Ultrasound-responsive polymers

Ultrasound is an important local stimulus for triggering drug release at the target tissue. Ultrasound-responsive drug delivery systems have become an important research focus in targeted therapy. 

Different polymer systems have been employed for the ultrasound-mediated drug release systems. Generally, pol5mieric systems otherwise impermeable to the drug are preferred for ultrasound-mediated release. This enables the drug to be delivered only at the desired time and location [68]. 

The enhanced release has also been observed in non-erodible systems exposed to ultrasound where the release is diffusion dependent. For example, release rates of zinc bovine insulin from ethylenevinylacetate copol5mier matrices were 15 times higher when exposed to ultrasound compared to the unexposed periods [164]. 

In another example, implants composed of polyanhydride pol5miers loaded with 10% para-aminohippuric acid (PAH) were implanted subcutaneously in the back of catheterized rats. 

When exposed to ultrasound, a significant increase in the PAH concentration in urine was detected [165]. 

It is difficult to pinpoint the specific macromolecular characteristics that allow response to ultrasound. Many polymers of varying composition, architecture, polarity, Tg, and so on, have been demonstrated to alter their behavior when exposed to ultrasonic stimulation. As opposed to magnetoresponsive polymers, foreign additives are not required [136]. However, polymers existing in a few specific physical states are mostly considered. Polymeric systems that respond to ultrasound have generally been gels or other nonswoUen macroscopic solids, polymeric micelles, or layer-by-layer (LbL) coated microbubbles. 

Acoustic destabilizationofsupramolecular polymer assemblies has also been considered [145-150]. Generally, polymeric micelles are induced to dissociate or adopt loosely associated morphologies when exposed to ultrasound [148]. Low-frequency ultrasound also enhances local cellular uptake of drugs, indicating that this approach could prove useful for delivery, provided precautions are taken to prevent cavitational damage to vital structures in the body. Pitt and coworkers [145, 

150] have demonstrated that hydrophobic drugs can be incorporated into PEO-b-PPO-b-PEO micelles and that release could be induced with low-frequency ultrasound. 

---

Paris, J.L., Cabanas, M.V., Manzano, M., Vallet-Regi, M., 2015. Polymer-grafted mesoporous silica nanoparticles as ultrasound-responsive drug carriers. ACS Nano 9 (11), 11023-11033. 

It is possible that microbubble shell may be shattered during the interaction with an ultrasound pulse. Indeed, drastic variation of microbubble size, up to several-fold in less than a microsecond, has been reported [33], with linear speeds of the wall motion of microbubble approaching hundreds of meters per second in certain conditions. At these rates, it is easy to shatter the materials that would otherwise flow under slow deformation conditions. In some cases (e.g., lipid monolayer shells, which are held together solely by the hydrophobic interaction of the adjacent molecules), after such shattering the re-formation of the shell maybe possible in other cases - e.g., with a solid crosslinked polymer or a denatured protein shells - the detached iceberg-like pieces of the microbubble shell coat would probably not re-form and anneal, and the acoustic response of microbubbles to the subsequent ultrasound pulses would be different [34]. 

Tanabe K, Serruys PW, Degertekin M, et al. Chronic arterial responses to polymer-controlled paclitaxel-eluting stents comparison with bare metal stents by serial intravascular ultrasound analyses data from the randomized TAXUS-II trial. Circulation 2004 109(2) 196-200. 

Enhanced (up to 20 times baseline) polymer erosion and drug release were observed when bioerodible samples were exposed to ultrasound. The system s response to the ultrasonic triggering was also rapid (within 2 min) and reversible. This was determined by an on-line UV spectrophotometric response in a closed-loop detection system where the concentration of the releasing agent was continuously monitored (42). 

Ultrasonically Stimulated Systems. Kost and co-workers (58) proposed that cavitation and acoustic streaming are responsible for the augmented degradation and release of biodegradable polymers. Miyazaki and co-workers (59) speculated that the ultrasound caused increased temperature in their delivery system, which may facilitate diffusion. 

Polymers responsive to the body s external stimuli contain polymers sensitive to temperature, near-infrared light, ultrasound, magnetic fields, light, and electrics fields. These kinds of energy, which are supplied from outside of the body, are used for drug delivery systems. 

---