【論文摘要】Clinical Research of Nanoparticle-mediated Drug Targeting System for Innovative Therapeutic Strategies in Treatment-Refractory Cardiovascular Diseases

Kensuke Egashira

《海峽循環醫學雜誌》 1卷2S期 (2019/09) Pp. 191-191

https://doi.org/10.6907/SCJ.201909/SP_1(2).0157

摘要

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. To develop innovative therapeutic modalities for treatment-refractory cardiovascular diseases such as no-option critical limb ischemia, myocardial/cerebral infarction, and pulmonary arterial hypertension, we recently developed a nanoparticle-mediated drug targeting/delivery system using bioabsorbable poly-lactic/glycolic acid (PLGA) nanoparticles. In several animal models, we reported that pitavastatin-incorporated nanoparticles (Pitava-NP) showed significant therapeutic effects on critical limb ischemia (therapeutic arteriogenesis), myocardial ischemia-reperfusion injury and remodeling after acute myocardial infarction, pulmonary arterial hypertension. Because PLGA nanoparticles are delivered selectively to inflammatory cells (inflammatory monocytes) and small arteries after intravenous/intramuscular administration, it is suggested that monocyte-mediated inflammation and/or angiogenesis play an important role in the mechanism by which Pitava-NP exerted beneficial therapeutic effects in these previous studies. To translate our experimental findings to clinical medicine, we have completed production of Pitava-NP in compliance with GMP regulations, performed required toxicity and pharmacokinetics studies in compliance with GLP regulations, and confirmed safety of Pitava-NP. Overall, Pitava-NP is a clinically feasible drug delivery system and represents a significant advance in therapeutic modalities over current unsatisfactory approaches. After the Investigational New Drug application to the Japanese regulatory agency (PMDA), we have completed a phase I/II clinical trial (UMIN000008011) and reported the safety and efficacy of intramuscular injection of Pitava-NP for 16 patients with critical limb ischemia. In addition, we have completed phase I clinical studies of intravenous administration of Pitava-NP in healthy volunteers (UMIN 000014940, UMIN 000019189) and are now conducting phase IIa clinical trial (UMIN000032531) to investigate effectiveness and safety of Pitava-NP in 12 patients with severe pulmonary arterial hypertension. In summary, GCP-guided clinical studies are now underway for marketing Pitava-NP to develop an innovative new therapeutic strategy that may advance currently unsatisfactory cardiovascular medicine. We are now negotiating a licence out of this Pitava-NP platform technology with a pharmaceutical company.