Emergent Bioengineering Materials Research Team, RIKEN Center for Emergent Matter Science (CEMS), 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan,; Department of Life Science and Technology, School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8502, Japan.
Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakouen, Minato-ku, Tokyo, 105-8512, Japan.
J Colloid Interface Sci. 2023 Dec;651:273-283. doi: 10.1016/j.jcis.2023.07.149. Epub 2023 Jul 26.
Liposomes coated with long polysarcosine (PSar) chains at a high density might enable long blood circulation and attenuate accelerated blood clearance (ABC) phenomenon.
In this study, we controlled the length (23, 45, 68 mers) and density (5, 10, 15 mol%) of PSar on liposomal coatings and, furthermore, investigated the effects of PSar length and density on the blood circulation time, biodistribution, immune response, and ABC phenomenon induction. Length-controlled PSar-bound lipids (PSar-PEs) were synthesized using a click reaction and inserted into bare liposomes at different combinations of chain lengths and proportions.
Although all PSar-coated liposomes (PSar-lipos) had similar morphological, physical, and chemical properties, they had different blood circulation times and biodistribution, and exerted varied effects on the immune system. All PSar-lipos with different PSar length and density showed a similar anti-PSar IgM response. Liposomes modified with the longest PSar chain (68 mers) at a high density (15 mol%) showed the longest blood circulation time and, additionally, attenuated ABC phenomenon compared with PEG-lipo. The ex vivo analysis of the biodistribution of liposomes revealed that a thick PSar layer enhanced the blood circulation time of liposomes due to the reduction of the accumulation of liposomes in the liver and spleen. These findings provide new insights into the relationship between IgM expression and ABC phenomenon inhibition.
用高密度的长多聚精氨酸（PSar）链涂覆的脂质体可能使血液循环时间延长，并减轻加速清除（ABC）现象。
在这项研究中，我们控制了脂质体涂层上 PSar 的长度（23、45、68 个残基）和密度（5、10、15 mol%），并进一步研究了 PSar 长度和密度对血液循环时间、生物分布、免疫反应和 ABC 现象诱导的影响。使用点击反应合成了长度可控的 PSar 结合脂质（PSar-PEs），并将其以不同长度和比例的组合插入裸脂质体中。
尽管所有 PSar 包被的脂质体（PSar-lipos）都具有相似的形态、物理和化学性质，但它们的血液循环时间和生物分布不同，对免疫系统的影响也不同。所有具有不同 PSar 长度和密度的 PSar-lipos 均表现出相似的抗 PSar IgM 反应。用最长 PSar 链（68 个残基）修饰、高密度（15 mol%）的脂质体显示出最长的血液循环时间，并且与 PEG-lipo 相比，还减轻了 ABC 现象。脂质体生物分布的离体分析表明，由于肝脏和脾脏中脂质体的积累减少，较厚的 PSar 层可延长脂质体的血液循环时间。这些发现为 IgM 表达与 ABC 现象抑制之间的关系提供了新的见解。
