaded nanogels targeted to ICAM-1 accumulated in murine LPS-injured lungs and blocked expression of ICAM-1 and VCAM-1 at 24 h 35. In an effort to both target the lung endothelium and enhance biological effect, researchers have fused single-chain fragments of PECAM-1 antibodies to recombinant TM and endothelial protein C receptor (EPCR).…”

Nanogel carrier design for targeted drug delivery

“…Nanogel synthesis typically results in spherical particles ranging in size from 20 to 200 nm in diameter, which can be demonstrated by dynamic light scattering and electron microscopy methods 3,4,28 . Other shapes are possible to manufacture, using micromolding and photolithographic techniques which also permit control over nanogel size, shape and chemical composition and allow drugs and macromolecules to be loaded as well 32–34 .…”

“…The toxicity of nanogels comprised of these polymers is expected to be low, as a result of the minimal toxicity of the hydrolyzed small molecule degradation products. Nanogels comprised of sugars (e.g., dextran) and stable proteins (e.g., lysozyme) are also expected to have very minimal toxic potential 3,4,28 . Other low toxicity nanogel systems have been synthesized via cross-linking of a self-assembling block copolymer consisting of a block of poly(oligoethylene glycol) and a block of randomly co-polymerized vinyl benzyl chloride and pentafluorophenyl acrylate 59 .…”

“…Hydrogel nanoparticles, or nanogels, are typically comprised of highly hydrated, crosslinked hydrophilic polymers 1–4 . Nanogels can be formulated to respond to external stimuli, which can lead to changes in various properties, including swelling, permeability, viscoelasticity, and hydrophobicity (or hydrophilicity).…”