D19 - Ultrasound Responsive Injectable Hydrogels for On-Demand Drug Delivery

Introduction: : In this work, we developed a novel class of ultrasound-responsive and injectable hydrogels that are biocompatible and specifically designed for localized, on-demand delivery of chemotherapeutic agents to solid tumors. The hydrogels remain stable at the injection site and release their drug payload upon exposure to focused ultrasound, allowing precise spatial and temporal control over drug delivery. This approach aims to reduce systemic toxicity while enhancing therapeutic efficacy at the tumor site.

Materials and

Methods: : Injectable hydrogels were prepared by using a zwitterionic monomer, sulfobetaine methacrylate (SBMA), without using any crosslinker. Gelation was performed at -20 C using APS/TEMED as initiator, allowing the formation of strong electrostatic interactions between poly(SBMA) chains to physically crosslink the hydrogels. Monomer and initiator concentrations were carefully optimized to achieve injectable hydrogels with mechanical and thermal stability. To render ultrasound responsivity to the hydrogels, we loaded the hydrogels with hydrophobically (dodecyl) modified mesoporous silica nanoparticles (hMSNs) with sizes around 50 nm. When insonated with High-intensity focused ultrasound (HIFU), the hMSNs incept acoustic cavitation (i.e., growth and collapse of microsized bubbles), which in turn generates mechanical effects in the hydrogels such as shock waves or water jets.

Results, Conclusions, and Discussions:: We found that loading the hydrogels with hMSN did not affect their injectability, and they remained mechanically stable at 37 °C for more than a week. hMSN-loaded hydrogels demonstrated strong ultrasound responsivity even at low particle concentrations (10 g/mL) and ultrasound powers (10 W, ? duty cycle). Furthermore, these hydrogels showed controlled release properties upon loading with chemotherapeutic drug doxorubicin (DOX, 0.2 mg/mL) and protein molecule Bovine Serum Albumin (BSA, 10 mM). In the absence of HIFU treatment, minimal release ( < 20% within a day) of cargos was observed. However, the release kinetics could be modulated by varying gel formulations and HIFU settings. Upon application of HIFU (150 W, % duty cycle) for 1 minute, the weakest hydrogel underwent almost complete mechanical disintegration, resulting in a burst release of cargos. Conversely, the strongest hydrogel released 50% of the cargos and remained intact even after ten repeated treatments at this HIFU power. In summary, our study presents the development of injectable hydrogels with robust ultrasound responsiveness, holding significant promise for localized and on-demand drug delivery to solid tumors. Ongoing investigations in our laboratory aim to further explore the potential of these hydrogels in mice models.

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