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.self-healing materials | alginate | on-demand delivery | sonophoresis

Repeatable and adjustable on-demand sciatic nerve block with phototriggerable liposomes

“…The basal release of TTX from the liposomes could be slowed by designing vesicles that can revert to their original state and maintain their physical integrity after irradiation, allowing further triggered events. Triggerability also might be achieved by using a lower, potentially safer, energy dose by coupling the NIR-triggered mechanism with other triggering mechanisms, e.g., photothermal effects (8,14), reversible chemical reactions (14,15), or mechanical disturbance (55,56).…”

Versatile click alginate hydrogels crosslinked via tetrazine–norbornene chemistry

“…Hydrogels are highly hydrated, crosslinked polymer networks that resemble the environment of natural soft tissue, making them attractive materials for a variety of biomedical applications such as tissue engineering, drug delivery, and vaccines [1][2][3][4][5][6][7]. Alginate biopolymers are versatile, naturally derived linear polysaccharides comprised of repeating (1,4)-linked β-D-mannuronic and α-Lguluronic acid, and can be crosslinked to form hydrogels via a variety of ionic and covalent crosslinking methods [8,9].…”

Progress in material design for biomedical applications

“…Light penetration can be attenuated at many depths and wavelengths; however, there are numerous examples where light has been used to either form materials (73) their properties when implanted (74). Ultrasound is another trigger that can be introduced to disrupt polymer structure and release therapeutics (75,76). As described with the biodegradable reservoirs above, a similar system has been developed with electrochemically activated microchips with release through the dissolution of a gold membrane (77).…”