A stimuli-responsive carrier-based delivery system seems relatively easy to achieve the target-specific delivery depending on the application site of the physical energy. In particular, the ultrasound-mediated delivery has attracted attention due to its safety. The combination of ultrasound and micro/nanobubbles allows for enhanced effects not only of imaging but also of delivery of drug, gene, and nucleic acids. We previously developed nanobubbles entrapping ultrasound contrast gas in liposomes and evaluated the usability for gene and nucleic acids delivery to various disease models. In this review, we describe the current status of the use of ultrasound in the medical field, and introduce the ultrasound-mediated delivery of drug, gene, and nucleic acids containing our research.

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Remote control of transgene expression by physical stimuli may provide a new approach for the controlled expression of therapeutic genes in cancer therapy and regenerative medicine. In this article, new approaches which use local heating of magnetic nanoparticles to transform magnetic signals into cell stimuli for gene expression are reviewed and discussed. By applying a synthetic biological approach, heat-inducible transgene expression systems are applied to target cells. The functionalized magnetite nanoparticles target cells to magnetically label them. Transgenic cells labeled with magnetite nanoparticles can express the transgene upon exposure to an alternating magnetic field. This approach may be applicable to the development of new gene therapies in cancer therapy and regenerative medicine based on the remote manipulation of cell function via transgene expression in a spatiotemporal manner.

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In recent years, boron neutron capture therapy and photoimmunotherapy have been covered by insurance, and such methods combining drugs and medical devices have attracted a significant attention as promising cancer treatment modalities. These technologies have the potential to be applied to cancers that could not be treated by conventional methods, and there is a strong demand for drug development to expand the application. Here, we introduce the design of drug delivery systems in boron neutron capture therapy and photodynamic therapy, including our recent research.

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Gold nanorods and silver nanoplates have absorption bands in near-infrared light region, and generate heat when excited with the near-infrared light. Since the near-infrared light penetrates deeply into tissues, the gold nanorods and silver nanoplates can be heated under the near-infrared light irradiation from outside of the body. Therefore, combining a drug with the gold nanorod via heat labile linkage, drug-release can be controlled by near-infrared light irradiation. In addition, a pulsed laser, which emits high energy intensity instantaneously, is used to release the drug more effectively. A simple combination of drugs, metal nanoparticles, and light irradiation that enables to release a required amount of drug at a target site and an expected timing.

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Functional macromolecules, such as siRNA, are expected as the ideal drugs to induce immune response and suppress specific genes for therapy of skin disorders and cancer. However, delivery of the macromolecules into skin is difficult due to large molecular weight and high hydrophilicity. Since iontophoresis is known to accelerate transdermal permeation of charged molecules by applying a weak electric current to the skin, we paid attention to iontophoresis as an ideal technology for transdermal delivery, and attempted transdermal delivery of macromolecules. siRNA is expected as novel nucleic acid medicines. Thus, we examined iontophoresis of naked siRNA on rat skin in vivo. Naked siRNA was effectively accumulated in the skin after iontophoresis. In addition, iontophoretic delivery of siRNA significantly reduced the target mRNA. From this result, it was suggested that siRNA was delivered into not only the skin tissue, but also cytoplasm of target cells. Then, we analyzed the in vitro intracellular delivery of fluorescent-labeled siRNA by weak electric current（WEC）, and found that cellular uptake of fluorescent-labeled siRNA was increased by WEC, while endocytosis inhibitors significantly prevented siRNA uptake. These results indicate that the cellular uptake mechanism by WEC is endocytosis. Moreover, we compared the intracellular trafficking of macromolecule FITC-dextran, which has different molecular weight, 10,000 and 70,000, taken up by weak electric current. The 10,000 dextran spread to cytoplasm, but 70,000 dextran remained in endosome/lysosomes. This result suggested that WEC treatment induced very unique endosome that leaked macromolecules with a molecular weight of less than 70,000. Transmission electron microscopy of cells treated by WEC showed that the WEC-induced endosomes exhibited an elliptical shape. In the WEC-induced endosomes, ceramide, which makes pore structures in the membrane, was localized. Interestingly, we found that WEC accelerates the production of exosomes as a result of stimulation of the endocytosis. In this review, we also introduce recent findings regarding IP-mediated transdermal drug delivery of bio-macromolecules such as antibody and WEC-mediated increases in vascular permeability.

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