title: Ultrasound-triggered disruption and self-healing of reversibly cross-linked hydrogels for drug delivery and enhanced chemotherapy.
abstract: Biological systems are exquisitely sensitive to the location and timing of physiologic cues and drugs. This spatiotemporal sensitivity presents opportunities for developing new therapeutic approaches. Polymer-based delivery systems are used extensively for attaining localized, sustained release of bioactive molecules. However, these devices typically are designed to achieve a constant rate of release. We hypothesized that it would be possible to create digital drug release, which could be accelerated and then switched back off, on demand, by applying ultrasound to disrupt ionically cross-linked hydrogels. We demonstrated that ultrasound does not permanently damage these materials but enables nearly digital release of small molecules, proteins, and condensed oligonucleotides. Parallel in vitro studies demonstrated that the concept of applying temporally short, high-dose "bursts" of drug exposure could be applied to enhance the toxicity of mitoxantrone toward breast cancer cells. We thus used the hydrogel system in vivo to treat xenograft tumors with mitoxantrone, and found that daily ultrasound-stimulated drug release substantially reduced tumor growth compared with sustained drug release alone. This approach of digital drug release likely will be applicable to a broad variety of polymers and bioactive molecules, and is a potentially useful tool for studying how the timing of factor delivery controls cell fate in vivo.
authors: Harvard University School of Engineering and Applied Sciences, Cambridge, MA 02138;Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 02138;Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139;
authors: Nathaniel
authors: N
authors: Huebsch
authors: Harvard University School of Engineering and Applied Sciences, Cambridge, MA 02138;Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 02138;
authors: Cathal J
authors: CJ
authors: Kearney
authors: Harvard University School of Engineering and Applied Sciences, Cambridge, MA 02138;Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 02138;Soft Active Materials Laboratory, Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27708; and.
authors: Xuanhe
authors: X
authors: Zhao
authors: Harvard University School of Engineering and Applied Sciences, Cambridge, MA 02138;Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 02138;School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors: Jaeyun
authors: J
authors: Kim
authors: Harvard University School of Engineering and Applied Sciences, Cambridge, MA 02138;Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 02138;
authors: Christine A
authors: CA
authors: Cezar
authors: Harvard University School of Engineering and Applied Sciences, Cambridge, MA 02138;
authors: Zhigang
authors: Z
authors: Suo
authors: Harvard University School of Engineering and Applied Sciences, Cambridge, MA 02138;Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 02138; mooneyd@seas.harvard.edu.
authors: David J
authors: DJ
authors: Mooney
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004337:Drug Carriers; D006801:Humans; D020100:Hydrogels; D051379:Mice; D008942:Mitoxantrone / Q000008:administration & dosage / Q000627:therapeutic use*; D014465:Ultrasonics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D020100:Hydrogels; D008942:Mitoxantrone
keywords: alginate; on-demand delivery; self-healing materials; sonophoresis