The effect of HIFU on pH responsive PEGylated micelles was investigated. Micelles can be used as drug carrier vehicles reducing unwanted drug toxicity. HIFU is able to release drugs from the circulating micelles, as well as improving intracellular uptake of both micelle-encapsulated and free drugs non-invasively. Large molecules generally enter cells by endocytosis. Endosomes gradually become acidic and fuse with enzyme containing lysosomes degrading the endosomal contents and preventing them from reaching their intracellular target. Using pH responsive polymers enables endosomes to be distrupted, releasing their contents into the cytoplasm before degradation occurs. Addition of poly(ethylene glycol), referred to as PEGylation, prolongs circulatory half-life and reduces degradation within the bloodstream. HIFU did enable release of encapsulated molecules from the modified micelles, and the micelles were taken up by H69 human carcinoma cells in vitro. Further work will investigate optimization of the micelles to maximize encapsulated drug release. The combined approach of using both pH responsive PEGylated micelles and HIFU to deliver drugs would provide more accurate targeting of therapies allowing higher therapeutic doses to be administered, reduce unwanted side effects and give patients a higher quality of life.
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[Show abstract][Hide abstract]ABSTRACT: Micelles of a diblock copolymer composed of poly(ethylene oxide) and poly(2-tetrahydropyranyl methacrylate) (PEO-b-PTHPMA) in aqueous solution could be disrupted by high-frequency ultrasound (1.1 MHz). It was found that, upon exposure to a high-intensity focused ultrasound (HIFU) beam at room temperature, the pH value of the micellar solution decreased over irradiation time. The infrared spectroscopic analysis of solid block copolymer samples collected from the ultrasound irradiated micellar solution revealed the formation of carboxylic acid dimers and hydroxyl groups. These characterization results suggest that the high-frequency HIFU beam could induce the hydrolysis reaction of THPMA at room temperature resulting in the cleavage of THP groups. The disruption of PEO-b-PTHPMA micelles by ultrasound was investigated by using dynamic light scattering, atomic force microscopy, and fluorescence spectroscopy. On the basis of the pH change, it was found that the disruption process was determined by a number of factors such as the ultrasound power, the micellar solution volume and the location of the focal spot of the ultrasound beam. This study shows the potential to develop ultrasound-sensitive block copolymer micelles by having labile chemical bonds in the polymer structure, and to use the high-frequency HIFU to trigger a chemical reaction for the disruption of micelles.
[Show abstract][Hide abstract]ABSTRACT: The synthesis of multi-functional nanocarriers and the design of new stimuli-responsive means are equally important for drug delivery. Ultrasound can be used as a remote, non-invasive and controllable trigger for the stimuli-responsive release of nanocarriers. Polymeric micelles are one kind of potential drug nanocarrier. By combining ultrasound and polymeric micelles, a new modality (i.e., ultrasound-mediated polymeric micelle drug delivery) has been developed and has recently received increasing attention. A major challenge remaining in developing ultrasound-responsive polymeric micelles is the improvement of the sensitivity or responsiveness of polymeric micelles to ultrasound. This chapter reviews the recent advance in this field. In order to understand the interaction mechanism between ultrasound stimulus and polymeric micelles, ultrasound effects, such as thermal effect, cavitation effect, ultrasound sonochemistry (including ultrasonic degradation, ultrasound-initiated polymerization, ultrasonic in-situ polymerization and ultrasound site-specific degradation), as well as basic micellar knowledge are introduced. Ultrasound-mediated polymeric micelle drug delivery has been classified into two main streams based on the different interaction mechanism between ultrasound and polymeric micelles; one is based on the ultrasound-induced physical disruption of the micelle and reversible release of payload. The other is based on micellar ultrasound mechanochemical disruption and irreversible release of payload.