Worldwide obesity has been nearly doubled since 1980. However, anti-obesity medications that have been developed so far have limited efficacies and considerable side effects. To solve this problem, we focused on the vascular endothelial cells in adipose tissue as a new therapeutic target, since the blood vessels play a crucial role for adipose tissue development and hypertrophy. Thus, we attempted to develop a novel platform for drug delivery based on the active targeting, and succeeded in in vivo obesity treatment via the Prohibitin-Targeted Nano Particle (PTNP) modified with the high affinity peptide (KGGRAKD) to prohibitin expressed on the surface of vascular endothelial cells in adi pose tissue. In addition, we found that the accumulation of long circulating nanoparticles into adipose tissue was passively enhanced by the enhanced permeability and retention (EPR) effect, when they were administered to obese animals. On the basis of these results, we firstly proposed the strategy of adipose vasculature targeted nanotherapy for obesity treatment.

Development of a nanotechnology to control an intracellular trafficking is highly desired as a gene/siRNA medication. In this review, we will first summarize our previous progress in quantitative comparison and underlying mechanisms of the intracellular trafficking between adenovirus vector and plasmid DNA (pDNA) transfected by non-viral vector (cationic lipoplex). Our analysis revealed that the poor post-nuclear delivery event, as well as nuclear delivery process are key processes to be overcome. Especially, less effective transcription and translation is most likely due to the electrostatic interaction of cationic component in lipoplex with pDNA cargo and mRNA, respectively. To overcome these drawback, we have developed a liposomal nanoparticle (LNP) that are formed using SS-cleavable and pH-activated lipid-like materials (ssPalm). The LNPs prepared using ssPalm are designed to destabilize the endosomal membrane in response to the acidic pH in endosomes, and be spontaneously collapsed in responsive to the reducing environment in the cytoplasm, aided by proton-sponge units (tertiary amines) and a cleavage unit (disulfide bonding), respectively. A series of ssPalm-containing particles were prepared containing myristic acid (ssPalmM), retinoic acid (ssPalmA) and α-tocopherol (ssPalmE) as hydrophobic scaffolds. In this review, we will summarize our recent achievement using this particle for the pDNA/siRNA delivery.

Indomethacin-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles with an average size of 50 nm and 100 nm were prepared by combining antisolvent diffusion with preferential solvation. Uncoated nanoparticles do not have a hydrophilic stabilizer (polyvinyl alcohol) on the surface, and therefore, have high hydrophobicity and a negative charge. Nanoparticles of both sizes exhibited the same electrophoretic mobility in 5 mM NaCl. Further, the release behaviour did not differ between particle sizes. The permeability of uncoated nanoparticles through ex vivo rat skin was significantly higher than that of an indomethacin suspension when iontophoresis was applied. Indomethacin accumulated in the hair follicles and stratum corneum after permeation with 50 nm nanoparticles. Transdermal routing of the 50 and 100 nm nanoparticles occurred through the transfollicular pathway, and migration to the follicles was enhanced by iontophoresis. Thus, PLGA nanoparticles prepared by antisolvent diffusion with preferential solvation are beneficial for transdermal iontophoretic delivery of therapeutic agents.

Iontophoresis (IP) is a noninvasive technology that physically enhances transdermal penetration of ionic medicines using faint electricity. IP was generally considered to be effective only for charged amphiphilic small molecules. However, in vivo iontophoretic transdermal delivery of various macromolecules was recently successfully achieved. Moreover, skin physiology is changed by faint electricity. Here, we summarize the recent topic regarding transdermal delivery of macromolecules and nanoparticles by faint electricity.