title: Supramolecular PEGylation of biopharmaceuticals.
abstract: The covalent modification of therapeutic biomolecules has been broadly explored, leading to a number of clinically approved modified protein drugs. These modifications are typically intended to address challenges arising in biopharmaceutical practice by promoting improved stability and shelf life of therapeutic proteins in formulation, or modifying pharmacokinetics in the body. Toward these objectives, covalent modification with poly(ethylene glycol) (PEG) has been a common direction. Here, a platform approach to biopharmaceutical modification is described that relies on noncovalent, supramolecular host-guest interactions to endow proteins with prosthetic functionality. Specifically, a series of cucurbit[7]uril (CB[7])-PEG conjugates are shown to substantially increase the stability of three distinct protein drugs in formulation. Leveraging the known and high-affinity interaction between CB[7] and an N-terminal aromatic residue on one specific protein drug, insulin, further results in altering of its pharmacological properties in vivo by extending activity in a manner dependent on molecular weight of the attached PEG chain. Supramolecular modification of therapeutic proteins affords a noncovalent route to modify its properties, improving protein stability and activity as a formulation excipient. Furthermore, this offers a modular approach to append functionality to biopharmaceuticals by noncovalent modification with other molecules or polymers, for applications in formulation or therapy.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.|Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Webber
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Eric A
authors.identifier: 0000-0002-2301-7126
authors.initials: EA
authors.lastname: Appel
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742.
authors.forename: Brittany
authors.initials: B
authors.lastname: Vinciguerra
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Abel B
authors.initials: AB
authors.lastname: Cortinas
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.|Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112.
authors.forename: Lavanya S
authors.initials: LS
authors.lastname: Thapa
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Jhunjhunwala
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742; lisaacs@umd.edu rlanger@mit.edu dgander@mit.edu.
authors.forename: Lyle
authors.initials: L
authors.lastname: Isaacs
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; lisaacs@umd.edu rlanger@mit.edu dgander@mit.edu.|Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.|Harvard-Massachusetts Institute of Technology Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; lisaacs@umd.edu rlanger@mit.edu dgander@mit.edu.|Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.|Harvard-Massachusetts Institute of Technology Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001702:Biopharmaceutics / Q000379:methods; D001952:Bridged-Ring Compounds / Q000737:chemistry; D002460:Cell Line; D057930:Click Chemistry; D004339:Drug Compounding / Q000379:methods*; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007328:Insulin / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011092:Polyethylene Glycols / Q000737:chemistry*; D015202:Protein Engineering; D055550:Protein Stability; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D001952:Bridged-Ring Compounds; D007093:Imidazoles; D007328:Insulin; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; C456276:cucurbit(7)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
keywords: drug delivery; protein engineering; protein formulation; supramolecular chemistry