Szebeni János, Alving Carl R, Rosivall László, Bünger Rolf, Baranyi Lajos, Bedöcs Péter, Tóth Miklós, Barenholz Yezheckel
Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, MD, USA.
J Liposome Res. 2007;17(2):107-17. doi: 10.1080/08982100701375118.
Intravenous injection of some liposomal drugs, diagnostic agents, micelles and other lipid-based nanoparticles can cause acute hypersensitivity reactions (HSRs) in a high percentage (up to 45%) of patients, with hemodynamic, respiratory and cutaneous manifestations. The phenomenon can be explained with activation of the complement (C) system on the surface of lipid particles, leading to anaphylatoxin (C5a and C3a) liberation and subsequent release reactions of mast cells, basophils and possibly other inflammatory cells in blood. These reactions can be reproduced and studied in pigs, dogs and rats, animal models which differ from each other in sensitivity and spectrum of symptoms. In the most sensitive pig model, a few miligrams of liposome (phospholipid) can cause anaphylactoid shock, characterized by pulmonary hypertension, systemic hypotension, decreased cardiac output and major cardiac arrhythmias. Pigs also display cutaneous symptoms, such as flushing and rash. The sensitivity of dogs to hemodynamic changes is close to that of pigs, but unlike pigs, dogs also react to micellar lipids (such as Cremophor EL) and their response includes pronounced blood cell and vegetative neural changes (e.g., leukopenia followed by leukocytosis, thrombocytopenia, fluid excretions). Rats are relatively insensitive inasmuch as hypotension, their most prominent response to liposomes, is induced only by one or two orders of magnitude higher phospholipid doses (based on body weight) compared to the reactogenic dose in pigs and dogs. It is suggested that the porcine and dog models are applicable for measuring and predicting the (pseudo)allergic activity of particulate "nanodrugs".
静脉注射某些脂质体药物、诊断剂、胶束和其他基于脂质的纳米颗粒可导致高达45%的患者出现急性超敏反应（HSR），伴有血流动力学、呼吸和皮肤表现。这种现象可以用脂质颗粒表面补体（C）系统的激活来解释，导致过敏毒素（C5a和C3a）释放，随后肥大细胞、嗜碱性粒细胞以及可能血液中的其他炎症细胞发生释放反应。这些反应可以在猪、狗和大鼠身上重现和研究，这些动物模型在敏感性和症状谱方面彼此不同。在最敏感的猪模型中，几毫克脂质体（磷脂）可导致类过敏休克，其特征为肺动脉高压、全身低血压、心输出量降低和严重心律失常。猪还会出现皮肤症状，如潮红和皮疹。狗对血流动力学变化的敏感性与猪相近，但与猪不同的是，狗对胶束脂质（如聚氧乙烯蓖麻油EL）也有反应，其反应包括明显的血细胞和自主神经变化（如白细胞减少后白细胞增多、血小板减少、液体分泌）。大鼠相对不敏感，因为它们对脂质体最突出的反应——低血压，只有在磷脂剂量（基于体重）比猪和狗的反应原性剂量高一个或两个数量级时才会诱发。有人认为猪和狗模型适用于测量和预测颗粒状“纳米药物”的（假）过敏活性。
