Pulsatile Chemotherapeutic Delivery Profiles Using Magnetically Responsive Hydrogels

Abstract

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.

Ultrasonic Generation of Pulsatile and Sequential Therapeutic Delivery Profiles from Calcium-Crosslinked Alginate Hydrogels

“…As discussed in the introduction, many emerging drug delivery strategies involve generating localized therapeutic delivery profiles that are more temporally complex. For example, there is growing evidence that pulsatile chemotherapeutic deliveries are more effective in destroying tumor cells than sustained deliveries [11,19,33,43]. Because of this potential, we aimed to demonstrate that ultrasonic stimulation could be used to generate pulsatile chemotherapeutic delivery profiles by periodically turning on and off the ultrasonic signal.…”

“…Because of this potential, we aimed to demonstrate that ultrasonic stimulation could be used to generate pulsatile chemotherapeutic delivery profiles by periodically turning on and off the ultrasonic signal. To mimic a pulsatile mitoxantrone delivery profile that was previously demonstrated to enhance melanoma cell destruction [43], we exposed mitoxantrone-loaded, calcium-crosslinked alginate hydrogels to a 1-h period of pulsed US stimulation one time a day for 3 days. Specifically, for a 1-h period each day (for 3 days total), gels were stimulated with various US pulse trains composed of 1-min pulses at 20% amplitude: (i) 0 pulses (control), (ii) one 1-min pulse (and 59 min of no stimulation), (iii) two 1-min pulses (with 29 min of no stimulation following each pulse), and (iv) three 1-min pulses (with 19 min of no stimulation following each pulse).…”

Hydrogels for Medical and Environmental Applications

“…E) Schematic of the custom magnetic stimulation setup used in these studies. Reproduced with permission . Copyright 2018, American Chemical Society.…”

“…Magnetic hydrogels or ferrogels are widely used for a lot of biomedical applications including drug delivery . We describe a few recent examples of the latest technologies used in magnetic hydrogels for efficient and well‐controlled drug delivery.…”

“…Emi et al designed a magnetic, macroporous alginate hydrogel for a pulsatile chemotherapeutic delivery of the drug mitoxantrone for cancer treatment . The group first conducted in vitro experiments to show that pulsatile administration of the cancer drug resulted in lower numbers of live melanoma cells than a continuous drug administration.…”