The initial injection of PEGylated nanoparticles can activate antibodies and the complement system, leading to the accelerated blood clearance (ABC) phenomenon, characterized by reduced circulation time and abnormal liver and spleen accumulation upon re-exposure. However, PEGylation is not essential for ABC induction, as non-PEGylated nanoparticles can also trigger the similar ABC phenomenon. In this study, we found non-PEGylated nanoemulsions (CE) could accelerate the blood clearance of subsequent injection of PEGylated nanoemulsions (PE) in beagles and rats, which was independent of antibodies and the complement system, but was associated with an increase in neutrophil numbers and phagocytic activity. We propose classifying this as a “general ABC phenomenon,” broadening clinical relevance and highlighting potential immune risks of ABC phenomenon. The intensity of the ABC phenomenon correlated with the initial CE phospholipid dose in both species. Notably, larger CE particles (∼ 300 nm) induced the ABC phenomenon in beagles, while smaller particles (∼ 80 nm) with higher immunogenicity were required in rats. This suggested that beagles are more susceptible to CE-induced ABC phenomenon. The higher neutrophil proportion in beagles likely contributed to species differences in ABC phenomenon. This is the first study to report neutrophil involvement in ABC induction by non-PEGylated nanoparticles, more importantly, underscoring potential immune risks in the cross-injection of non-PEGylated and PEGylated nanoparticles during the developments and clinical applications of nano-drug delivery systems.

Objective To study the pharmacokintics of emulsions coated with different GM1-surface density in Beagles.Methods 10％,30％,50％ GM1-modified emulsions (GM1-CEs) were prepared and the actual GM1 modification density on emulsion surface was determined.The pharmacokintics of 10％,30％,50％GM1-CEs and the mixture of conventional emulsions and GM1 solution (CEs + mGM1) were studied.Results The actual GM1 modification density of 10％,30％,50％ GM1 coated emulsions were 7.67％,19.85％ and 30.01％.The AUC(0-12h) of 10％,30％,50％ GM1-CEs were 1.46,2.19 and 2.54 fold larger than that of conventional emulsions.The t1/2β of 10％,30％,50％ GM1-CEs were 1.17,1.61 and 2.02 fold lower than that of conventional emulsions.The AUC(0-12h) of CE + 10％ mGM1,CE + 30％ mGM1,CE +50％ mGM1 were 1.05,1.10 and 1.19 fold larger than that of conventional emulsions.The t1/2β of CE +10％ mGM1,CE + 30％ mGM1,CE + 50％ mGM1 were 1.07,1.10 and 1.11 fold lower than that of conventional emulsions.Conclusions The circulation times of GM1-modified emulsions prolong with the increase of GM1-surface density and unmodified GM1 micelles do not affect the pharmacokinetics of conventional emulsions in Beagle.

The accelerated blood clearance (ABC) phenomenon which is induced by repeated injection of poly (ethylene glycol) (PEG)-coated colloidal carriers gives clinical challenge to the promising drug delivery system. It is necessary to decrease this unexpected immunological response. A novel 4-arm poly (ethylene glycol-5000)4-cholesteryl methyl amide (4-arm PEG5000-CHMA) has been synthesized. The structure of 4-arm PEG5000-CHMA was confirmed by IR and 1H-NMR spectrum. The pharmacokinetics of the tocopheryl nicotinate (TN)-loaded nanoemulsions modified with 4-arm PEG5000-CHMA or/and 1, 2-distearoyl-Sn-glycero-3-phosphoethanolamine-n-[methoxy(poly-ethyleneglycol)-2000] (mPEG2000-DSPE) have been studied. Furthermore, the ABC phenomenon has been detailed investigated in rats by TN-loaded nanoemulsions modified with 4-arm PEG5000-CHMA and mPEG2000-DSPE (CPNE). The plasma levels of TN and anti-PEG IgM antibody were determined by HPLC and ELISA, respectively. The circulation time of the CPNEs were comparable to the mPEG2000-DSPE coated nanoemulsions. Moreover, the ABC phenomenon can be decreased by CPNEs. This study designs a method to decrease the ABC phenomenon and develops a clinical promising nanoemulsion for therapeutic or imaging purpose.

Researchers reported that intravenously injected PEGylated colloidal drug carriers lose their long-circulating characteristic and accumulated extensively in liver when they are administrated twice in the same animal with certain intervals. This phenomenon was referred to as the "accelerated blood clearance（ABC） phenomenon". Some former studies had found that complement-mediated phagocytosis, activated by antigen–antibody complex, was responsible for inducing the phenomenon. According to the theory, we have used cobra venom factor to deplete complement in vivo and to investigate the effect of complement inhibition on the ABC phenomenon. Rats were administered by injection of cobra venom factor solution to build up the model of complement exhaustion/inhibition, and the effect of the inhibition of complement on ABC phenomenon was carried out. It seemed that inhibition of complement didn’t affect the pharmacokinetic of the first infection. By contrast, in rats of which complement had been depleted, the second dose of PEGylated nanoemulsions showed enhanced circulation time compared with normal rats in a complement inhibition-independent manner, but the ABC phenomenon was not completely eliminated. It indicated that complement inhibition could certainly weaken the accelerated clearance; meanwhile, there were other factors causing the ABC effect.These findings provide novel insights into the attenuating of ABC phenomenon and lay foundation for further study of immune mechanism.

目的 以泊洛沙姆188-胆固醇碳酸酯为例,探寻去除接枝胆固醇的两亲性高分子材料中4-二甲氨基吡啶(4-dimethylaminopyridine,DMAP)中间体的最优方法.方法 以DMAP中间体残余百分率为评价指标,考察酸洗-饱和NaCl洗-水洗法、阳离子交换树脂法、透析冻干法及甲苯沉淀法对泊洛沙姆188-胆固醇碳酸酯的纯化效率.结果 上述四种方法中,甲苯沉淀法的DMAP中间体残余百分率最低,接近于0.结论 通过与酸洗-饱和NaC1洗-水洗法、阳离子交换树脂法及透析冻干法进行对比,证明了甲苯沉淀法在此合成中的简便性和高效性,为接枝胆固醇的两亲性高分子材料中DMAP的去除提供了参考.

Cancer poses a significant threat to human health worldwide, and many therapies have been used for its palliative and curative treatments. Vincristine has been extensively used in chemotherapy. However, there are two major challenges concerning its applications in various tumors: (1) Vincristine's antitumor mechanism is cell-cycle-specific, and the duration of its exposure to tumor cells can significantly affect its antitumor activity and (2) Vincristine is widely bio-distributed and can be rapidly eliminated. One solution to these challenges is the encapsulation of vincristine into liposomes. Vincristine can be loaded into conventional liposomes, but it quickly leak out owing to its high membrane permeability. Numerous approaches have been attempted to overcome this problem. Vincristine has been loaded into PEGylated liposomes to prolong circulation time and improve tumor accumulation. These liposomes indeed prolong circulation time, but the payout characteristic of vincristine is severer, resulting in a compromised outcome rather than a better efficacy compared to conventional sphingomyelin (SM)/cholesterol (Chol) liposomes. In 2012, the USA Food and Drug Administration (FDA) approved SM/Chol liposomal vincristine (Marqibo®) for commercial use. In this review, we mainly focus on the drug's rapid leakage problem and the potentially relevant solutions that can be applied during the development of liposomal vincristine and the reason for conventional liposomal vincristine rather than PEGylated liposomes has access to the market.

Phospholipids have the characteristics of excellent biocompatibility and a especial amphiphilicity. These unique properties make phospholipids most appropriate to be employed as important pharmaceutical excipients and they have a very wide range of applications in drug delivery systems. The aim of this review is to summarize phospholipids and some of their related applications in drug delivery systems, and highlight the relationship between the properties and applications, and the effect of the species of phospholipids on the efficiency of drug delivery. We refer to some relevant literatures, starting from the structures, main sources and properties of phospholipids to introduce their applications in drug delivery systems. The present article focuses on introducing five types of carriers based on phospholipids, including liposomes, intravenous lipid emulsions, micelles, drug-phospholipids complexes and cochleates.

Based on the knowledge that sialic acid is a critical element for tumor development and its receptors are highly expressed on the tumor-associated macrophages (TAMs) which play important roles in the growth and metastasis of tumors, we synthesized a sialic acid-octadecylamine conjugate (SA-ODA) and anchored it on the surface of pixantrone (Pix)-loaded liposomes, to achieve an improved anticancer effect. Four Pix formulations (Pix-S, Pix-CL, Pix-PL and Pix-SAL represent solution, conventional liposome, stealth liposome, and SA-ODA modified liposome, respectively) were developed, and various parameters, including drug loading, stability, in vitro release, cytotoxicity and pharmacokinetics, were evaluated. The tumor growth inhibition and toxicity studies were performed in S180-bearing Kunming mice. Pix-S exhibited a strong toxicity to the immune system, accelerated the growth of tumors and reduced the lifespan of mice. In contrast, Pix-SAL displayed the strongest anticancer and life-prolonging effects among all of the formulations in this study. More importantly, injection of Pix-SAL induced a phenomenon whereby the cancerous tissues were "shed" from mice, after which the wound healed. We speculate that this special efficacy may be partly due to the killing of TAMs by Pix-SAL. This study suggests that SA-ODA modified liposomes may serve as an effective intravenous delivery vehicle for Pix.