A functionalized, injectable hydrogel for localized drug delivery with tunable thermosensitivity: synthesis and characterization of physical and toxicological properties.
Thermosensitive injectable hydrogels have been used for the delivery of pharmacological and cellular therapies in a variety of soft tissue applications. A promising class of synthetic, injectable hydrogels based upon oligo(ethylene glycol) methacrylate (OEGMA) monomers has been previously reported, but these polymers lack reactive groups for covalent attachment of therapeutic molecules. In this work, thermosensitive, amine-reactive and amine-functionalized polymers were developed by incorporation of methacrylic acid N-hydroxysuccinimide ester or 2-aminoethyl methacrylate into OEGMA-based polymers. A model therapeutic peptide, bivalirudin, was conjugated to the amine-reactive hydrogel to investigate effects on the polymer thermosensitivity and gelation properties. The ability to tune the thermosensitivity of the polymer in order to compensate for peptide hydrophilicity and maintain gelation capability below physiological temperature was demonstrated. Cell encapsulation studies using an H9 T-cell line (CD4+) were conducted to evaluate feasibility of the hydrogel as a carrier for cellular therapies. Although this class of polymers is generally considered to be non-toxic, it was found that concentrations required for gelation were incompatible with cell survival. Investigation into the cause of cytotoxicity revealed that a hydrolysis byproduct, diethylene glycol monomethyl ether, is likely a contributing factor. While modifications to structure or composition will be required to enable viable cell encapsulation, the functionalized injectable hydrogel has the potential for controlled delivery of a wide range of drugs.
Department of Bioengineering and Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA 98195, United States.
Paul Z
PZ
Elias
Department of Bioengineering and Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA 98195, United States.
Gary W
GW
Liu
Department of Bioengineering and Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA 98195, United States.
Hua
H
Wei
Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, United States.
Michael C
MC
Jensen
Department of Neurological Surgery, University of Washington, Seattle, WA 98195, United States. Electronic address: phorner@uw.edu.
Philip J
PJ
Horner
Department of Bioengineering and Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA 98195, United States. Electronic address: spun@uw.edu.
Suzie H
SH
Pun
D000588:Amines / Q000737:chemistry; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D004337:Drug Carriers; D004339:Drug Compounding; D016503:Drug Delivery Systems; D006461:Hemolysis / Q000187:drug effects; D006629:Hirudins / Q000008:administration & dosage / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D020100:Hydrogels / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D066298:In Vitro Techniques; D008689:Methacrylates / Q000737:chemistry; D051379:Mice; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D011109:Polymethacrylic Acids; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
D000588:Amines; D000925:Anticoagulants; D004337:Drug Carriers; D006629:Hirudins; D020100:Hydrogels; D008689:Methacrylates; D010446:Peptide Fragments; D011109:Polymethacrylic Acids; D011994:Recombinant Proteins; C528061:poly(poly(ethylene glycol)methacrylate); D011092:Polyethylene Glycols; D003300:Copper; C074619:bivalirudin
Cell therapy; Drug delivery; Immunotherapy; Injectable hydrogel; Peptide; Spinal cord injury