title: Reactive polymer enables efficient in vivo bioorthogonal chemistry.
abstract: There has been intense interest in the development of selective bioorthogonal reactions or "click" chemistry that can proceed in live animals. Until now however, most reactions still require vast surpluses of reactants because of steep temporal and spatial concentration gradients. Using computational modeling and design of pharmacokinetically optimized reactants, we have developed a predictable method for efficient in vivo click reactions. Specifically, we show that polymer modified tetrazines (PMT) are a key enabler for in vivo bioorthogonal chemistry based on the very fast and catalyst-free [4 + 2] tetrazine/trans-cyclooctene cycloaddition. Using fluorescent PMT for cellular resolution and (18)F labeled PMT for whole animal imaging, we show that cancer cell epitopes can be easily reacted in vivo. This generic strategy should help guide the design of future chemistries and find widespread use for different in vivo bioorthogonal applications, particularly in the biomedical sciences.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Neal K
authors.initials: NK
authors.lastname: Devaraj
authors.forename: Greg M
authors.initials: GM
authors.lastname: Thurber
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Keliher
authors.forename: Brett
authors.initials: B
authors.lastname: Marinelli
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D057930:Click Chemistry / Q000379:methods*; D000939:Epitopes / Q000276:immunology; D007700:Kinetics; D051379:Mice; D008856:Microscopy, Fluorescence; D011108:Polymers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D014057:Tomography, X-Ray Computed; D023041:Xenograft Model Antitumor Assays
chemical_list: D001672:Biocompatible Materials; D000939:Epitopes; D011108:Polymers; D011725:Pyridines