Shell Cleavable Dendritic Polyglycerol Sulfates Show High Anti‐Inflammatory Properties by Inhibiting L‐Selectin Binding and Complement Activation

Abstract

A new class of fully synthetic shell cleavable multivalent polysulfates is prepared by introducing degradable linkers into a stable biocompatible dendritic polyglycerol scaffold and subsequent sulfation. The sulfated polymers show different degradation profiles, low anticoagulant and high anti-inflammatory properties, are able to efficiently bind to L-selectin and inhibit the complement activation at very low concentrations in vitro.

dPGS Regulates the Phenotype of Macrophages via Metabolic Switching

“…dPGS Synthesis : The polymer was produced as recently described . In brief, first the dendritic polyglycerol (dPG) as the core scaffold was synthesized via a controlled living anionic ring‐opening multibranching polymerization of glycidol by slow monomer addition on partially deprotonated pentaerythritol as the starter.…”

“…Multivalent macromolecules such as dendritic polyglycerol sulfates (dPGS) were designed to interrupt the interaction between leukocytes and endothelial cells. Our previous data showed that dPGS exhibit a high binding affinity for L‐ and P‐selectin and target complement proteins in vitro . dPGS treatment could also effectively prevent the extravasation of immune cells in a dermatitis and polymyositis model in vivo …”

Heparin Mimetics: Their Therapeutic Potential

“…It has long being recognized that heparin has range of biological effects in addition to its well characterized anticoagulant properties, and possibly one of its best known non-anticoagulant activities are its anti-inflammatory effects [ 92 , 93 , 94 ]. The anti-inflammatory properties of heparin and heparin mimetics have primarily, but not exclusively, been linked to their ability to interact with three different types of proteins: complement system proteins, selectins and chemokines; each of which function in different ways to facilitate inflammation [ 95 , 96 , 97 ]. The potential of heparin as an anti-inflammatory drug is supported by a number of small, and several modestly sized clinical trials.…”

“…To overcome this problem shell cleavable polysulfated dendrimers were synthesized and investigated for competitive L-selectin binding, blood coagulation, complement activation and degradation in vitro. This synthesis and the biological activities are described in the report by Reimann et al [ 95 ]. This work revealed that two of these compounds dPG-thioglyceryl pentanoatyl sulfate ( Figure 11 C(h)) and pPG-thioglyceryl methylpropanoatyl sulfate ( Figure 11 C(g)) containing long flexible hydrophobic linkers which included respectively, either an ester functionality, or a carbamate and an ester functionality, had potent complement pathway inhibition activity, minimal anticoagulant activity and high picomolar IC 50 values in the L-selectin binding assay.…”

“…This work revealed that two of these compounds dPG-thioglyceryl pentanoatyl sulfate ( Figure 11 C(h)) and pPG-thioglyceryl methylpropanoatyl sulfate ( Figure 11 C(g)) containing long flexible hydrophobic linkers which included respectively, either an ester functionality, or a carbamate and an ester functionality, had potent complement pathway inhibition activity, minimal anticoagulant activity and high picomolar IC 50 values in the L-selectin binding assay. These two compounds also degraded quite readily and so were considered as interesting compounds for long term treatment of chronic inflammation or as a new class of anti-complement therapeutic for preventing tissue damage within inflammatory disease [ 95 ].…”