Research
Development of HDL Mimetic Eye Drops
HDL has various protective effecs during blood circulation in human, including anti-inflammatory and antioxidative effects, lipid excretion, and anti-pathological angiogenesis, wich conteract the pathological mechanisms of neovascular age-related macular degeneration (nAMD). There is no clinically effective eye drops for the treatment of nAMD. In this context, we developed corneal absorption-enhancing HDL mimetics by genetic engineering with functional peptides, and found that their eye drops were theraeutically beneficial in an nAMD mouse model. At the same time, the HDL functionalies of the mimetics were significantly augumented. Our current focus is to further enhance corneal absorption using various strategies.
Development of HDL Mimetic Drug Carriers for Photodynamic Therapy
Photodynamic therapy (PDT) was once the first-line treatment for nAMD; however, after the approval of anti-VEGF proteins for intravitreal injection, it has rarely been used because of its high risk of photdamage to the normal retina and its difficulty in limiting the laser irradiation area to minimize photodamage. These two drawbacks are due to the insufficient DDS capability of the current drug for PDT, that is, the liposomal formulation of verteporfin (Visudyne). We found that HDL mimetics developed as eye drops were better verteporfin carriers than liposomes in terms of the lesion site delivery specificity for verteporfin. With our mimetics loaded with verteporfin, much higher PDT efficacy was obtained without apparent photodamage to the normal retina, even under laser irradiation of the entire retina (no limitation). We are currently optimizing the structure of the mimetics.
Development of In Vivo Screening Systems of HDL Mimetics in Zebrafish Larvae
Zebrafish have been utilized as a vertebrate model in developmental biology research. Owing to its availability in large numbers, its high physiological homology with humans, and the optical transparency of its larvae, zebrafish has recently gained attention as an efficient vertebrate model to enable fast in vivo screening of nanocarriers functions with less cost and labor. In close joint research with Prof. Huwyler at the University of Basel, Switzerland, our efforts have been devoted to the development of a new screening system for HDL mimetics capable of better vasoprotection.
Restoring Vision with Donor-Acceptor-Linked Molecules-Loaded HDL Mimetics (supported by JSPS Grant "Dynamic Excition")
Donor-acceptor-linked (D-A) molecules are photosensitizers in which a light harvester is sandwiched between an electron donor and an electron acceptor. Under visible light illumination, our D-A molecules yield a long-lived charge separeted state, which can be regarded as a "nano-electric field". We have previously reported that illuminated D-A molecules are capable of neuronal firing by decreasing the membrane potential (depolarization). In retinal ganglion cells, neuronal firing following depolarization triggers visual transduction. By combining D-A molecules synthesized by Prof. Imahori (Kyoto Univ.) and Prof. Sakuda (Nagasaki Univ) with our HDL mimetic drug carriers, we are developing a novel therapy for restoring vision.
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