Ultrasound-triggered disruption and self-healing of reversibly cross-linked hydrogels for drug delivery and enhanced chemotherapy

TLDR

Biological systems are highly sensitive to the timing and location of physiological cues, and polymer‑based delivery systems are widely used for localized, sustained release, but typically provide a constant release rate. The study aimed to create a digitally controllable drug release system that could be activated and deactivated on demand using ultrasound. This was achieved by designing ionically cross‑linked hydrogels that can be disrupted by ultrasound to release encapsulated drugs. Ultrasound stimulation triggered near‑digital release of small molecules, proteins, and oligonucleotides without damaging the hydrogels, and in vitro and in vivo experiments showed that brief, high‑dose drug bursts enhanced mitoxantrone toxicity against breast cancer cells and significantly reduced tumor growth compared to continuous release.

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.