Ultrasound‐Responsive Microfluidic Microbubbles for Combination Tumor Treatment

Abstract

Anticancer treatment is a worldwide challenge, and there are constant endeavors in this field to develop intelligent drug delivery systems to improve the therapeutic effect. This paper presents novel ultrasound-responsive delivery microbubbles (UDMs), with chemotherapeutic-encapsulated hydrogel shells and therapeutic gas cores. These are developed using microfluidic electrospray to treat pancreatic tumors. As the hydrogel shells are composed of thermo-sensitive poly(N-isopropylacrylamide) (PNIPAM), they can contract under mild hyperthermia generated by the acoustic-wave-induced oscillation of the encapsulated gas. Thus, by triggering with ultrasound, the chemotherapeutic Gemcitabine (Gem) encapsulated in the hydrogel shells and the hydrogen sulfide (H 2 S) encased in the cores can be controllably released. Based on the UDMs, it is demonstrated that the multiple drug-loaded microcarriers exhibit an excellent tumor-killing effect through combination therapy. The Gem and H 2 S coloaded UDMs have good therapeutic efficacy and adaptability in an orthotopic pancreatic implantation tumor model established in mice. These results indicate that the proposed UDMs have a large potential for codelivery of multiple drugs for treating deep-seated tumors and for realizing combination drug treatment to avoid untoward reactions.

Making waves: how ultrasound-targeted drug delivery is changing pharmaceutical approaches

“…156 These microbubbles release gemcitabine under the mild hyperthermia induced by insonation (3 MHz, 2 W cm À2 , duty cycle of 50%, 1 minute) and have demonstrated therapeutic efficacy (10% apoptosis) in orthotopic pancreatic tumor models in mice, suggesting that this platform could be useful for UTDD in conjunction with thermal ablation of cancerous tumors. 156 Additionally, Liang et al designed HIFU thermosensitive cerasomes by combining cerasome-forming lipid with conventional lipids (DPPC and DSPE-PEG) to create a drug-carrying vehicle that is highly stable at 37 1C with an 8-times increase in blood circulation time, but releases its payload at 42 1C under HIFU exposure (0.5 MHz, duty cycle 30%, 190 mV, 5 minutes) and provides significant inhibition of MDA-MB-231 breast cancer tumors in mice, with B3-fold reduction in tumor volume compared to controls. 157 However, these mildhyperthemia-triggered liposomes are highly susceptible to instability during circulation, which can lead to significant off-target release of the drug payload.…”

Microbubbles Stabilized by Protein Shell: From Pioneering Ultrasound Contrast Agents to Advanced Theranostic Systems

“…In flow-focusing devices, inner channels with a gaseous phase and outer channels with a continuous phase are merged into a small orifice, leading to MB formation. In T-junction devices, a continuous phase channel is placed perpendicular to a gas phase channel; thus, when gas penetrates the continuous phase under required pressure and flow velocity, local instability at the gas-liquid interface results in MB formation (Figure 3b) [10,[114][115][116][117]. However, the scalability of MB production with microfluidics remains the main current limitation.…”

“…Ideal microfluidic-based fabrication may allow producing (i) MBs with predefined diameter in the range of 1-7 µm and small size polydispersity, which is relevant to advance US contrast properties, (ii) MBs with the controllable concentration needed for the procedure, which can be a crucial advantage for clinical translation of the technology [10,[114][115][116][117]. With two types of microfluidic devices highlighted in Figure 3b, all known examples of protein MB microfluidic-assisted MB fabrication are listed in Table 1.…”

Microfluidic Preparation of Gelatin Methacryloyl Microgels as Local Drug Delivery Vehicles for Hearing Loss Therapy

“…Microgels are microsized polymer particles of macromolecular networks with compartmentalization ability and selective permeability, which are favorable for the encapsulation and release of drug agents. Although microparticles have been exploited in middle ear drug delivery in several studies, their biocompatibility, morphology, and adhesion can be further improved. , Numerous technologies, such as spray drying, emulsification solvent evaporation, and microfluidics, are employed to microparticle syntheses. , In particular, microfluidic technology is excellent in manipulating small amounts of fluids at the microscale, and thus, it is capable of generating microparticles with finely controlled sizes and structures. , To date, numerous studies on microfluidic-derived microparticles for use as vehicles in oral delivery, wound healing, antitumor treatments, etc., have been carried out, − whereas their applications in otic treatments have been less explored . Considering the issues associated with intratympanic delivery, the component, size, and physicochemical properties of the microgels must be carefully selected to maintain sustained drug release and overcome the obstacle to air conduction of sound .…”