Synthesis and characterization of heparosan-granulocyte-colony stimulating factor conjugates: a natural sugar-based drug delivery system to treat neutropenia

摘要: Many injectable drugs require delivery strategies for enhancing their pharmacokinetics due to rapid loss via renal filtration if possess low molecular weight (<60-70 kDa) and/or clearance by the body's components (e.g., proteases, antibodies, high-efficiency receptors) in native form. FDA-approved polyethylene glycol (PEG) is a vehicle improving therapeutics, but artificial polymers have potential biocompatibility and immunogenicity liabilities. Here, we utilized natural vertebrate carbohydrate, heparosan (HEP), biosynthetic precursor of heparan sulfate heparin, enhance performance biologic drug. The HEP polysaccharide was stable with long half-life (~8 days 99-kDa chain) nonhuman primate bloodstream, efficiently degraded very short oligosaccharides when internalized cells, then excreted into urine feces. Several HEP-modified human granulocyte-colony stimulating factor (G-CSF) conjugates were synthesized defined quasi-monodisperse chains. Single dosing 55- or HEP-G-CSF rats increased blood neutrophil levels comparable PEG-G-CSF conjugates. Repeated alone 2 weeks did not cause HEP-specific toxic effects rats. anticoagulant behavior its daughter, based on testing clinical diagnostic assays plasma. Neither anti-HEP IgG nor IgM antibodies detected long-term (9 doses over 7 months) study HEP-drug conjugate These proof-of-concept experiments indicate that it valid drug candidate neutropenia suggest this HEP-based platform as safe alternative other therapeutics.