Lai Chaoyang, Li Cong, Liu Mengyang, Qiu Qiujun, Luo Xiang, Liu Xinrong, Hu Ling, Deng Yihui, Song Yanzhi
Shenyang Pharmaceutical University, Shenyang 110016, China.
Asian J Pharm Sci. 2019 Jul;14(4):455-464. doi: 10.1016/j.ajps.2018.07.004. Epub 2018 Sep 4.
Accelerated blood clearance (ABC) phenomenon is common in many PEGylated nanocarriers, whose mechanism has not been completely elucidated yet. In this study, the correlation between Kupffer cells (KCs) and ABC phenomenon has been studied by KCs-targeted liposomes inducing ABC phenomenon and KCs depletion. In other words, the 4-aminophenyl-α-D-mannopyranoside (APM) lipid derivative DSPE-PEG-APM (DPM), and 4-aminophenyl-β-L-fucopyranoside (APF) lipid derivative DSPE-PEG-APF (DPF) were conjugated and modified on alendronate sodium (AD) liposomes to specifically target and deplete KCs. The dual-ligand modified PEGylated liposomes (MFPL) showed stronger ability to damage KCs and , which also could indirectly illustrate that dual-ligand modification could better target KCs. Besides, the hepatic biodistribution and pharmacokinetics could directly prove that MFPL had a stronger targeting ability to KCs. In addition, in depletion rats, plasma concentration and splenic biodistribution of MFPL and PEGylated liposomes (PL) were significantly elevated and hepatic biodistribution was significantly reduced, which demonstrated that KCs played an important role on elimination of nanoparticles. What's more, ABC phenomenon of the secondary injection of PL was stronger in KCs depletion rats than that in normal rats, which indicated that depletion of KCs prolonged the circulation of PL in the first injection repeatedly stimulating B-cells in the marginal region of the spleen and causing it to secrete more IgM antibodies. This could also illustrate that anti-PEG IgM takes up a major station compared with KCs. Most important of all, KCs-targeted liposomes could induce a stronger ABC phenomenon than PL in normal rats, which declared that based on the same IgM concentration, the more the KCs were stimulated, the stronger ABC phenomenon was induced. However, in depletion rats, this difference of ABC phenomenon between PL and MFPL could no more exist, further demonstrating that KCs could participate and play a certain role in the ABC phenomenon.
加速血液清除（ABC）现象在许多聚乙二醇化纳米载体中很常见，其机制尚未完全阐明。在本研究中，通过库普弗细胞（KCs）靶向脂质体诱导ABC现象和KCs耗竭，研究了KCs与ABC现象之间的相关性。也就是说，将4-氨基苯基-α-D-甘露吡喃糖苷（APM）脂质衍生物DSPE-PEG-APM（DPM）和4-氨基苯基-β-L-岩藻吡喃糖苷（APF）脂质衍生物DSPE-PEG-APF（DPF）偶联并修饰在阿仑膦酸钠（AD）脂质体上，以特异性靶向和耗竭KCs。双配体修饰的聚乙二醇化脂质体（MFPL）对KCs的损伤能力更强，这也间接说明双配体修饰能更好地靶向KCs。此外，肝脏生物分布和药代动力学可以直接证明MFPL对KCs具有更强的靶向能力。此外，在KCs耗竭的大鼠中，MFPL和聚乙二醇化脂质体（PL）的血浆浓度和脾脏生物分布显著升高，肝脏生物分布显著降低，这表明KCs在纳米颗粒的清除中起重要作用。更重要的是，PL二次注射的ABC现象在KCs耗竭的大鼠中比正常大鼠更强，这表明KCs耗竭延长了PL在首次注射中的循环时间，反复刺激脾脏边缘区的B细胞并使其分泌更多的IgM抗体。这也可以说明，与KCs相比，抗聚乙二醇IgM起主要作用。最重要的是，在正常大鼠中，KCs靶向脂质体比PL能诱导更强的ABC现象，这表明在相同IgM浓度下，KCs受到的刺激越多，诱导的ABC现象越强。然而，在KCs耗竭的大鼠中，PL和MFPL之间的这种ABC现象差异不再存在，进一步证明KCs可以参与ABC现象并发挥一定作用。
