Acute myocardial infarction (AMI) is an acute ischemic heart disease, which can be attributed to a plaque rupture and acute thrombosis of coronary atherosclerotic lesions. Despite decreased acute mortality for AMI with the widespread use of percutaneous coronary intervention (PCI) in japan, an increase in patients with chronic heart failure following cardiac ischemia-reperfusion injury has become a crucial issue. Therefore, preventing the progression of AMI to chronic heart failure is a significant unmet medical need in cardiovascular diseases. In this review, together with our previous work, we will highlight recent advances in the development of nanotechnology-based drug delivery system (DDS) for the treatment of AMI, and discuss their therapeutic potential for clinical applications.

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Percutaneous coronary intervention (PCI), which was invented by Grntzig in 1977, has become the most important therapeutic procedure in patients with coronary heart disease. Although the use of balloon angioplasty was limited by abrupt vessel closure and chronic re-stenosis, coronary stents improved procedural safety and long-term efficacy. Drug-eluting stents (DES) with controlled local release of antiproliferative agents have consistently reduced restenosis rate after implantation as compared with bare-metal stent. Although first generation DESs has an adverse effect of very late stent thrombosis that needs to continue dual antiplatelet therapy for more than one year, new polymers and platforms for new DESs that are aimed at improving safety and efficacy have been developed. This review provides the history of PCI and information of currently available DESs.

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Coronary artery disease including acute myocardial infarction is a significant concern in cardiovascular medicine, because of their high acute mortality and morbidity causing lethal heart failure. Atherosclerotic plaque destabilization and rupture are central pathogenesis of acute myocardial infarction, whereas myocardial ischemia-reperfusion injury is another adverse phenomenon in the heart undergoing early reperfusion therapy for acute myocardial infarction. There are un-met needs for these pathological conditions to be overcome by the use of nanoparticle-mediated drug delivery system (DDS). We provide overview of the mechanistic background for the use of DDS and the efficacy of nano-medicine in preclinical disease models.

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Ischemic stroke is a high-mortality disease and a leading cause of neurological disability. Tissue plasminogen activator (t-PA) is the only therapeutic agent used worldwide for the treatment of acute ischemic stroke; however, the proportion of patients given t-PA is limited. Thus, the development of an effective neuroprotective agent is urgently required. It has been reported that, under ischemic stroke conditions, the vascular permeability of the blood-brain barrier is increased around the ischemic core region. Our previous investigation of this phenomenon revealed that drug delivery using liposomes is applicable in the ischemic state and at an early stage after reperfusion, and that intravenous administration of liposomal neuroprotectants is effective for the treatment of cerebral ischemia/reperfusion injury in a rat ischemic stroke model. In this review, we summarize our recent findings on the treatment of ischemic stroke using liposomal DDS.

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In this review, we describe novel targeting diagnoses and therapies for acute cerebral ischemic stroke with introducing the present medical situation of this disease as well as our recent research results using a polymeric MRI contrast agent. Disabilities (e.g., paralyses and dysbasia) are very serious problems of acute cerebral ischemic stroke. At present, against this disease, the only efficacious therapy is intravenous injection of recombinant tissue plasminogen activator (rt-PA) that dissolves clots in occluded cerebral blood vessels. Suppression of intracerebral hemorrhage, that is the most serious adverse effect of the therapy, is strongly wanted. This rt-PA-related hemorrhage is believed to result from biological activities of the rt-PA in the cerebral space after rt-PA has extravazated from the bloodstream into this space, therefore we intend to identify hemorrhage-risky area using a macromolecular MRI contrast agent because this contrast agent may depict the degree of rt-PA's extravazation. We found this macromolecular contrast agent accumulated rapidly at the disease site in a short period. Therefore, we believe high feasibility of a novel diagnosis method of the hemorrhage-risky area using this macromolecular system.In the final part, we propose a novel pathology based on material translocation between the bloodstream and disease organ/tissue. In this pathology, we can analyze relationships between disease states and the translocation behaviors of materials in various sizes. Developments of the novel pathology not only reveal unknown living body's mechanisms, but also can contribute to creation of new medical diagnoses and therapies.

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Reactive oxygen species (ROS) are highly reactive molecules containing oxygen, which cause strong oxidative damage to lipid, protein, nucleic acid, etc. Excessive generation of ROS in the biological system leads to an increase in oxidative stress, which is a possible risk factor for systemic diseases such as arteriosclerosis, diabetes, renal failure, Alzheimer's disease, and myocardial infarction. ROS scavenging activity has become important to suppress the aggravation of local inflammation, as well as to prevent the progression of systemic diseases via penetration of ROS from the site of inflammation. Nitroxide radical compounds such as 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) catalytically scavenge ROS such as superoxide anion and hydroxyl radical and prevent the propagation of an ROS-dependent reaction. However, the diffusion of low-molecular-weight (LMW) compounds in the entire body is one of the most important factors that cause various adverse effects. For example, normal ATP-based energy would not be obtained if the mitochondrial electron transport chain is inhibited by LMW antioxidants such as TEMPO. To address these issues, we have focused on redox polymer therapeutics as a key form of nanomedicine, viz., we have developed a nitroxide-radical-containing nanoparticle (RNP^N), a core-shell type of self-assembling polymeric micelle using poly(ethylene glycol)-b-poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene] (PEG-b-PMNT) diblock copolymer in aqueous media. The developed RNP^N had a suppressive effect on oxidative stress in an in vitro study, and showed a therapeutic effect against cerebral and myocardial ischemia reperfusion injuries and intracerebral hemorrhage after intravenous administration. It should be noted that RNP^N tends to avoid non-specific diffusion of nitroxide radicals to the entire body, especially important electron-transporting systems in the mitochondria.

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Microneedle (MN) technology has recently attracted considerable attention as an effective means of transdermal delivery with a high degree of safety. Clinical research is focusing especially on MN containing influenza vaccine or insulin. Generally, MN can be divided into two types, a solid type consisting of silicon or stainless material, and a self-dissolving type made mainly from biodegradable materials, such as hyaluronic acid (HA) or saccharides. All of them have multiple micro-projections to deliver agents into cutaneous tissue, with a pinholder pattern on the patch. We evaluated the efficacy of self-dissolving MNs made of HA for cosmetic use, focusing on their solubility in stratum corneum (SC). We found that continuous administration of MN at the eye corner resulted in significant increases of the water content of the SC and of skin elasticity. These findings suggested that this might be an effective approach for cosmetic improvement of wrinkles. MN was launched as‘NAVISION HA fill-patch’ on March 2011 as an anti-wrinkle cosmetic. Here, we review the efficacy of self-dissolving MN, the effect of HA on cutaneous cells, and the mechanism of wrinkle formation.

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