To address the issue of excess polyethylene glycol (PEG)-lipid degradation observed when PEG-modified liposomes are prepared using the pH-gradient method, a concept using a novel PEG-modification method, called the post-modification method, was proposed and evaluated. To assess the proof concept, a preservation-stability study and a pharmacokinetic study were performed that compared the conventional PEG-modification method, called the pre-modification method, with the post-modification method. The results show that PEG-lipid degradation could be markedly inhibited in the post-modification method. Furthermore, the post-modification method could be used without any manufacturing process difficulties, especially with high PEG-lipid content. In addition, a higher blood circulation capability was observed in the post-modification method. Through comparative studies, it was found that the post-modification method was advantageous compared to the pre-modification method. In conclusion, the post-modification method has the potential to be a novel PEG-modification method that can achieve a higher preservation stability of PEG-lipid, a greater ease of manufacturing, and a higher blood circulation capability, especially in the manufacturing of pH-gradient liposomal products.
Clinical application of artificial oxygen carriers as a substitute for blood transfusion has long been expected to solve some of the problems associated with blood transfusion. Use for oxygen delivery treatment for ischemic disease by oxygen delivery has also been examined. These prospective applications of artificial oxygen carriers are, however, still in development. We have developed liposome-encapsulated hemoglobin (LEH), developmental code TRM-645, using technologies for encapsulation of concentrated hemoglobin (Hb) with high encapsulation efficiency as well as surface modification to achieve stability in circulating blood and a long shelf life. We have confirmed the basic efficacy and safety of TRM-645 as a red blood cell substitute in studies on the efficacy of oxygen delivery in vivo, and the safety of TRM-645 has been studied in some animal species. We are now examining various issues related to clinical studies, including further preclinical studies, management of manufacturing and the quality assurance for the Hb solution and liposome preparations manufactured by the GMP facility.
Objective-TRM-484 is a novel drug consisting of nanoparticles of prednisolone with high affinity to chondroitin sulfate proteoglycans (CSPGs). This may allow for neointimal suppression via directed targeting to areas of injury at systemic concentrations low enough to avoid adverse side effects known to occur with oral delivery of steroids. Methods and Results-Atherosclerotic New Zealand white Rabbits were implanted with bare metal stents and randomized to receive intravenous TRM-484 at doses of 1 mg/kg or 0.32 mg/kg starting at the day of stenting and continuing 3 times a week for the duration of the study. Control animals received empty liposomes (placebo) or saline infusion. Stented arterial segments were harvested at 42 days and processed for histomorphometry and immunohistochemistry. Tissue and plasma levels were determined along with confocal microscopic analysis to determine distribution of rhodamine-labeled TRM-484 at various time points. TRM-484 was exclusively observed at sites of stent-induced injury, with absence of drug in contralateral nonstented arteries. Tissue concentration of stented arteries exceeded that of contralateral nonstented arteries by 100-fold 24 hours after administration of 1 mg/kg TRM-484 and resulted in significant reduction of percent stenosis compared to saline and placebo treated rabbits (22.5Ϯ4.4 versus 31.0Ϯ8.4 and 29.5Ϯ8.1%, PϽ0.03). Conclusion-TRM-484 at doses of 1 mg/kg resulted in significant suppression of in-stent neointimal growth in atherosclerotic rabbits. Site-specific targeting by this nanoparticle steroid in injured atherosclerotic areas might be a valuable and cost-effective approach for the prevention of in-stent restenosis. (Arterioscler
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