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1. At last year’s ESC Congress, you were awarded the Young Investigator Award for Basic Science. Could you tell us what that award meant to you? How important is this type of recognition?
ESC Congress is one of the world famous congresses in cardiology. This award is definitely the highest honor for my present and future career, and it was a precious reward for my three years’ painstaking work. The present recognition has encouraged me to further improve this line of research and increases my motivation to work harder. This recognition is quite different from publishing papers, but it is very important for rapid exchange of research interests, especially among young researchers from all over the world.
2. As a researcher based in Japan, what attracts you to ESC Congress?
There is no doubt that ESC Congress is the world leading congress in the field of cardiology. Many young cardiologists and researchers in Japan are willing to attend the ESC congress every year. As a cardiologist, as well as a researcher, joining ESC Congress brings me to the forefront of the field and provides an excellent perspective around my own research interest.
3. A key focus of your research has been on nanoparticles and their application for drug delivery. What excites you about this field, in particular, and do you see this as the future for treatment of cardiovascular diseases?
There are many drugs which have favourable effects on cardiovascular disease, however, the use of some strong drugs is limited because of side effects or off-target effects. Such as in the field of cancer chemotherapy, an appropriate drug delivery system could enhance the therapeutic effects of these promising drugs by eliminating the unfavourable side effects. Since our nanoparticle is relatively nonspecific for the target organ, it is known to be extremely safe, and thus can be the first clinical oriented drug delivery system in the field of cardiology.
4. Why is it that we find a career in research so rewarding (perhaps most of the time, I’m sure you would agree that it can also be frustrating at times)?
Research is a never-ending journey. There are always new seeds and many challenges waiting to be solved.
5. What motivates you as a scientist?
Basic research is the only way to develop the future of medicine. Although large clinical trials are increasingly becoming important to build the evidence for new treatment, the origin of these new therapeutics are always based on basic research. There are still many unsolved challenges in the field of medicine, which strongly motivates me to continue my challenge.
6. What do you think are the main challenges that we face in our academic research careers, particularly at the early stages?
Because of the shortage of government–based research funds, even in Japan, it is difficult to obtain sufficient research funds and academic positions as a young researcher. Too many post-doc medical doctors give up their careers in basic research and go back to clinical fields. What the young researcher needs most to get started is a good working environment and a good amount of research funds.
2002-2008: M.D., Faculty of Medicine, Kyushu University, Fukuoka, Japan
2008-2010: Junior Resident, Aso Iizuka Hospital, Fukuoka, Japan
2010-2011: Senior Resident, Department of Emergency Medicine, Aso Iizuka Hospital, Fukuoka, Japan
2011-2013: Clinical Fellow, Department of Cardiovascular Medicine, Aso Iizuka Hospital, Fukuoka, Japan
2013-2017: Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Nanoparticle-mediated targeting of pitavastatin into small pulmonary arteries by intravenous administration attenuates the progression of monocrotaline-induced pulmonary arterial hypertension in rats
Kenzo Ichimura, Tetsuya Matoba, Jun-ichiro Koga, Kaku Nakano, Daiki Funamoto, Hiroyuki Tsutusi, Kensuke Egashira
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan (K.I., T.M., H.T.)
Department of Cardiovascular Research, Development, and Translational Medicine, Center for Disruptive Cardiovascular Medicine, Kyushu University, Fukuoka, Japan (J.K., K. N., D.F., K.E.).
Statins are known to improve pulmonary arterial hypertension (PAH) by their anti-inflammatory and anti-proliferative effects in animal models. However, recent clinical studies reported that clinically approved doses of statins failed to improve clinical outcome in patients with PAH. We have been working on the development of bioabsorbable poly-lactic/glycolic acid (PLGA)-nanoparticle (NP) mediated drug delivery system for cardiovascular diseases. Previously, we have shown that intravenously administered PLGA-NP was selectively delivered to tissues with enhanced vascular permeability by passive targeting, and to tissues with inflammation by direct incorporation and delivery by circulating monocytes in a mouse model of atherosclerosis as well as in rat and porcine models of myocardial ischemia-reperfusion injury. So, we hypothesized that intravenously administered pitavastatin-NP could be selectively delivered to pulmonary arteries and inflammatory cells in the lung and exert its anti-inflammatory and anti-proliferative effects on PAH.
We induced PAH by subcutaneous injection of monocrotaline (MCT) to SD rats. On day 14 after MCT injection, only animals that displayed established PAH on echocardiography were included. On day 17, they were randomly assigned to the following 5 groups; daily intravenous administration of 1) vehicle, 2) FITC-NP, 3) pitavastatin (1, 3, 10 or 30 mg/kg), 4) pitavastatin-NP (containing 1 or 3 mg/kg pitavastatin), or 5) oral sildenafil (10 mg/kg/day). Intravenous NP was selectively delivered into small pulmonary arteries and circulating CD11b positive leukocytes. On day 21, pitavastatin-NP attenuated the progression of PAH at lower doses compared with pitavastatin alone. This was associated with inhibition of monocyte-mediated inflammation, proliferation and remodeling of pulmonary arteries. Interestingly, sildenafil attenuated the development of PAH but had no effects on inflammation and remodeling of pulmonary arteries. In separate experiments, only treatment with pitavastatin-NP reduced the mortality rate at day 35.
We concluded that NP-mediated targeting of pitavastatin into small pulmonary arteries and leukocytes attenuated the progression of established MCT-induced PAH and improved survival. The therapeutic effects of pitavastatin-NP were associated with anti-inflammatory and anti-proliferative effects on small pulmonary arteries, which was completely distinct from vasodilatory effect of sildenafil. Phase I clinical trial of pitavastatin-NP has already been completed, and phase II clinical trial of pitavastatin-NP for PAH has been under contemplation. Pitavastatin-NP can be developed as a novel category of therapeutics for PAH.
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