title: Sustained local delivery of bioactive nerve growth factor in the central nervous system via tunable diblock copolypeptide hydrogel depots.
abstract: Biomaterial vehicles that can provide sustained, site-specific molecular delivery in the central nervous system (CNS) have potential for therapeutic and investigative applications. Here, we present in vitro and in vivo proof of principle tests of diblock copolypeptide hydrogels (DCH) to serve as depots for sustained local release of protein effector molecules. We tested two DCH, K(180)L(20) and E(180)L(20), previously shown to self-assemble into biocompatible, biodegradable deposits that persist four to eight weeks after injection into mouse forebrain. In vitro tests demonstrated sustained release from dialysis cassettes of the representative protein, lysozyme, dissolved in K(180)L(20) or E(180)L(20) hydrogels. Release time in vitro varied in relation to DCH charge and mechanical properties, and ionic strength of the media. To evaluate bioactive protein delivery in vivo, we used nerve growth factor (NGF) and measured the size of mouse forebrain cholinergic neurons, which respond to NGF with cellular hypertrophy. For in vivo tests, the storage modulus of DCH depots was tuned to just below that of CNS tissue. In comparison with NGF injected in buffer, depots of NGF dissolved in either K(180)L(20) or E(180)L(20) provided significantly longer delivery of NGF bioactivity, maintaining hypertrophy of local forebrain cholinergic neurons for at least 4 weeks and inducing hypertrophy a further distance away (up to 5 mm) from injection sites. These findings show that depots of DCH injected into CNS can provide sustained delivery within the blood-brain barrier of a bioactive protein growth factor that exerts a predicted, quantifiable effect on local cells over a prolonged subacute time.
authors.affiliation: Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1763, USA.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Song
authors.forename: Jinsuk
authors.initials: J
authors.lastname: Song
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Anderson
authors.forename: Yan
authors.initials: Y
authors.lastname: Ao
authors.forename: Chu-Ya
authors.initials: CY
authors.lastname: Yang
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Deming
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sofroniew
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D059329:Cholinergic Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D020932:Nerve Growth Factor / Q000493:pharmacokinetics*; D010455:Peptides / Q000737:chemistry*; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D010455:Peptides; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D020932:Nerve Growth Factor