title: Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates.
abstract: Conjugation to macromolecular carriers is a proven strategy for improving the pharmacokinetics of drugs, with many stable polyethylene glycol conjugates having reached the market. Stable conjugates suffer several limitations: loss of drug potency due to conjugation, confining the drug to the extracellular space, and the requirement for a circulating conjugate. Current research is directed toward overcoming such limitations through releasable conjugates in which the drug is covalently linked to the carrier through a cleavable linker. Satisfactory linkers that provide predictable cleavage rates tunable over a wide time range that are useful for both circulating and noncirculating conjugates are not yet available. We describe such conjugation linkers on the basis of a nonenzymatic β-elimination reaction with preprogrammed, highly tunable cleavage rates. A set of modular linkers is described that bears a succinimidyl carbonate group for attachment to an amine-containing drug or prodrug, an azido group for conjugation to the carrier, and a tunable modulator that controls the rate of β-eliminative cleavage. The linkers provide predictable, tunable release rates of ligands from macromolecular conjugates both in vitro and in vivo, with half-lives spanning from a range of hours to >1 y at physiological pH. A circulating PEG conjugate achieved a 56-fold half-life extension of the 39-aa peptide exenatide in rats, and a noncirculating s.c. hydrogel conjugate achieved a 150-fold extension. Using slow-cleaving linkers, the latter may provide a generic format for once-a-month dosage forms of potent drugs. The releasable linkers provide additional benefits that include lowering C(max) and pharmacokinetic coordination of drug combinations.
authors.affiliation: ProLynx, Hayward, CA 94545, USA. Daniel.V.Santi@prolynxllc.com
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Santi
authors.forename: Eric L
authors.initials: EL
authors.lastname: Schneider
authors.forename: Ralph
authors.initials: R
authors.lastname: Reid
authors.forename: Louise
authors.initials: L
authors.lastname: Robinson
authors.forename: Gary W
authors.initials: GW
authors.lastname: Ashley
mesh_terms: D000465:Algorithms; D000818:Animals; D002254:Carbonates / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics*; D000077270:Exenatide; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics; D007700:Kinetics; D046911:Macromolecular Substances / Q000737:chemistry*; D008297:Male; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D013388:Succinimides / Q000737:chemistry; D014688:Venoms / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D002254:Carbonates; D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D046911:Macromolecular Substances; D010455:Peptides; D011355:Prodrugs; D013388:Succinimides; D014688:Venoms; C085786:succinimidyl carbonate; D011092:Polyethylene Glycols; D000077270:Exenatide