Ferenz Katja B, Waack Indra N, Laudien Julia, Mayer Christian, Broecker-Preuss Martina, Groot Herbert de, Kirsch Michael
University of Duisburg-Essen, Institute for Physiological Chemistry, University Hospital Essen, Hufelandstr. 55, Essen 45122, Germany.
University of Duisburg-Essen, Institute for Physical Chemistry, CeNIDE, Universitaetsstr. 5, Essen 45141, Germany.
Results Pharma Sci. 2014 Apr 30;4:8-18. doi: 10.1016/j.rinphs.2014.04.001. eCollection 2014.
The host response against foreign materials designates the biocompatibility of intravenously administered microcapsules and thus, widely affects their potential for subsequent clinical use as artificial oxygen/drug carriers. Therefore, body distribution and systemic parameters, as well as markers of inflammation and indicators of organ damage were carefully evaluated after administration of short-chained poly (vinyl alcohol, (PVA)) solution or poly (ethylene glycol (PEG))-shielded perfluorodecalin-filled poly (d,l-lactide-co-glycolide, PFD-filled PLGA) microcapsules into Wistar rats. Whereas PVA infusion was well tolerated, all animals survived the selected dose of 1247 mg microcapsules/kg body weight but showed marked toxicity (increased enzyme activities, rising pro-inflammatory cytokines and complement factors) and developed a mild metabolic acidosis. The observed hypotension emerging immediately after start of capsule infusion was transient and mean arterial blood pressure restored to baseline within 70 min. Microcapsules accumulated in spleen and liver (but not in other organs) and partly occluded hepatic microcirculation reducing sinusoidal perfusion rate by about 20%. Intravenous infusion of high amounts of PFD-filled PLGA microcapsules was tolerated temporarily but associated with severe side effects such as hypotension and organ damage. Short-chained PVA displays excellent biocompatibility and thus, can be utilized as emulsifier for the preparation of drug carriers designed for intravenous use.
机体对外源物质的反应决定了静脉注射微胶囊的生物相容性，因此，这在很大程度上影响了它们作为人工氧/药物载体后续临床应用的潜力。因此，在向Wistar大鼠静脉注射短链聚乙烯醇（PVA）溶液或聚乙二醇（PEG）包被的全氟萘烷填充的聚（d，l-丙交酯-共-乙交酯，PFD填充的PLGA）微胶囊后，仔细评估了其体内分布和全身参数，以及炎症标志物和器官损伤指标。虽然PVA输注耐受性良好，所有动物在选定剂量为1247mg微胶囊/千克体重的情况下均存活，但表现出明显的毒性（酶活性增加、促炎细胞因子和补体因子升高）并出现轻度代谢性酸中毒。在开始输注微胶囊后立即出现的低血压是短暂的，平均动脉血压在70分钟内恢复到基线水平。微胶囊在脾脏和肝脏中蓄积（但不在其他器官中），并部分阻塞肝微循环，使肝血窦灌注率降低约20%。静脉输注大量PFD填充的PLGA微胶囊暂时可耐受，但伴有严重的副作用，如低血压和器官损伤。短链PVA具有优异的生物相容性，因此可作为乳化剂用于制备设计用于静脉注射的药物载体。
