title: Encapsulation-free controlled release: Electrostatic adsorption eliminates the need for protein encapsulation in PLGA nanoparticles.
abstract: Encapsulation of therapeutic molecules within polymer particles is a well-established method for achieving controlled release, yet challenges such as low loading, poor encapsulation efficiency, and loss of protein activity limit clinical translation. Despite this, the paradigm for the use of polymer particles in drug delivery has remained essentially unchanged for several decades. By taking advantage of the adsorption of protein therapeutics to poly(lactic-co-glycolic acid) (PLGA) nanoparticles, we demonstrate controlled release without encapsulation. In fact, we obtain identical, burst-free, extended-release profiles for three different protein therapeutics with and without encapsulation in PLGA nanoparticles embedded within a hydrogel. Using both positively and negatively charged proteins, we show that short-range electrostatic interactions between the proteins and the PLGA nanoparticles are the underlying mechanism for controlled release. Moreover, we demonstrate tunable release by modifying nanoparticle concentration, nanoparticle size, or environmental pH. These new insights obviate the need for encapsulation and offer promising, translatable strategies for a more effective delivery of therapeutic biomolecules.
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario M5S 3E5, Canada.; Institute for Biomaterials and Biomedical Engineering, University of Toronto, Ontario M5S 3G9, Canada.
authors.forename: Malgosia M
authors.initials: MM
authors.lastname: Pakulska
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario M5S 3E5, Canada.; Institute for Biomaterials and Biomedical Engineering, University of Toronto, Ontario M5S 3G9, Canada.
authors.forename: Irja
authors.identifier: 0000-0002-0064-7141
authors.initials: I
authors.lastname: Elliott Donaghue
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario M5S 3E5, Canada.; Institute for Biomaterials and Biomedical Engineering, University of Toronto, Ontario M5S 3G9, Canada.
authors.forename: Jaclyn M
authors.identifier: 0000-0003-4112-5662
authors.initials: JM
authors.lastname: Obermeyer
authors.affiliation: Institute for Biomaterials and Biomedical Engineering, University of Toronto, Ontario M5S 3G9, Canada.
authors.forename: Anup
authors.identifier: 0000-0002-3942-2732
authors.initials: A
authors.lastname: Tuladhar
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario M5S 3E5, Canada.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: McLaughlin
authors.affiliation: The Rudolf Peierls Centre for Theoretical Physics, University of Oxford, Oxford OX1 3NP, UK.
authors.forename: Tyler N
authors.identifier: 0000-0001-7671-2184
authors.initials: TN
authors.lastname: Shendruk
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario M5S 3E5, Canada.; Institute for Biomaterials and Biomedical Engineering, University of Toronto, Ontario M5S 3G9, Canada.; Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada.
authors.forename: Molly S
authors.initials: MS
authors.lastname: Shoichet
mesh_terms: D000327:Adsorption; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry; D004339:Drug Compounding; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000737:chemistry; D009010:Monte Carlo Method; D053758:Nanoparticles / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011506:Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D055672:Static Electricity
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011506:Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: PLGA; affinity release; central nervous system; controlled release; drug delivery; hydrogel; protein