Pulsatile chemotherapeutic delivery profiles may provide a number advantages by maximizing the anticancer toxicity of chemotherapeutics, reducing off-target side effects, and combating adaptive resistance. While these temporally dynamic deliveries have shown some promise, they have yet to be clinically deployed from implantable hydrogels, whose localized deliveries could further enhance therapeutic outcomes. Here, several pulsatile chemotherapeutic delivery profiles were tested on melanoma cell survival in vitro and compared to constant (flatline) delivery profiles of the same integrated dose. Results indicated that pulsatile delivery profiles were more efficient at killing melanoma cells than flatline deliveries. Furthermore, results suggested that parameters like the duration of drug “on” periods (pulse width), delivery rates during those periods (pulse heights), and the number/frequency of pulses could be used to optimize delivery profiles. Optimization of pulsatile profiles at tumor sites in vivo would require hydrogel materials capable of producing a wide variety of pulsatile profiles (e.g., of different pulse heights, pulse widths, and pulse numbers). This work goes on to demonstrate that magnetically responsive, biphasic ferrogels are capable of producing pulsatile mitoxantrone delivery profiles similar to those tested in vitro. Pulse parameters such as the timing and rate of delivery during “on” periods could be remotely regulated through the use of simple, hand-held magnets. The timing of pulses was controlled simply by deciding when and for how long to magnetically stimulate. The rate of release during pulse “on” periods was a function of the magnetic stimulation frequency. These findings add to the growing evidence that pulsatile chemotherapeutic delivery profiles may be therapeutically beneficial and suggest that magnetically responsive hydrogels could provide useful tools for optimizing and clinically deploying pulsatile chemotherapeutic delivery profiles.

Control over of biological processes can potentially be therapeutically regulated through localized biomolecular deliveries. While implantable hydrogels can provide localized therapeutic deliveries, they do not traditionally provide the temporally complex therapeutic delivery profiles required to regulate complex biological processes. Ionically crosslinked alginate hydrogels have been shown to release encapsulated payloads in response to a remotely applied ultrasonic stimulus, thus potentially enabling more temporally complex therapeutic delivery profiles. However, thorough characterizations of how different types of therapeutic payloads are retained and ultrasonically released need to be performed. Additionally, the impact of potentially disruptive ultrasonic stimulations on hydrogel structure and temperature need to be characterized to better understand what range of ultrasonic signals can be used to trigger release. To perform these characterizations, calcium-crosslinked alginate hydrogels were loaded with various model macromolecules (dextrans), chemotherapeutics, and protein signaling factors and exposed to a variety of single-pulse and multi-pulse ultrasonic signals at various amplitudes and durations. In response to single-pulsed ultrasonic exposures, quantifications of molecular release, degree of gel erosion, and increase in hydrogel temperature revealed that the ultrasonic stimulations required for statistically significant therapeutic deliveries often eroded and heated the gels to unacceptable levels. However, multi-pulse ultrasonic exposures were shown to achieve significant amounts of therapeutic release while keeping gel erosion and temperature increase at modest levels. Finally, experiments were performed demonstrating that ultrasonic stimulation could be used to generate drug release profiles shown to have potential therapeutic benefits (e.g., pulsatile and sequential anticancer delivery profiles). This work underscores the potential of using ultrasonically responsive polymeric hydrogels for providing on-demand control over more complex therapeutic deliver profiles and enhancing drug delivery strategies in cancer therapies and beyond.