title: Refilling drug delivery depots through the blood.
abstract: Local drug delivery depots have significant clinical utility, but there is currently no noninvasive technique to refill these systems once their payload is exhausted. Inspired by the ability of nanotherapeutics to target specific tissues, we hypothesized that blood-borne drug payloads could be modified to home to and refill hydrogel drug delivery systems. To address this possibility, hydrogels were modified with oligodeoxynucleotides (ODNs) that provide a target for drug payloads in the form of free alginate strands carrying complementary ODNs. Coupling ODNs to alginate strands led to specific binding to complementary-ODN-carrying alginate gels in vitro and to injected gels in vivo. When coupled to a drug payload, sequence-targeted refilling of a delivery depot consisting of intratumor hydrogels completely abrogated tumor growth. These results suggest a new paradigm for nanotherapeutic drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug-eluting vascular grafts and stents.
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
authors.forename: Yevgeny
authors.initials: Y
authors.lastname: Brudno
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; Department of Biomedical Engineering, University of California, Davis, CA 95616; and.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Silva
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; Department of Anatomy, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Cathal J
authors.initials: CJ
authors.lastname: Kearney
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115;
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Lewin
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
authors.forename: Alex
authors.initials: A
authors.lastname: Miller
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115;
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Martinick
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115;
authors.forename: Michael
authors.initials: M
authors.lastname: Aizenberg
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; mooneyd@seas.harvard.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mooney
mesh_terms: D000464:Alginates / Q000493:pharmacokinetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000097:blood / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D020723:Glucuronic Acid / Q000097:blood / Q000493:pharmacokinetics; D006603:Hexuronic Acids / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D006835:Hydrazones / Q000097:blood / Q000493:pharmacokinetics; D020100:Hydrogels / Q000493:pharmacokinetics; D015552:Injections, Intralesional; D007275:Injections, Intravenous; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides / Q000097:blood / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000464:Alginates; D000903:Antibiotics, Antineoplastic; D006603:Hexuronic Acids; D006835:Hydrazones; D020100:Hydrogels; D009838:Oligodeoxyribonucleotides; D004317:Doxorubicin; D020723:Glucuronic Acid
keywords: DNA nanotechnology; biomaterials; controlled release; nanoparticle; targeting