title: Reloadable multidrug capturing delivery system for targeted ischemic disease treatment.
abstract: Human clinical trials of protein therapy for ischemic diseases have shown disappointing outcomes so far, mainly because of the poor circulatory half-life of growth factors in circulation and their low uptake and retention by the targeted injury site. The attachment of polyethylene glycol (PEG) extends the circulatory half-lives of protein drugs but reduces their extravasation and retention at the target site. To address this issue, we have developed a drug capture system using a mixture of hyaluronic acid (HA) hydrogel and anti-PEG immunoglobulin M antibodies, which, when injected at a target body site, can capture and retain a variety of systemically injected PEGylated therapeutics at that site. Furthermore, repeated systemic injections permit "reloading" of the capture depot, allowing the use of complex multistage therapies. This study demonstrates this capture system in both murine and porcine models of critical limb ischemia. The results show that the reloadable HA/anti-PEG system has the potential to be clinically applied to patients with ischemic diseases, who require sequential administration of protein drugs for optimal outcomes.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Jasmine P J
authors.initials: JP
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Bill
authors.initials: B
authors.lastname: Cheng
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. phsieh@ibms.sinica.edu.tw sroff@ibms.sinica.edu.tw.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Steve R
authors.initials: SR
authors.lastname: Roffler
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lundy
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Christopher Y T
authors.initials: CY
authors.lastname: Yen
authors.affiliation: Research Center for Applied Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Peilin
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lai
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Suzie H
authors.initials: SH
authors.lastname: Pun
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Stayton
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. phsieh@ibms.sinica.edu.tw sroff@ibms.sinica.edu.tw.|Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.|Institute of Medical Genomics and Proteomics and Department of Surgery, National Taiwan University and Hospital, Taipei 100, Taiwan.
authors.forename: Patrick C H
authors.initials: PC
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000737:chemistry; D016503:Drug Delivery Systems; D005121:Extremities / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry; D007075:Immunoglobulin M / Q000737:chemistry; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic; D011092:Polyethylene Glycols / Q000737:chemistry; D013552:Swine; D014652:Vascular Diseases / Q000628:therapy*
chemical_list: D003176:Complement C3; D020100:Hydrogels; D007075:Immunoglobulin M; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid